Modified oligonucleotides Field of the invention [0001] The present invention relates to oligonucleotides that inhibit Toll-Like Receptor 7 (TLR7) and/or Toll-Like Receptor 8 (TLR8), or potentiate TLR8, and uses thereof. Related applications [0002] This application claims the benefit of priority to Australian provisional application no.2022902992 filed 12 October 2022, and Australian provisional application no.2023901499 filed 16 May 2023, the entire disclosures of which are incorporated herein by reference. Background of the invention [0003] RNA-targeting therapeutics based on synthetic oligonucleotides have been gaining a lot of interest, with several regulatory approvals in the US and European Union, and multi-billion license deals in recent years. To ensure their essential functions related to gene targeting activities, oligonucleotides-based therapeutics require both increased affinity for their targets and stabilisation against nuclease activities. [0004] An understanding of the intricate relationship between synthetic oligonucleotides and nucleic acid sensors of the innate immune system, such as Toll- Like Receptors (TLR), is important for the design of oligonucleotide therapeutics. These oligonucleotides are designed to evade activation of innate immune sensors and avoid strong off-target pro-inflammatory immune responses in patients. From this angle, chemical modifications may have the dual benefit of increasing the targeting efficacy of the oligonucleotides, while decreasing their immunostimulatory effects. [0005] Nonetheless, it has also been clear for some time that select PS-modified DNA oligonucleotides (ODN) have broad immunosuppressive effects. This is best exemplified with the “TTAGGG” containing PS-ODN A151, involved in the inhibition of TLR9, TLR7, Absent In Melanoma 2 (AIM2) and cyclic-GMP-AMP synthase (cGAS). These effects are sequence-dependent, with some PS-DNA ODNs displaying limited immunosuppressive activities on individual immune sensors. These observations suggest a complex picture of immunosuppression by chemically modified oligonucleotides where sequences dictate their activities on nucleic acid sensors. Since 1004921453 only a handful of ODNs have been studied to date across different receptors, a detailed understanding of the immunosuppressive sequence determinants of ODNs is currently lacking. Further, our understanding of the immunosuppressive effects of oligonucleotides combining base and/or backbone modifications, as is seen in most oligonucleotide therapeutics approved and in development, is nearly non-existent. While potentially useful to generate anti-inflammatory ODNs, characterizing the immunosuppressive effects of therapeutic RNAs is becoming important to help avoid increased susceptibility to infection in the large patient populations who are beginning to receive ODN therapies. [0006] There is a need for new or improved inhibitors of Toll-Like Receptor 7 (TLR7), and/or Toll-Like Receptor 8 (TLR8) activity, or new or improved molecules that potentiate TLR8 activity. [0007] Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and/or combined with other pieces of prior art by a skilled person in the art. Summary of the invention [0008] In a first aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: [mX/modified mX]* ^y X ^A * ^z X ^B wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage, wherein at least one of * ^y and * ^z is not phosphorodiamidate; X ^A and X ^B are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, morpholino-X, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX and modified morpholino-X; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE 1004921453 and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification, morpholino-X is a nucleotide comprising a morpholine ring; and wherein when [mX/modified mX] is mX, at least one of X ^A and X ^B is not mX; wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0009] Preferably, both * ^y and * ^z are not phosphorodiamidate. [0010] Preferably, X ^A is independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX; and X ^B is independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, morpholino-X, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX and modified morpholino-X. [0011] In an embodiment of the first aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: [mX/modified mX]* ^y X ^A * ^z X ^B wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^A and X ^B are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX, modified moX, modified LX, and modified fX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification; and wherein when [mX/modified mX] is mX, at least one of X ^A and X ^B is not mX; 1004921453 wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0012] Preferably, at least one of * ^y and * ^z is not phosphorodiamidate. More preferably, both * ^y and * ^z are not phosphorodiamidate. [0013] Any oligonucleotide of the first aspect inhibits TLR7 activity, preferably human TLR7 activity. In one preferred embodiment, an oligonucleotide of the first aspect does not potentiate TLR8 activity, preferably human TLR8 activity. In a particularly preferred embodiment, an oligonucleotide of the first aspect further inhibits TLR8 activity, preferably human TLR8 activity. In an alternative preferred embodiment, an oligonucleotide of the first aspect potentiates TLR8 activity, preferably human TLR8 activity. [0014] Each internucleotide linkage may be selected from the group consisting of: 3′- 5′-, 5′-5′-, 5′-3′-, 3′-3′-, 3′-2′-, 2′-3′-, 2′-2′-, 2′-5′-, and 5′-2′- linkage. Preferably, each internucleotide linkage may be selected from: 3′-5′- and 5′-5′- linkage. Preferably, each internucletodie linkage is a 3′-5′- linkage. [0015] In one preferred embodiment of the first aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: 5′-[mX/modified mX]* ^y X ^A * ^z X ^B -3′ wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage, wherein at least one of * ^y and * ^z is not phosphorodiamidate; X ^A and X ^B are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, morpholino-X, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX and modified morpholino-X; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide 1004921453 comprising a 2′-fluor and/or 3′-fluor modification, morpholino-X is a nucleotide comprising a morpholine ring; and wherein when [mX/modified mX] is mX, at least one of X ^A and X ^B is not mX; wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0016] In a particularly preferred embodiment, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: 5′-[mX/modified mX]* ^y X ^A * ^z X ^B -3′ wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^A and X ^B are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX, modified moX, modified LX, and modified fX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification; and wherein when [mX/modified mX] is mX, at least one of X ^A and X ^B is not mX; wherein the sequence is optionally functionalised. [0017] Preferably, each internucleotide linkage is a 3′-5′ linkage. [0018] Preferably, each internucleotide linkage is independently selected from the group consisting of: biphosphate, triphosphate, phosphorothioate, and phosphodiester. Each internucleotide linkage may be the same or different. In a preferred embodiment, each internucleotide linkage is independently selected from phosphorothioate and phosphodiester. Most preferably, each internucleotide linkage is phosphorothioate. 1004921453 [0019] In a particularly preferred embodiment, each internucleotide linkage is a 3′-5′- phosphorothioate linkage. [0020] In one embodiment, the oligonucleotide comprises a mixture of different oligonucleotide stereoisomers, preferably a mixture of different oligonucleotide phosphorothioate stereoisomers. In another embodiment, the oligonucleotide of the first aspect comprises a single phosphorothioate stereoisomer, preferably wherein * ^y is in the S configuration. [0021] Preferably, mX is a nucleotide comprising a 2′-OMe modification. [0022] Preferably, moX, is a nucleotide comprising a 2′-MOE modification. [0023] Preferably, fX, is a nucleotide comprising a 2′-fluor modification. [0024] Modified dX, modified rX and modified morpholino comprise at least one modification or substitution at positions of the base and/or sugar. Modified mX, modified moX, modified LX and modified fX comprise at least one additional modification or substitution at additional positions of the base and/or sugar. Preferably, the modification or substitution is selected from the group consisting of: pseudouridine, 3′-deoxy, hydroxyl, des-amino, amino, thio, halo, oxo, aza, deaza, polyethylene glycol, alkyl, alkenyl, alkynyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl and combinations thereof. [0025] Exemplary modified mX includes but is not limited to: mG1, mI, mU1, mU2, mU3, mC1, and ^m7 G, wherein mG1 is 2′-OMe-2,6-Diaminopurine, mI is 2′-OMe-I (2′-O- methylinosine), mU1 is 2′-OMe-5-Me-U (2′-O-methyl-5-methyluridine), mU2 is 2′-OMe-5- Br-U (2′-O-methyl-5-bromouridine), mU3 is N3-Me-U (3-methyluridine), mC1 is 2′-OMe- 5-Me-C (2′-O-methyl-5-methylcytidine), and ^m7 G is 3′-OMe-N7-methylated guanosine. Preferably, modified mX is selected from the group consisting of: mG1, mI, mU1, mU2 and mC1. Most preferably, modified mX is mC1. [0026] Exemplary modified dX includes but is not limited to: 5-Me-dC, 5-Br-dC, 5- CH2OH-dC, ddC, pdC, PSU, N3-Me-dC, 5-I-dC, dI, 8-Br-dG, 7-deaza-dG, 8-Br-dA, 8- oxo-dA, O6-Me-dG, 8-NH2-dG, wherein 5-Me-dC is 5-methyl substituted deoxycytidine, 5-Br-dC is 5-bromo substituted deoxycytidine5-CH2OH-dC is 5-hydroxymethyl substituted deoxycytidine, ddC is 2′-deoxy-3′-deoxy cytidine, pdC is 5-propynyl 1004921453 substituted deoxycytidine, PSU is pseudo uridine, N3-Me-dC is 3-methyl deoxycytidine, 5-I-dC is 5-iodo deoxycytidine, dI is deoxyinosine, 8-Br-dG is 8-bromodeoxyguanosine, 7-deaza-dG is 7-deazadeoxyguanosine, 8-Br-dA is 8-bromodeoxyadenosine, 8-oxo-dA is 8-oxodeoxyadenosine, O6-Me-dG is O6-methyldeoxyguanosine, and 8-NH2-dG is 8- aminodeoxyguanosine. [0027] Exemplary modified rX includes but is not limited to PSU, 2′-NH2-rX, and ara- rX, wherein 2′-NH2-rX is a 2′-amino modified RNA base, and ara-rX is an arabinose modified RNA base. Exemplary 2′-NH2-rX includes but is not limited to 2′-NH2-U and 2′- NH2-C, wherein 2′-NH2-U is 2′-NH2-uridine, and 2′-NH2-C is 2′-NH2-cytidine. Exemplary ara-rX is ara-C (aracytidine). [0028] In one embodiment, [mX/modified mX] is selected from the group consisting of: mG, mI, mG1 and mU. Preferably, [mX/modified mX] is mG or mI. In one embodiment, [mX/modified mX] is modified mX. Preferably, modified mX is mI or mG1, preferably mI. Preferably, modified mX is not 2′-OMe-N1-Me-G (2′-O-methyl-N1- methylguanosine). In another embodiment, [mX/modified mX] is mX. Preferably, mX is mG or mU, preferably mG. [0029] In a preferred embodiment, [mX/modified mX] is [mG/modified mG]. Preferably, modified mG is not 2′-OMe-N1-Me-G (2′-O-methyl-N1-methylguanosine). Modified mG includes but is not limited to: mG1 and mI, wherein mG1 is 2′-OMe-2,6- Diaminopurine, and mI is 2′-OMe-I (2′-O-methylinosine). Preferably, [mG/modified mG] is [mG/mI]. In one embodiment, [mG/modified mG] is mG. In another embodiment, [mG/modified mG] is mI. [0030] In a preferred embodiment, X ^A and X ^B are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX and morpholino-X. In a particularly preferred embodiment, X ^A and X ^B are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, and modified dX. [0031] In one embodiment, X ^A is selected from the group consisting of: mX, dX, rX, LX, modified mX, modified dX, and modified rX. Preferably, X ^A is selected from the group consisting of: mX, dX, rX, modified mX, modified dX, and modified rX. Preferably, X ^A is selected from the group consisting of: mU, mU1, mU2, mU3, PSU, mG, mA, mC, 1004921453 dT, dG, dA, dC, rU, 2′-NH2-rU, 8-Br-dA, and 8-oxo-dA. In one embodiment, X ^A is selected from the group consisting of: mX, dX, rX, and modified mX. Preferably, X ^A is selected from the group consisting of: mU, mU1, mU2, PSU, mG, mA, mC, dT, dG, dA, dC, and rU. More preferably, X ^A is mU. [0032] In one embodiment, X ^B is selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX and morpholino-X. Preferably, X ^B is selected from the group consisting of: dA, dC, dG, dT, mC, mC1, mG, rC, moC, LC, , LA, LT, LG, fC, 5-Me-dC, 5-Br-dC, 5-CH2OH-dC, ddC, pdC, N3-Me-dC, 5-I-dC, 2′-NH2- C, ara-C, morpholino-C, N3-Me-mU, dI, 8-Br-dG, 7-deaza-dG, O6-Me-dG, and 8-NH2- dG. In one embodiment, X ^B is selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX and modified dX. Preferably, X ^B is selected from the group consisting of: dA, dC, dG, dT, mC, mC1, mG, rC, moC, LC, fC, 5-Me-dC, 5-Br-dC, 5- CH2OH-dC, ddC, and pdC. In one preferred embodiment, X ^B is selected from the group consisting of: mX, dX, LX, modified mX, modified dX and modified rX. Preferably, X ^B is selected from the group consisting of: LC, dC, 5-Me-dC, 5-Br-dC, mC, mC1, ara-C. In a particularly preferred embodiment, X ^B is selected from the group consisting of: LX, modified mX, modified dX and modified rX. Preferably, X ^B is selected from the group consisting of: LC, 5-Me-dC, 5-Br-dC, and mC1. In an even more preferred embodiment, X ^B is LX, preferably LC. [0033] In one embodiment, at least one of X ^A and X ^B is LX. In one embodiment, X ^A and X ^B are independently LX. In another embodiment, one of X ^A and X ^B is LX. Preferably, X ^B is LX. Preferably, X ^B is LX and X ^A is mX. [0034] In one embodiment, at least one of X ^A and X ^B is dX. In one embodiment, X ^A and X ^B are independently dX. In another embodiment, one of X ^A and X ^B is dX. Preferably, X ^B is dX. Preferably, X ^B is dX and X ^A is mX. More preferably, X ^B is dX and X ^A is mU. [0035] In one embodiment, at least one of X ^A and X ^B is rX. In one embodiment, X ^A and X ^B are independently rX. In another embodiment, one of X ^A and X ^B is rX. Preferably, X ^A is rX. Preferably, X ^B is mX or rX and X ^A is rX. More preferably, X ^B is mX and X ^A is rU; X ^A is rA and X ^B is rA; or X ^A is rU and X ^B is rC. Preferably, where at least one of X ^A and X ^B is rX, each internucleotide linkage is a 3′-5′- phosphorothioate linkage. 1004921453 [0036] In a particularly preferred embodiment, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: 5′-[mG/mI]*mU*X ^B -3′ wherein: * each independently represent a 3′-5′- phosphorothioate linkage; X ^B is selected from the group consisting of: dX, rX, moX, LX, fX, morpholino-X, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX, and modified morpholino-X; wherein dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification, morpholino-X is a nucleotide comprising a morpholine ring; and wherein the sequence is optionally functionalised. [0037] Preferably, X ^B is selected from the group consisting of: mX, dX, LX, modified mX, modified rX, and modified dX. [0038] In one embodiment, the sequence may be functionalised. Preferably, the functionalised sequence comprises a compound selected from the group consisting of: polyethylene glycol, alkyl, alkenyl, alkynyl, heterocycyl, arylalkyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heterocycyl, substituted arylalkyl, and hydrophobic lipid. Prefearbly, the hydrophobic lipid is selected from cholesterol and tocopherol. Preferably, the compound is selected from the group consisting of: polyethylene glycol, cholesterol and tocopherol. [0039] In one embodiment, the compound is conjugated directly to the sequence. In another embodiment, the compound is conjugated to the sequence via a linker. The linker may be cleavable or non-cleavable. Preferably, the linker is a non-cleavable linker. 1004921453 [0040] Preferably, the compound is conjugated to a terminal nucleotide of the sequence, preferably the terminal 3′- nucleotide. Preferably, the compound is conjugated to the terminal 3′-nucleotide at the 3′- position. [0041] Functionalised sequences may comprise functionalised nucleotides selected from the group consisting of: dX-TEG, dX-Chol and dX-Toco, wherein dX-TEG is a DNA base with triethylene glycol covalently linked to the 3′-position via a monophosphate group, dX-Chol is a DNA base with an (N-cholesteryl-3-aminopropyl)-triethyleneglycol- glyceryl group covalently linked to the 3′-position via a monophosphate group, dX-Toco is a DNA base with a [(9-DL-α-tocopheryl)-triethyleneglycol-1-yl]-glyceryl group covalently linked to the 3′-position via a monophosphate group. Preferably, functionalised sequences may comprise functionalised nucleotides selected from the group consisting of: dC-TEG, dC-Chol, dC-Toco, wherein dC-TEG is deoxycytidine with an (N-cholesteryl-3-aminopropyl)-triethyleneglycol-glyceryl group covalently linked to the 3′-position via a monophosphate group, dC-Chol, is deoxycytidine with triethylene glycol covalently linked to the 3′-position via a monophosphate group, and dC-Toco is deoxycytidine with a [(9-DL-α-tocopheryl)-triethyleneglycol-1-yl]-glyceryl group covalently linked to the 3′-position via a monophosphate group. [0042] Preferably, the sequence is selected from the group consisting of: 1004921453 1004921453 1004921453 [0043] In one embodiment, [mX/modified mX] is [mG/mI]; X ^A is mU; and X ^B is selected from the group consisting of: mX, dX, rX, moX, LX, fX, morpholino-X, modified mX, modified rX and modified dX, wherein the sequence is optionally functionalised. Preferably, X ^B is selected from the group consisting of: LX, mX, dX, modified mX, modified rX, and modified dX. More preferably, X ^B is selected from the group consisting of: LC, mC, ara-C, dC, mC1, and modified dC. Preferably, modified dC is selected from the group consisting of: 5-Me-dC, 5-Br-dC and 5-I-dC. Preferably, the sequence is selected from the group consisting of: mG*mU*LC, mI*mU*LC, mG*mU*mC1, mG*mU*5-Me-dC, mG*mU*5-Br-dC, mG*mU*dC, mG*mU*dC-TEG, mI*mU*mC, mG*mU*dC-Chol, mG*mU*dC-Toco, mG*mU*ara-C and mG*mU*5-I-dC. [0044] In another preferred embodiment, [mX/modified mX] is [mG/mI]; X ^A is mU; and X ^B is selected from the group consisting of: mX, dX, rX, LX, modified mX modified rX, and modified dX. Preferbaly, X ^B is selected from the group consisting of: LC, mC1, dC, mC, and modified dC. Preferably, modified dC is selected from the group consisting of: 5-Me-dC, 5-Br-dC and 5-I-dC. Preferably, the sequence is selected from the group consisting of: mG*mU*LC, mI*mU*LC, mG*mU*mC1, mG*mU*5-Me-dC, mG*mU*5-Br- dC and mG*mU*5-I-dC. [0045] In another preferred embodiment, [modified mX] is [mG/mI]; and X ^A and X ^B are rX. Preferably, the sequence is selected from the group consisting of: mG*rA*rA, mG*rU*rC, mG*rG*rA, mG*rU*rA, mG*rU*rU, mG*rA*rG, mG*rG*rC, mG*rA*rU, mG*rG*rG. More preferably, the sequence is selected from: mG*rA*rA, mG*rU*rC and mG*rG*rA. [0046] In another preferred embodiment, the oligonucleotide of the first aspect further inhibits TLR8 activity, preferably human TLR8 activity. Preferably, the oligonucleotide that further inhibits TLR8 activity comprises or consists of the sequence mI*mU*mC or mI*mA*dG. [0047] In one embodiment, the oligonucleotide consists of the sequence. [0048] In another embodiment, the oligonucleotide comprises the sequence. Preferably, the oligonucleotide comprising the sequence is no more than 20 bases in 1004921453 length, preferably 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, or 4 bases in length. Preferably, the sequence is at the terminal 5′- and/or 3′- end of the oligonucleotide, preferably the terminal 5′- end. In one preferred embodiment, the oligonucleotide comprises the sequence 5′-mG*mU*X ^B -3′, wherein X ^B is dX, preferably X ^B is dC. Even more preferably, the oligonucleotide comprises the sequence 5′- mG*mU*dC*dC*dC*dC-3′. [0049] In another embodiment of the first aspect, there is provided a method of modifying the TLR7 activity of an oligonucleotide, the method comprising modifying the oligonucleotide by adding the sequence to the terminal 5′- and/or 3′- end of the oligonucleotide, preferably the terminal 5′- end. In one embodiment, the method reduces the TLR7 potentiating activity of the oligonucleotide. In another embodiment, the method increases the TLR7 inhibitory activity of the oligonucleotide. [0050] In another embodiment of the first aspect, there is provided a fusion oligonucleotide comprising two or more oligonucleotides according to the first aspect linked by a cleavable linker. Preferably, the fusion oligonucleotide comprises: A-[Y-A]n wherein each A independently represents an oligonucleotide according to the first aspect, each A may be the same or different; Y represents a cleavable linker, each Y may be the same or different; and n is equal to or greater than 1. [0051] Preferably, Y is cleavable by an enzyme. Preferably, Y is selected from the group consisting of: a TEG linker, carbon spacers (such as C3, C6, C9, C12), glycerol and PolydT. More preferably, Y is a TEG linker. [0052] Preferably, each A is independently bound to Y by an internucleotide linkage (*). Preferably, each internucleotide linkage is independently selected from the group consisting of: biphosphate, triphosphate, phosphorothioate, and phosphodiester. Each internucleotide linkage may be the same or different. In a preferred embodiment, each 1004921453 internucleotide linkage is independently selected from phosphorothioate and phosphodiester. Most preferably, each internucleotide linkage is phosphorothioate. [0053] Each internucleotide linkage may be selected from the group consisting of: 3′- 5′-, 5′-5′-, 5′-3′-, 3′-3′-, 3′-2′-, 2′-3′-, 2′-2′-, 2′-5′-, and 5′-2′- linkage. Preferably, each internucleotide linkage may be selected from: 3′-5′- and 5′-5′- linkage. Preferably, each internucletodie linkage is a 3′-5′- linkage. More preferably, each internucleotide linkage is a 3′-5′- phosphorothioate linkage. [0054] In one embodiment, the fusion oligonucleotide comprises or consists of the sequence 5′-mG*mU*dC-3′-*TEG*-3′-dC*mU*mG-5′. [0055] In another embodiment of the first aspect, there is provided a modified oligonucleotide comprising an agent linked to an oligonucleotide or fusion oligonucleotide according to the first aspect by a linker. The agent may be a therapeutic and/or diagnostic agent. Preferably, the agent is a therapeutic agent, more preferably, a therapeutic RNA selected from the group consisting of: DNA, RNA, mRNA, siRNA, RNA aptamers, antisense oligonucleotides, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. In one preferred embodiment, the therapeutic RNA is selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. The linker may be cleavable or non-cleavable. Preferably, the linker is a cleavable linker. [0056] In another embodiment of the first aspect, there is provided a composition comprising an oligonucleotide or fusion oligonucleotide according to the first aspect, and a pharmaceutically acceptable excipient. [0057] In one embodiment, the composition is an immunogenic composition comprising a therapeutic RNA and an oligonucleotide or fusion oligonucleotide according to the first aspect. Preferably, the therapeutic RNA is selected from the group consisting of: DNA, RNA, mRNA, siRNA, RNA aptamers, antisense oligonucleotides, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. In one embodiment, the immunogenic composition comprises a modified oligonucleotide according to the first aspect. Preferably, the modified oligonucleotide comprises a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA 1004921453 aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. [0058] In one embodiment, the composition may comprise at least one additional active agent, including but not limited to, an anti-inflammatory agent. [0059] In another embodiment of the first aspect, there is provided a method of inhibiting TLR7 activity in a subject, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect, thereby inhibiting TLR7 activity in the subject. [0060] In another embodiment of the first aspect, there is provided a method of inhibiting TLR7 activity in a cell, the method comprising contacting the cell with an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect, thereby inhibiting TLR7 activity in the cell. [0061] In another embodiment of the first aspect, there is provided use of an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect in the manufacture of a medicament for inhibiting TLR7 activity in a subject. [0062] In another embodiment of the first aspect, there is provided use of a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect, for inhibiting TLR7 activity in a subject. [0063] In another embodiment of the first aspect, there is provided a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect, for use in inhibiting TLR7 activity in a subject. [0064] In another embodiment of the first aspect, there is provided a method of inhibiting TLR7 activation by a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof, in a subject, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect, thereby inhibiting TLR7 activation in the subject. In one embodiment, the method comprises administering an immunogenic composition comprising an oligonucleotide or fusion oligonucleotide according to the first aspect, and a therapeutic RNA selected from the group consisting 1004921453 of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. In one embodiment, the immunogenic composition comprises a modified oligonucleotide according to the first aspect, wherein the therapeutic agent is a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. [0065] In one embodiment, the oligonucleotide, the fusion oligonucleotide, or the composition does not substantially reduce translation of the therapeutic RNA. [0066] In one embodiment, the therapeutic RNA comprises pseudouridine. [0067] In another embodiment, the therapeutic RNA does not comprise pseudouridine. [0068] In another embodiment of the first aspect, there is provided use of an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect in the manufacture of a medicament for inhibiting TLR7 activation by a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, , self-amplifying RNAs, circular RNAs and combinations thereof, in a subject. In one embodiment, the subject has received, is receiving, or about to receive the therapeutic RNA. In another embodiment, there is provided use of a first composition and a second composition in the manufacture of a medicament for inhibiting TLR7 activation by a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof in a subject, wherein the first composition comprises an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect, and the second composition comprises the therapeutic RNA. In another embodiment, there is provided use of an immunogenic composition comprising a modified oligonucleotide according to the first aspect, wherein the therapeutic agent is a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof, in the manufacture of a medicament for inhibiting TLR7 activation by the therapeutic RNA in a subject. 1004921453 [0069] In another embodiment of the first aspect, there is provided use of a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect, for inhibiting TLR7 activation by a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof in a subject. In one embodiment, the subject has received, is receiving, or about to receive the therapeutic RNA. In another embodiment, there is provided use of a therapeutically effective amount of an immunogenic composition comprising a modified oligonucleotide according to the first aspect, wherein the therapeutic agent is a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof, for inhibiting TLR7 activation by the therapeutic RNA in a subject. [0070] In another embodiment of the first aspect, there is provided a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect, for use in inhibiting TLR7 activation by a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof in a subject. In one embodiment, the subject has received, is receiving, or about to receive the therapeutic RNA. In another embodiment, there is provided a therapeutically effective amount of an immunogenic composition comprising a modified oligonucleotide according to the first aspect, wherein the therapeutic agent is a therapeutic selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof, for use in inhibiting TLR7 activation by the therapeutic RNA in a subject. [0071] In another embodiment of the first aspect, there is provided a method of treating or preventing a disease, disorder or condition in a subject responsive to TLR7 inhibition, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect, thereby treating or preventing the disease, disorder or condition in the subject. [0072] In another embodiment of the first aspect, there is provided use of an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect 1004921453 in the manufacture of a medicament for treating or preventing a disease, disorder or condition in a subject responsive to TLR7 inhibition. [0073] In another embodiment of the first aspect, there is provided use of a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect, for treating or preventing a disease, disorder or condition in a subject responsive to TLR7 inhibition. [0074] In another embodiment of the first aspect, there is provided a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect, for use in the prevention or treatment of a disease, disorder or condition in a subject responsive to TLR7 inhibition. [0075] Preferably the disease, disorder or condition responsive to TLR7 inhibition is selected from the group consisting of: inflammation-related diseases, allergic diseases, infections, cancers and auto-immune diseases. [0076] In a second aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: X ^C * ^y X ^D * ^z X ^E wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^C is selected from the group consisting of: mX, modified mX, dG, and morpholino-X; X ^D and X ^E are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, morpholino-X, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX and modified morpholino-X; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification, morpholino-X is a nucleotide comprising a morpholine ring; and 1004921453 wherein: when X ^C is mX, at least one of X ^D and X ^E is not mX; when X ^C is dG, at least one of X ^D and X ^E is not dX; when X ^C is mG and when: X ^D is dG, X ^E is not dA or dC; X ^D is dT or mU, X ^E is not dC or dT; X ^D is mC, X ^E is not dT, dG, or dC; and X ^D is mG or dC, X ^E is not dX; or when X ^C is dG, X ^E is not mG; wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0077] Preferably, X ^C is selected from the group consisting of: mX, modified mX, dG; X ^D is selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX; and X ^E is selected from the group consisting of: mX, dX, rX, moX, LX, fX, morpholino-X, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX and modified morpholino-X. [0078] In an embodiment of the second aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: X ^C * ^y X ^D * ^z X ^E wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^C is selected from the group consisting of: mX, modified mX, and dG; 1004921453 X ^D and X ^E are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX, modified moX, modified LX, and modified fX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification; and wherein: when X ^C is mX, at least one of X ^D and X ^E is not mX; when X ^C is dG, at least one of X ^D and X ^E is not dX; when X ^C is mG and when: X ^D is dG, X ^E is not dA or dC; X ^D is dT or mU, X ^E is not dC or dT; X ^D is mC, X ^E is not dT, dG, or dC; and X ^D is mG or dC, X ^E is not dX; or when X ^C is dG, X ^E is not mG; wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0079] Any oligonucleotide of the second aspect inhibits TLR8 activity, preferably human TLR8 activity. In one preferred embodiment, an oligonucleotide of the second aspect further inhibits TLR7 activity, preferably human TLR7 activtiy. In an alternative preferred embodiment, an oligonucleotide of the second aspect does not substantially inhibit TLR7 activity, preferably human TLR7 activtiy. 1004921453 [0080] Each internucleotide linkage may be selected from the group consisting of: 3′- 5′-, 5′-5′-, 5′-3′-, 3′-3′-, 3′-2′-, 2′-3′-, 2′-2′-, 2′-5′-, and 5′-2′- linkage. Preferably, each internucleotide linkage may be selected from: 3′-5′- and 5′-5′- linkage. Preferably, each internucletodie linkage is a 3′-5′- linkage. [0081] In a particularly preferred embodiment of the second aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: 5′-X ^C * ^y X ^D * ^z X ^E -3′ wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^C is selected from the group consisting of: mX, modified mX, dG, and morpholino-X; X ^D and X ^E are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, morpholino-X, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX and modified morpholino-X; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification, morpholino-X is a nucleotide comprising a morpholine ring; and wherein: when X ^C is mX, at least one of X ^D and X ^E is not mX; when X ^C is dG, at least one of X ^D and X ^E is not dX; when X ^C is mG and when: X ^D is dG, X ^E is not dA or dC; X ^D is dT or mU, X ^E is not dC or dT; X ^D is mC, X ^E is not dT, dG, or dC; and 1004921453 X ^D is mG or dC, X ^E is not dX; or when X ^C is dG, X ^E is not mG; wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0082] In a particularly preferred embodiment of the second aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: 5′-X ^C * ^y X ^D * ^z X ^E -3′ wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^C is selected from the group consisting of: mX, modified mX, and dG; X ^D and X ^E are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX, modified moX, modified LX, and modified fX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification; and wherein: when X ^C is mX, at least one of X ^D and X ^E is not mX; when X ^C is dG, at least one of X ^D and X ^E is not dX; when X ^C is mG and when: X ^D is dG, X ^E is not dA or dC; X ^D is dT or mU, X ^E is not dC or dT; 1004921453 X ^D is mC, X ^E is not dT, dG, or dC; and X ^D is mG or dC, X ^E is not dX; or when X ^C is dG, X ^E is not mG; wherein the sequence is optionally functionalised. [0083] Preferably, each internucleotide linkage is a 3′-5′ linkage. [0084] Preferably, each internucleotide linkage is independently selected from the group consisting of: biphosphate, triphosphate, phosphorothioate, phosphodiester, phosphoramidate and phosphorodiamidate. Each internucleotide linkage may be the same or different. In a preferred embodiment, each internucleotide linkage is independently selected from phosphorothioate and phosphodiester. Most preferably, each internucleotide linkage is phosphorothioate. [0085] In a particularly preferred embodiment, each internucleotide linkage is a 3′-5′- phosphorothioate linkage. [0086] In one embodiment, the oligonucleotide comprises a mixture of different oligonucleotide stereoisomers. In another embodiment, the oligonucleotide comprises a single stereoisomer. [0087] Preferably, mX is a nucleotide comprising a 2′-OMe modification. [0088] Preferably, moX, is a nucleotide comprising a 2′-MOE modification. [0089] Preferably, fX, is a nucleotide comprising a 2′-fluor modification. [0090] Modified dX, modified rX and modified morpholino-X comprise at least one modification or substitution at positions of the base and/or sugar. Modified mX, modified moX, modified LX and modified fX comprise at least one additional modification or substitution at additional positions of the base and/or sugar. Preferably, the modification or substitution is selected from the group consisting of: pseudouridine, 3′-deoxy, hydroxyl, des-amino, amino, thio, halo, oxo, aza, deaza, polyethylene glycol, alkyl, alkenyl, alkynyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl and combinations thereof. 1004921453 [0091] Exemplary modified mX includes but is not limited to: mG1, mI, mU1, mU2, mU3, mC1, and ^m7 G, wherein mG1 is 2′-OMe-2,6-Diaminopurine, mI is 2′-OMe-I (2′-O- methylinosine), mU1 is 2′-OMe-5-Me-U (2′-O-methyl-5-methyluridine), mU2 is 2′-OMe-5- Br-U (2′-O-methyl-5-bromouridine), mU3 is N3-Me-U (3-methyluridine), mC1 is 2′-OMe- 5-Me-C (2′-O-methyl-5-methylcytidine), and ^m7 G is N7-methylated guanosine. Preferably, modified mX is selected from the group consisting of: mG1, mI, mU1, mU2 and mC1. [0092] Exemplary modified dX includes but is not limited to: 5-Me-dC, 5-Br-dC, 5- CH2OH-dC, ddC, pdC, PSU, dI, 8-Br-dG, N1-Me-dG, 7-deaza-dG, 8-Br-dA, 8-oxo-dA, O6-Me-dG, and 8-NH2-dG, wherein 5-Me-dC is 5-methyl substituted deoxycytidine, 5- Br-dC is 5-bromo substituted deoxycytidine, 5-CH2OH-dC is 5-hydroxymethyl substituted deoxycytidine, ddC is 2′-deoxy-3′-deoxy cytidine, pdC is 5-propynyl substituted deoxycytidine, PSU is pseudo uridine, dI is deoxyinosine, 8-Br-dG is 8- bromodeoxyguanosine, N1-Me-dG is 1-methyl deoxyguanosine, 7-deaza-dG is 7- deaza-deoxyguanosine, 8-Br-dA is 8-bromo deoxyadenosine, 8-oxo-dA is 8-oxo deoxyadenosine, O6-Me-dG is O6-methyl deoxyguanosine and 8-NH2-dG is 8- aminodeoxyguanosine. [0093] Exemplary modified rX includes but is not limited to PSU, 2′-NH2-rX, and ara- rX, wherein 2′-NH2-rX is a 2′-amino modified RNA base, and ara-rX is an arabinose modified RNA base. Exemplary 2′-NH2-rX includes but is not limited to 2′-NH2-U and 2′- NH2-C, wherein 2′-NH2-U is 2′-NH2-uridine, and 2′-NH2-C is 2′-NH2-cytidine. Exemplary ara-rX is ara-C (aracytidine). [0094] In one embodiment, X ^C is selected from the group consisting of: mG, mU, mC, mI, mG1, and dG. [0095] In one embodiment, X ^C is selected from the group consisting of: mX and modified mX. Preferably, mX is selected from the group consisting of: mG, mC and mU, more preferably mG; and modified mX is mI. In a preferred embodiment, X ^C is selected from the group consisting of: mG and mI. In a particularly preferred embodiment, X ^C is mI. [0096] In one embodiment, X ^D is selected from the group consisting of: mX, dX, rX, LX, modified mX, modified dX and modified rX. Preferably, X ^D is selected from the 1004921453 group consisting of: mA, mU, mC, dA, dT, dG, mU1, mU2, mU3, PSU, 8-Br-dA, 8-oxo- dA, rA, rG, rU, and 2′-NH2-rU. In one embodiment, X ^D is selected from the group consisting of: mX, dX, LX, modified mX, and modified dX. Preferably, X ^D is selected from the group consisting of: mX, dX, modified mX, and modified dX. Preferably, X ^D is selected from the group consisting of: mA, mU, mC, dA, dT, dG, mU1, mU2, and PSU. More preferably, X ^D is selected from the group consisting of: mA, mU, dA, dT, and dG. [0097] In one embodiment, X ^E is selected from the group consisting of: mX, dX, rX, morpholino-X, moX, LX, fX, rX, modified mX, modified dX and modified rX. Preferably, X ^E is selected from the group consisting of: dA, dC, dG, dT, rG, mC, mC1, mG, mU3, moC, LA, LC, LG, LT, fC, 5-Me-dC, 5-Br-dC, 5-CH2OH-dC, ddC, pdC, dI, 8-Br-dG, N1- Me-dG, 7-deaza-dG, O6-Me-dG, 8-NH2-dG, morpholino-G, rA, rG, rU, rC, N3-Me-dC, 5- I-dC, 2′-NH2-C, ara-C, and morpholino-C. In one embodiment, X ^E is selected from the group consisting of: mX, dX, moX, LX, fX, rX, modified mX and modified dX. Preferably, X ^E is selected from the group consisting of: dA, dC, dG, dT, rG, mC, mC1, mG, moC, LA, LC, LG, LT, fC, 5-Me-dC, 5-Br-dC, 5-CH2OH-dC, ddC, and pdC. More preferably, X ^E is selected from the group consisting of: dA, dC, dG, dT, rG, mC, mC1, mG, moC, LA, LC, LG, LT, fC, 5-Me-dC, 5-Br-dC, 5-CH2OH-dC, and pdC. In one embodiment, X ^E is selected from the group consisting of: mX, dX, rX and LX. Preferably, X ^E is selected from the group consisting of: dA, dC, dG, dT, rG, mC, LA, LC, LG, and LT. Even more preferably, X ^E is selected from the group consisting of: mX and dX. Preferably, X ^E is selected from the group consisting of: dC, dG, dT and mC. [0098] In one embodiment, at least one of X ^D and X ^E is LX. In one embodiment, X ^D and X ^E are independently LX. In another embodiment, one of X ^D and X ^E is LX. Preferably, X ^E is LX. Preferably, X ^E is LX and X ^D is mX. [0099] In one embodiment, at least one of X ^D and X ^E is dX. In one embodiment, X ^D and X ^E are independently dX. In another embodiment, one of X ^D and X ^E is dX. Preferably, X ^E is dX. Preferably, X ^E is dX and X ^D is mX. [0100] In one embodiment, at least one of X ^D and X ^E is rX. In one embodiment, one of X ^D and X ^E is rX. In another embodiment, X ^D and X ^E are each independently rX. Preferably, X ^D is selected from rA and rG, and X ^E is selected from rA, rG and rC. Preferably, X ^D is rA and X ^E is rA; X ^D is rG and X ^E is rA; X ^D is rA and X ^E is rG; X ^D is rA 1004921453 and X ^E is rC. Preferably, where at least one of X ^A and X ^B is rX, each internucleotide linkage is a 3′-5′- phosphorothioate linkage. [0101] In one embodiment, the sequence may be functionalised. Preferably, the functionalised sequence comprises a compound selected from the group consisting of: polyethylene glycol, alkyl, alkenyl, alkynyl, heterocycyl, arylalkyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heterocycyl, substituted arylalkyl, and hydrophobic lipid. Prefearbly, the hydrophobic lipid is selected from cholesterol and tocopherol. Preferably, the compound is selected from the group consisting of: polyethylene glycol, cholesterol and tocopherol. [0102] In one embodiment, the compound is conjugated directly to the sequence. In another embodiment, the compound is conjugated to the sequence via a linker. The linker may be cleavable or non-cleavable. Preferably, the linker is a non-cleavable linker. [0103] Preferably, the compound is conjugated to a terminal nucleotide of the sequence, preferably the terminal 3′- nucleotide. Preferably, the compound is conjugated to the terminal 3′-nucleotide at the 3′- position. [0104] Functionalised sequences may comprise functionalised nucleotides selected from the group consisting of: dX-TEG, dX-Chol and dX-Toco, wherein dX-TEG is a DNA base with triethylene glycol covalently linked to the 3′-position via a monophosphate group, dX-Chol is a DNA base with an (N-cholesteryl-3-aminopropyl)-triethyleneglycol- glyceryl group covalently linked to the 3′-position via a monophosphate group, dX-Toco is a DNA base with a [(9-DL-α-tocopheryl)-triethyleneglycol-1-yl]-glyceryl group covalently linked to the 3′-position via a monophosphate group. [0105] Preferably, the sequence is selected from the group consisting of: 1004921453 1004921453 [0106] Preferably, the sequence is selected from the group consisting of: mI*mA*dG, mI*mU*mC, mG*dA*dG, mG*mA*dT, mG*mA*dG, mG*mA*dC, mG*mA*LG, 1004921453 mG*mA*rG, mG*mA*LT, mG*mA*LC, mU*dT*dC, mU*dA*dC, mG*mA*LA, mU*dA*dG, mC*dA*dG, mU*dT*dT, mU*dA*dT, mU*dA*dA, mC*dT*dA, mU*dG*dT, mC*dT*dC, mC*dA*dT, mU*dG*dG, mC*dT*dT, mC*dT*dG, mU*dT*dA, mU*dT*dG, mG*mA*O6- Me-dG, mG*rA*rA, mG*rG*rA, mG*rA*rG, and mG*rA*rU. [0107] More preferably, the sequence is selected from the group consisting of: mI*mA*dG, mI*mU*mC, mG*dA*dG, mG*mA*dT, mG*mA*dG, mG*mA*dC, mG*rA*rA and mG*rG*rA. Even more preferably, the sequence is selected from the group consisting of: mI*mA*dG and mI*mU*mC. [0108] In another preferred embodiment, the oligonucleotide of the second aspect further inhibits TLR7 activity, preferably human TLR7 activity. Preferably, the oligonucleotide that further inhibits TLR7 activity comprises or consists of the sequence of mI*mU*mC or mI*mA*dG. [0109] In one embodiment, the oligonucleotide consists of the sequence. [0110] In another embodiment, the oligonucleotide comprises the sequence. Preferably, the oligonucleotide comprising the sequence is no more than 20 bases in length, preferably 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, or 4 bases in length. Preferably, the sequence is at the terminal 5′- and/or 3′- end of the oligonucleotide, preferably the terminal 5′- end. [0111] In another embodiment of the second aspect, there is provided a method of modifying the TLR8 activity of an oligonucleotide, the method comprising modifying the oligonucleotide by adding the sequence to the terminal 5′- and/or 3′- end of the oligonucleotide, preferably the terminal 5′- end. In one embodiment, the method reduces the TLR8 potentiating activity of the oligonucleotide. In another embodiment, the method increases the TLR8 inhibitory activity of the oligonucleotide. [0112] In another embodiment of the second aspect, there is provided a fusion oligonucleotide comprising two or more oligonucleotides according to the second aspect linked by a cleavable linker. Preferably, the fusion oligonucleotide comprises: A-[Y-A]n wherein 1004921453 each A independently represents an oligonucleotide according to the second aspect, each A may be the same or different; Y represents a cleavable linker, each Y may be the same or different; and n is equal to or greater than 1. [0113] Preferably, Y is cleavable by an enzyme. Preferably, Y is selected from the group consisting of: a TEG linker, carbon spacers (such as C3, C6, C9, C12), glycerol and PolydT. More preferably Y is a TEG linker. [0114] Preferably, each A is independently bound to Y by an internucleotide linkage (*). Preferably, each internucleotide linkage is independently selected from the group consisting of: biphosphate, triphosphate, phosphorothioate, and phosphodiester. Each internucleotide linkage may be the same or different. In a preferred embodiment, each internucleotide linkage is independently selected from phosphorothioate and phosphodiester. Most preferably, each internucleotide linkage is phosphorothioate. [0115] In another embodiment of the second aspect, there is provided a modified oligonucleotide comprising an agent linked to an oligonucleotide or fusion oligonucleotide according to the second aspect by a linker. The agent may be a therapeutic and/or diagnostic agent. Preferably, the agent is a therapeutic agent, more preferably, a therapeutic RNA selected from the group consisting of: DNA, RNA, mRNA, siRNA, RNA aptamers, antisense oligonucleotides, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. In one preferred embodiment, the therapeutic RNA is selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. The linker may be cleavable or non-cleavable. Preferably, the linker is a cleavable linker. [0116] In another embodiment of the second aspect, there is provided a composition comprising an oligonucleotide or fusion oligonucleotide according to the second aspect, and a pharmaceutically acceptable excipient. [0117] In one embodiment, the composition is an immunogenic composition comprising a therapeutic RNA and an oligonucleotide or fusion oligonucleotide according to the second aspect. Preferably, the therapeutic RNA is selected from the 1004921453 group consisting of: DNA, RNA, mRNA, siRNA, RNA aptamers, antisense oligonucleotides, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. In one embodiment, the immunogenic composition comprises a modified oligonucleotide according to the second aspect. Preferably, the modified oligonucleotide comprises a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. [0118] In one embodiment, the composition may comprise at least one additional active agent including, but not limited to, an anti-inflammatory agent. [0119] In another embodiment of the second aspect, there is provided a method of inhibiting TLR8 activity in a cell, the method comprising contacting the cell with an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect, thereby inhibiting TLR8 activity in the cell. [0120] In another embodiment of the second aspect, there is provided a method of inhibiting TLR8 activity in a subject, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect, thereby inhibiting TLR8 activity in the subject. [0121] In another embodiment of the second aspect, there is provided use of an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect in the manufacture of a medicament for inhibiting TLR8 activity in a subject. [0122] In another embodiment of the second aspect, there is provided use of a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect, for inhibiting TLR8 activity in a subject. [0123] In another embodiment of the second aspect, there is provided a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect, for use in inhibiting TLR8 activity in a subject. [0124] In another embodiment of the second aspect, there is provided a method of inhibiting TLR8 activation by a therapeutic RNA selected from the group consisting of: 1004921453 RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNA, Circular RNA and combinations thereof in a subject, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect, thereby inhibiting TLR8 activation in the subject. In one embodiment, the method comprises administering an immunogenic composition comprising an oligonucleotide or fusion oligonucleotide according to the second aspect, and a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. In one embodiment, the immunogenic composition comprises a modified oligonucleotide according to the second aspect, wherein the therapeutic agent is a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof . [0125] In one embodiment, the oligonucleotide, the fusion oligonucleotide, or the composition does not substantially reduce translation of the therapeutic RNA. [0126] In one embodiment, the therapeutic RNA comprises pseudouridine. [0127] In another embodiment, the therapeutic RNA does not comprise pseudouridine. [0128] In another embodiment of the second aspect, there is provided use of an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect in the manufacture of a medicament for inhibiting TLR8 activation by a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof in a subject. In one embodiment, the subject has received, is receiving, or about to receive the therapeutic RNA. In another embodiment, there is provided use of a first composition and a second composition in the manufacture of a medicament for inhibiting TLR8 activation by a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof in a subject, wherein the first composition comprises an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect, and the second composition comprises the therapeutic RNA. In another embodiment, there is provided use of an immunogenic composition comprising a 1004921453 modified oligonucleotide according to the second aspect, wherein the therapeutic agent is a therapeutic RNA is selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof, in the manufacture of a medicament for inhibiting TLR8 activation by the therapeutic RNA in a subject. [0129] In another aspect, there is provided use of a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect, for inhibiting TLR8 activation by a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof in a subject. In one embodiment, the subject has received, is receiving, or about to receive the therapeutic RNA. In another embodiment, there is provided use of a therapeutically effective amount of an immunogenic composition comprising a modified oligonucleotide according to the second aspect, wherein the therapeutic agent is a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self- amplifying RNAs, circular RNAs and combinations thereof, for inhibiting TLR8 activation by the therapeutic RNA in a subject. [0130] In another aspect, there is provided a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect, for use in inhibiting TLR8 activation by a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self- amplifying RNAs, circular RNAs and combinations thereof in a subject. In one embodiment, the subject has received, is receiving, or about to receive the therapeutic RNA. In another embodiment, there is provided a therapeutically effective amount of an immunogenic composition comprising a modified oligonucleotide according to the second aspect, wherein the therapeutic agent is a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self- amplifying RNAs, circular RNAs and combinations thereof, for use in inhibiting TLR8 activation by the therapeutic RNA in a subject. [0131] In another embodiment of the second aspect, there is provided a method of treating or preventing a disease, disorder or condition in a subject responsive to TLR8 inhibition, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to 1004921453 the second aspect, thereby treating or preventing the disease, disorder or condition in the subject. [0132] In another embodiment of the second aspect, there is provided use of an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect in the manufacture of a medicament for treating or preventing a disease, disorder or condition in a subject responsive to TLR8 inhibition. [0133] In another embodiment of the second aspect, there is provided use of a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect, for treating or preventing a disease, disorder or condition in a subject responsive to TLR8 inhibition. [0134] In another embodiment of the second aspect, there is provided a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect, for use in the prevention or treatment of a disease, disorder or condition in a subject responsive to TLR8 inhibition. [0135] Preferably the disease, disorder or condition responsive to TLR8 inhibition is selected from the group consisting of: inflammation-related diseases, allergic diseases, infections, cancers and auto-immune diseases. [0136] In another aspect, there is provided a fusion oligonucleotide comprising at least one first oligonucleotide according to the first aspect linked to at least one second oligonucleotide according to the second aspect by a cleavable linker. Preferably, the fusion oligonucleotide comprises: A-[Y-A]n wherein each A independently represents an oligonucleotide according to the first or second aspect, each A may be the same or different, with the proviso that at least one A is an oligonucleotide according to the first aspect and at least one further A is an oligonucleotide according to the second aspect; Y represents a cleavable linker, each Y may be the same or different; and n is equal to or greater than 1. 1004921453 [0137] Preferably, Y is cleavable by an enzyme. Preferably, Y is selected from the group consisting of: a TEG linker, carbon spacers (such as C3, C6, C9, C12), glycerol and PolydT. More preferably Y is a TEG linker. [0138] Preferably, each A is independently bound to Y by an internucleotide linkage (*). Preferably, each internucleotide linkage is independently selected from the group consisting of: biphosphate, triphosphate, phosphorothioate, and phosphodiester. Each internucleotide linkage may be the same or different. In a preferred embodiment, each internucleotide linkage is independently selected from phosphorothioate and phosphodiester. Most preferably, each internucleotide linkage is phosphorothioate. [0139] In another embodiment, there is provided a modified oligonucleotide comprising a synthetic oligonucleotide linked to at least one first oligonucleotide according to the first aspect and at least one second oligonucleotide according to the second aspect by one or more linkers. In another embodiment, there is provided a modified oligonucleotide comprising a synthetic oligonucleotide linked to a fusion oligonucleotide by a linker, wherein the fusion oligonucleotide comprises at least one first oligonucleotide according to the first aspect linked to at least one second oligonucleotide according to the second aspect by a linker. Preferably, the synthetic oligonucleotide is a therapeutic and/or diagnostic oligonucleotide, more preferably a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. The linker may be cleavable or non-cleavable. Preferably, the linker is a cleavable linker. [0140] The fusion oligonucleotide and modified oligonucleotide comprising at least one first oligonucleotide according to the first aspect linked to at least one second oligonucleotide according to the second aspect may be used in the methods and uses of the first and second aspects described herein. [0141] In a third aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: [mX/modified mX]* ^y X ^F * ^z X ^G wherein: 1004921453 * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^F and X ^G are each independently selected from the group consisting of: mX, dX, rX, LX, modified mX, modified dX and modified LX; wherein at least one of X ^F and X ^G is dX, LX, rX, modified dX or modified LX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, LX is a LNA modified base; when mX is mC, X ^F is dG, X ^G is not mG or dG; or when mX is mG and when: X ^F is mU, mC or dG, X ^G is not dT, dA, dG; X ^F is dT, dA, or mA, X ^G is not dX; X ^F is dG, X ^G is not dA, dG, dT; wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0142] In an embodiment of the third aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: mX* ^y X ^F * ^z X ^G wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^F and X ^G are each independently selected from the group consisting of: mX, dX, LX, modified mX, modified dX and modified LX; wherein at least one of X ^F and X ^G is dX, LX, modified dX or modified LX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, LX is a LNA modified base; 1004921453 when mX is mC, X ^F is dG, X ^G is not mG or dG; or when mX is mG and when: X ^F is mU, mC or dG, X ^G is not dT, dA, dG; X ^F is dT, dA, or mA, X ^G is not dX; X ^F is dG, X ^G is not dA, dG, dT; wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0143] Any oligonucleotide of the third aspect potentiates TLR8 activity, preferably human TLR8 activity. In one preferred embodiment, an oligonucleotide of the third aspect does not substantially inhibit TLR7 activity, preferably human TLR7 activity. In an alternative preferred embodiment, an oligonucleotide of the third aspect inhibits TLR7 activity, preferably human TLR7 activity. [0144] Each internucleotide linkage may be selected from the group consisting of: 3′- 5′-, 5′-5′-, 5′-3′-, 3′-3′-, 3′-2′-, 2′-3′-, 2′-2′-, 2′-5′-, and 5′-2′- linkage. Preferably, each internucleotide linkage may be selected from: 3′-5′- and 5′-5′- linkage. Preferably, each internucletodie linkage is a 3′-5′- linkage. [0145] In a particularly preferred embodiment of the third aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: 5′-[mX/modified mX]* ^y X ^F * ^z X ^G -3′ wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^F and X ^G are each independently selected from the group consisting of: mX, dX, rX, LX, modified mX, modified dX and modified LX; wherein at least one of X ^F and X ^G is dX, rX, LX, modified dX or modified LX; 1004921453 wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, LX is a LNA modified base; when mX is mC, X ^F is dG, X ^G is not mG or dG; or when mX is mG and when: X ^F is mU, mC or dG, X ^G is not dT, dA, dG; X ^F is dT, dA, or mA, X ^G is not dX; X ^F is dG, X ^G is not dA, dG, dT; wherein the sequence is optionally functionalised. [0146] In a particularly preferred embodiment of the third aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: 5′-mX* ^y X ^F * ^z X ^G -3′ wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^F and X ^G are each independently selected from the group consisting of: mX, dX, LX, modified mX, modified dX and modified LX; wherein at least one of X ^F and X ^G is dX, LX, modified dX or modified LX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, LX is a LNA modified base; when mX is mC, X ^F is dG, X ^G is not mG or dG; or when mX is mG and when: X ^F is mU, mC or dG, X ^G is not dT, dA, dG; X ^F is dT, dA, or mA, X ^G is not dX; X ^F is dG, X ^G is not dA, dG, dT; wherein the sequence is optionally functionalised. 1004921453 [0147] Preferably, each internucleotide linkage is a 3′-5′ linkage. [0148] Preferably, each internucleotide linkage is independently selected from the group consisting of: biphosphate, triphosphate, phosphorothioate, and phosphodiester. Each internucleotide linkage may be the same or different. In a preferred embodiment, each internucleotide linkage is independently selected from phosphorothioate and phosphodiester. Most preferably, each internucleotide linkage is phosphorothioate. [0149] In a particularly preferred embodiment, each internucleotide linkage is a 3′-5′- phosphorothioate linkage. [0150] In one embodiment, the oligonucleotide comprises a mixture of different oligonucleotide stereoisomers, preferably a mixture of different oligonucleotide phosphorothioate stereoisomers. In another embodiment, the oligonucleotide of the third aspect comprises a single phosphorothioate stereoisomer, preferably wherein * ^z is in the R configuration. [0151] Preferably, mX is a nucleotide comprising a 2′-OMe modification. [0152] Modified dX and modified rX comprise at least one modification or substitution at positions of the base and/or sugar. Modified mX, modified moX, modified LX and modified fX comprise at least one additional modification or substitution at additional positions of the base and/or sugar. Preferably, the modification or substitution is selected from the group consisting of: pseudouridine, 3′-deoxy, hydroxyl, des-amino, amino, thio, halo, oxo, aza, deaza, polyethylene glycol, alkyl, alkenyl, alkynyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl and combinations thereof. [0153] Exemplary modified mX includes but is not limited to: mG1, mI, mU1, mU2, mC1, ^m7 G, and N1-Me-G, wherein mG1 is 2′-OMe-2,6-Diaminopurine, mI is 2′-OMe-I (2′-O-methylinosine), mU1 is 2′-OMe-5-Me-U (2′-O-methyl-5-methyluridine), mU2 is 2′- OMe-5-Br-U (2′-O-methyl-5-bromouridine), mC1 is 2′-OMe-5-Me-C (2′-O-methyl-5- methylcytidine), ^m7 G is 3′-OMe-N7-methylated guanosine and N1-Me-G (1- methylguanosine). Preferably, modified mX is selected from the group consisting of: mG1, mI, mU1, mU2 and mC1. 1004921453 [0154] Exemplary modified dX includes but is not limited to: 5-Me-dC, 5-Br-dC, 5- CH2OH-dC, ddC, pdC, and PSU, wherein 5-Me-dC is 5-methyl substituted deoxycytidine, 5-Br-dC is 5-bromo substituted deoxycytidine, 5-CH ² OH-dC is 5- hydroxymethyl substituted deoxycytidine, ddC is 2′-deoxy-3′-deoxy cytidine, pdC is 5- propynyl substituted deoxycytidine, and PSU is pseudo uridine. [0155] In one embodiment, X ^F and X ^G are each independently selected from the group consisting of: mX, dX, and LX; wherein at least one of X ^F and X ^G is dX or LX. [0156] In one embodiment, mX is selected from the group consisting of: mG, mC, and mU. In one preferred embodiment, mX is mG. In another preferred embodiment, mX is mC. In yet another preferred embodiment, mX is mU. [0157] In one embodiment, X ^F is selected from the group consisting of: mX and dX. Preferably, X ^F is selected from the group consisting of: dC, dG, dA, dT, mG, mC, and mU. Preferably, X ^F is selected from the group consisting of: dC, dG and mG. In a preferred embodiment, X ^F is dX, preferably dC. [0158] In one embodiment, X ^G is selected from the group consisting of: dX and LX. Preferably, X ^G is selected from the group consisting of: dC, dT, dA, dG, LG, LC, LT, and LA. More preferably, X ^G is selected from the group consisting of: dX and LG, preferably dX. [0159] In one embodiment, at least one of X ^F and X ^G is dX. In one embodiment, one of X ^F and X ^G is dX. In a preferred embodiment, X ^F and X ^G are independently dX. [0160] In one embodiment, X ^F is selected from the group consisting of: dX and mX; and X ^G is dX. In another embodiment, X ^F is mX; and X ^G is selected from the group consisting of: dX and LX. In yet another embodiment, when X ^F is dC or mG, X ^F is dX or LX. [0161] In one embodiment, the sequence may be functionalised. Preferably, the functionalised sequence comprises a compound selected from the group consisting of: polyethylene glycol, alkyl, alkenyl, alkynyl, heterocycyl, arylalkyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heterocycyl, substituted arylalkyl, and hydrophobic lipid. Prefearbly, the hydrophobic lipid is selected from cholesterol and tocopherol. Preferably, the 1004921453 compound is selected from the group consisting of: polyethylene glycol, cholesterol and tocopherol. [0162] In one embodiment, the compound is conjugated directly to the sequence. In another embodiment, the compound is conjugated to the sequence via a linker. The linker may be cleavable or non-cleavable. Preferably, the linker is a non-cleavable linker. [0163] Preferably, the compound is conjugated to a terminal nucleotide of the sequence, preferably the terminal 3′- nucleotide. Preferably, the compound is conjugated to the terminal 3′-nucleotide at the 3′- position. [0164] Functionalised sequences may comprise functionalised nucleotides selected from the group consisting of: dX-TEG, dX-Chol and dX-Toco, wherein dX-TEG is a DNA base with triethylene glycol covalently linked to the 3′-position via a monophosphate group, dX-Chol is a DNA base with an (N-cholesteryl-3-aminopropyl)-triethyleneglycol- glyceryl group covalently linked to the 3′-position via a monophosphate group, dX-Toco is a DNA base with a [(9-DL-α-tocopheryl)-triethyleneglycol-1-yl]-glyceryl group covalently linked to the 3′-position via a monophosphate group. [0165] Preferably, the sequence is selected from the group consisting of: 1004921453 [0166] Preferably, the sequence is selected from the group consisting of: mG*dC*dC, mC*dC*dT, mG*dC*dA, mG*dC*dG, mC*dC*dC, mU*dC*dC, mC*dG*dC, mG*dC*dT, mG*mG*dA, mU*dC*dG, mU*mG*LG, mU*dC*dA, and mU*dC*dT. [0167] More preferably, the sequence is selected from the group consisting of: mG*dC*dC, mC*dC*dT, mU*mG*LG, mC*dC*dC, mU*dC*dC, mG*dC*dA, mG*dC*dG, and mG*dC*dT. Even more preferably the oligonucleotide is mG*dC*dC. [0168] In one embodiment, the oligonucleotide consists of the sequence. [0169] In another embodiment, the oligonucleotide comprises the sequence. Preferably, the oligonucleotide comprising the sequence is no more than 20 bases in length, preferably 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, or 4 bases in length. Preferably, the sequence is at the terminal 5′- and/or 3′- end of the oligonucleotide, preferably the terminal 5′- end. In one preferred embodiment, the oligonucleotide comprises the sequence 5′-mG*mU*dC-3′. Even more preferably, the oligonucleotide comprises the sequence 5′-mG*mU*dC*dC*dC*dC-3′. 1004921453 [0170] In another embodiment of the third aspect, there is provided a method of modifying the TLR8 activity of an oligonucleotide, the method comprising modifying the oligonucleotide by adding the sequence to the terminal 5′- and/or 3′- end of the oligonucleotide, preferably the terminal 5′- end. In one embodiment, the method increases the TLR8 potentiating activity of the oligonucleotide. In another embodiment, the method reduces the TLR8 inhibitory activity of the oligonucleotide. [0171] In another embodiment of the third aspect, there is provided a fusion oligonucleotide comprising two or more oligonucleotides according to the third aspect linked by a cleavable linker. Preferably, the fusion oligonucleotide comprises: A-[Y-A]n wherein each A independently represents an oligonucleotide according to the third aspect, each A may be the same or different; Y represents a cleavable linker, each Y may be the same or different; and n is equal to or greater than 1. [0172] Preferably, Y is cleavable by an enzyme. Preferably, Y is selected from the group consisting of: a TEG linker, carbon spacers (such as C3, C6, C9, C12), glycerol and PolydT. More preferably Y is a TEG linker. [0173] Preferably, each A is independently bound to Y by an internucleotide linkage (*). Preferably, each internucleotide linkage is independently selected from the group consisting of: biphosphate, triphosphate, phosphorothioate, and phosphodiester. Each internucleotide linkage may be the same or different. In a preferred embodiment, each internucleotide linkage is independently selected from phosphorothioate and phosphodiester. Most preferably, each internucleotide linkage is phosphorothioate. [0174] In another embodiment of the third aspect, there is provided a modified oligonucleotide comprising an agent linked to an oligonucleotide or fusion oligonucleotide according to the third aspect by a linker. The agent may be a therapeutic and/or diagnostic agent. Preferably, the agent is a therapeutic agent, more preferably, a therapeutic RNA selected from the group consisting of: DNA, RNA, mRNA, 1004921453 siRNA, RNA aptamers, antisense oligonucleotides, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. In one preferred embodiment, the therapeutic RNA is selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. The linker may be cleavable or non-cleavable. Preferably, the linker is a cleavable linker. [0175] In another embodiment of the third aspect, there is provided a composition comprising an oligonucleotide or fusion oligonucleotide according to the third aspect, and a pharmaceutically acceptable excipient. [0176] In one embodiment, the composition is an immunogenic composition comprising a therapeutic RNA and an oligonucleotide or fusion oligonucleotide according to the third aspect. Preferably, the therapeutic RNA is selected from the group consisting of: DNA, RNA, mRNA, siRNA, RNA aptamers, antisense oligonucleotides, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. In one embodiment, the immunogenic composition comprises a modified oligonucleotide according to the third aspect. Preferably, the modified oligonucleotide comprises a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. [0177] In one embodiment, the composition may comprise at least one additional active agent selected from: a gene targeting agent and a TLR8 agonist. [0178] In another embodiment of the third aspect, there is provided a method of potentiating TLR8 activity in a cell, the method comprising contacting the cell with an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect, thereby potentiating TLR8 activity in the subject. [0179] In another embodiment of the third aspect, there is provided a method of potentiating TLR8 activity in a subject, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect, thereby potentiating TLR8 activity in the subject. 1004921453 [0180] In another embodiment of the third aspect, there is provided use of an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect in the manufacture of a medicament for potentiating TLR8 activity in a subject. [0181] In another embodiment of the third aspect, there is provided use of a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect, for potentiating TLR8 activity in a subject. [0182] In another embodiment of the third aspect, there is provided a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect, for use in potentiating TLR8 activity in a subject. [0183] In another embodiment of the third aspect, there is provided a method of potentiating TLR8 activation by a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof in a subject, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect, thereby potentiating TLR8 activation in the subject. In one embodiment, the method comprises administering an immunogenic composition comprising an oligonucleotide or fusion oligonucleotide according to the third aspect, and a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self- amplifying RNAs, circular RNAs and combinations thereof. In one embodiment, the immunogenic composition comprises a modified oligonucleotide according to the third aspect, wherein the therapeutic agent is a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. [0184] In another embodiment of the third aspect, there is provided use of an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect in the manufacture of a medicament for potentiating TLR8 activation by a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof in a subject. In one embodiment, the subject has received, is receiving, or about to receive the therapeutic RNA. In another embodiment, there is provided use of a first composition and a second composition in the manufacture of a medicament for potentiating TLR8 1004921453 activation by a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof in a subject, wherein the first composition comprises an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect, and the second composition comprises the therapeutic RNA. In another embodiment, there is provided use of an immunogenic composition comprising a modified oligonucleotide according to the third aspect, wherein the therapeutic agent is a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof, in the manufacture of a medicament for potentiating TLR8 activation by the therapeutic RNA in a subject. [0185] In another aspect, there is provided use of a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect, for potentiating TLR8 activation by a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof in a subject. In one embodiment, the subject has received, is receiving, or about to receive the therapeutic RNA. In another embodiment, there is provided use of a therapeutically effective amount of an immunogenic composition comprising a modified oligonucleotide according to the third aspect, wherein the therapeutic agent is a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof, for potentiating TLR8 activation by the therapeutic RNA in a subject. [0186] In another aspect, there is provided a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect, for use in potentiating TLR8 activation by a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof in a subject. In one embodiment, the subject has received, is receiving, or about to receive the therapeutic RNA. In another embodiment, there is provided a therapeutically effective amount of an immunogenic composition comprising a modified oligonucleotide according to the third aspect, wherein the therapeutic agent is a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, 1004921453 circular RNAs and combinations thereof for use in potentiating TLR8 activation by the therapeutic RNA in a subject. [0187] In one embodiment, the oligonucleotide, the fusion oligonucleotide, or the composition does not substantially increase translation of the therapeutic RNA. [0188] In one embodiment, the therapeutic RNA comprises pseudouridine. [0189] In another embodiment, the therapeutic RNA does not comprise pseudouridine.In another embodiment of the third aspect, there is provided a method of treating or preventing a disease, disorder or condition in a subject responsive to increased TLR8 signalling, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect, thereby treating or preventing the disease, disorder or condition in the subject. [0190] In another embodiment of the third aspect, there is provided use of an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect in the manufacture of a medicament for treating or preventing a disease, disorder or condition in a subject responsive to increased TLR8 signalling. [0191] In another embodiment of the third aspect, there is provided use of a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect, for treating or preventing a disease, disorder or condition in a subject responsive to increased TLR8 signalling. [0192] In another embodiment of the third aspect, there is provided a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect, for use in the prevention or treatment of a disease, disorder or condition in a subject responsive to increased TLR8 signalling. [0193] Preferably, the oligonucleotides, fusion oligonucleotides, or compositions according to the third aspect activate or increase TLR8 signalling. [0194] Preferably the disease, disorder or condition responsive to increased TLR8 signalling is selected from the group consisting of: cancer, chronic viral (eg HBV) and bacterial infection. 1004921453 [0195] In another embodiment of the third aspect, the method or use further comprises administration of a TLR8 agonist. Preferably, the TLR8 agonist is administered at a sub-therapeutic dose. [0196] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings. Brief description of the drawings [0197] Figure 1: HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with 100 nM indicated oligos, prior to R848 (1ug/ml) stimulation overnight. Data shown are averaged from 3 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with Dunnett’s multiple comparisons to C2Mut1-dC condition are shown. All internucleotide linkages are phosphorothioate (only the first 4 are indicated with a *). [0198] Figure 2: HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with 5 μM indicated oligos, prior to R848 (1μg/ml) stimulation overnight. Data shown are averaged from 3 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with Dunnett’s multiple comparisons to 5-Short-Mut1-Hyb condition are shown. [0199] Figure 3: HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with 5 μM indicated trimer, prior to R848 (1μg/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with Dunnett’s multiple comparisons to 2′OMe GUC condition are shown. [0200] Figure 4: HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with 5μM indicated trimer, prior to with or without R848 (1μg/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition 1004921453 after background correction to NT control. All trimer conditions are with R848 co- stimulation. SEM and One-way ANOVA with Dunnett’s multiple comparisons to R848 condition are shown. [0201] Figure 5: HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with indicated doses of trimers, prior to R848 (1μg/ml) stimulation overnight. mG*mU*mC, in (A) was used at 500nM. Data shown are averaged from 1 independent experiment (A) or 3 independent experiments (B,C) in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with Dunnett’s multiple comparisons to GUC condition are shown. [0202] Figure 6: Chemical structures of nucleotides, trimers and linked trimers used in the studies. Chemical structures of nucleotides that are modified compared to parent GUC (mG*mU*mC) or parental GAG (mG*mA*mA) are shown. [0203] Figure 7: A and B) HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre-treated ~60 min with 5uM indicated trimer, prior to R848 (1μg/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with Dunnett’s multiple comparisons to GUC (mG*mU*mC) condition are shown. [0204] Figure 8: HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with with indicated doses of oligos, prior to R848 (1μg/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. [0205] Figure 9: A) HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre-treated ~60 min with 5μM of oligos, prior to R848 (1μg/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. B) HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with indicated doses of oligos, prior to R848 (1μg/ml) stimulation 1004921453 overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with Dunnett’s multiple comparisons to R848 condition are shown. [0206] Figure 10: A) HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre-treated ~60 min with 5μM of oligos, prior to R848 (1μg/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. B and C) HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre-treated ~60 min with indicated doses of oligos, prior to R848 (1μg/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. A, B and C) All trimer conditions are with R848 co- stimulation. SEM and One-way ANOVA with Dunnett’s multiple comparisons to R848 (A, B) or NT (C) condition are shown. [0207] Figure 11: HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with indicated doses of oligos, prior to R848 (1μg/ml) stimulation overnight. Data shown are averaged from 3 biological triplicate for each screen. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. U is to be read as T for DNA trimers. [0208] Figure 12: HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with indicated doses of oligos, prior to R848 (1μg/ml) stimulation overnight. Data shown are averaged from 3 biological triplicate for each screen. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. [0209] Figure 13: RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with indicated doses of oligos, prior to R848 (indicated dose) stimulation overnight. Data shown are averaged from 3 biological triplicate for each screen. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. 1004921453 [0210] Figure 14: RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with 5uM oligos, prior to R848 (0.125μg/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with Dunnett’s multiple comparisons to GGC or GAG condition are shown. [0211] Figure 15: RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with indicated doses of oligos, prior to R848 (0.125ug/ml) stimulation overnight. Data shown are averaged from 3 independent experiments in biological triplicate. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEMs are shown. [0212] Figure 16: RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with 500nM GGC or not (NT), prior to transfection with 500nM of B406AS1 ssRNA with DOTAP overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The ELAM-luciferase values are reported to the NT condition. SEMs and two tailed unpaired t-test are shown. [0213] Figure 17: RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with 5uM of DNA or 2′-OMe trimers, prior to R848 (0.125μg/ml) stimulation overnight. Data shown are averaged from 3 biological triplicate for each screen. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. [0214] Figure 18: RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with indicated doses of oligos, prior to R848 (0.125μg/ml) stimulation overnight. Data shown are averaged from 3 biological triplicate for each screen. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. [0215] Figure 19: A) THP-1 were pre-treated ~60 min with indicated doses of oligos, prior to R848 (1μg/mL) stimulation for 8hours and supernatants analysed by IP-10 ELISA. B) HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre-treated 1004921453 ~60 min with indicated doses of oligos, prior to Motolimod (600nM) stimulation overnight. Data shown are averaged from 3 biological triplicate for each screen. The NF-κB-luciferase values in B are reported to the Motolimod only condition after background correction to NT control. All trimer conditions in A and B are with R848 or Motolimod co-stimulation, respectively. [0216] Figure 20: HEK-TLR8 cells (A, C) expressing an NF-κB-luciferase reporter were pre-treated ~60 min with 5 μM indicated oligos, prior to Motolimod (Mo) (600nM) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the Motolimod condition. All trimer conditions are with Motolimod co-stimulation. SEM and One-way ANOVA with Dunnett’s multiple comparisons to Motolimod only condition are shown. THP-1 cells (B, D) were pre-treated ~60 min with 5 μM, prior to R848 stimulation with 1μg/ml overnight. Supernatants were collected and analysed for IP-10 production by ELISA. Data shown is averaged from 2 independent experiments in biological triplicate. SEM and One-way ANOVA with Dunnett’s multiple comparisons to R848 only (B) or NT (D) condition are shown. [0217] Figure 21: HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with indicated doses of oligos, prior to Motolimod (400 for MOE and 600nM for DNA) stimulation overnight. Data shown are averaged from 3 biological triplicate for each screen. The NF-κB-luciferase values are reported to the Motolimod condition after background correction to NT control. All trimer conditions are with Motolimod co-stimulation. [0218] Figure 22: A) HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre-treated ~60 min with 5μM of oligos, prior to Motolimod (600nM) stimulation overnight. Data shown are averaged from 3 biological triplicate for each screen. B) HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre-treated ~60 min with 500nM of the selected oligos prior to Motolimod (600nM) stimulation overnight. Data shown are averaged from 2 independent experiments with biological triplicates. The NF- κB-luciferase values are reported to the Motolimod condition after background correction to NT control. All trimer conditions are with Motolimod co-stimulation. [0219] Figure 23: HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with 50 nM indicated oligos, prior to R848 (1 μg/ml) stimulation 1004921453 overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with multiple comparisons R848 condition are shown. All internucleotide linkages are phosphorothioate. [0220] Figure 24. HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with various doses of indicated oligos, prior to R848 (1 μg/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate (except for GUC-v1, data from n = 1). The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM are shown. [0221] Figure 25. HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with 2 μM indicated oligos, prior to R848 (1 μg/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition (no background correction was applied here). All trimer conditions are with R848 co- stimulation. SEM are shown. [0222] Figure 26. HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with either 5 μM or 400 nM concentration of 3rd base LNA modified trimers (A) or 400 nM of fully 2′-OMe or 3rd base LNA modified trimers (B), prior to R848 (1ug/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. All internucleotide linkages are phosphorothioate. [0223] Figure 27. HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with indicated amount of oligos (A, 200 nM and B, 100 nM), prior to R848 (1 ^g/ml) stimulation overnight. Data shown are averaged from 3 independent experiments in biological triplicate except for GUC-v1 sequence in Fig 27.b is from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer 1004921453 conditions are with R848 co-stimulation. SEM and One-way ANOVA with multiple comparisons R848 condition are shown. [0224] Figure 28. HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with indicated amount of oligos (A, is 5 ^M and B, is 1 ^M), prior to R848 (1 ^g/ml) stimulation overnight.Data shown in (A) and (B) are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with multiple comparisons R848 condition are shown. [0225] Figure 29. HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with various doses of indicated oligos or Enpatoran, prior to R848 (1 ^g/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co- stimulation. SEM and One-way ANOVA with multiple comparisons R848 condition are shown. [0226] Figure 30. HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with indicated amount of oligos (5 ^M), prior to R848 (1 ^g/ml) stimulation overnight. Data shown are averaged from 1 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co- stimulation. SEM is shown. [0227] Figure 31. RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with 100 nM doses of oligos, prior to R848 (0.125 ^g/ml) stimulation overnight. Data shown are averaged from 3 independent experiments in biological triplicate. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with multiple comparisons R848 condition are shown. All internucleotide linkages are phosphorothioate (only the first 4/5 are indicated with a *). [0228] Figure 32. RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with 5 ^M doses of oligos, prior to R848 (0.125 ^g/ml) 1004921453 stimulation overnight. Data shown are averaged from 3 independent experiments in biological triplicate. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with multiple comparisons to R848 condition are shown. All internucleotide linkages are phosphorothioate (only the first few are indicated with a *). [0229] Figure 33. RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with 5 ^M of oligos, prior to R848 (0.125 ^g/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with multiple comparisons to R848 condition are shown (non-significant comparisons are not shown). [0230] Figure 34. RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with 500 nM of oligos, prior to R848 (0.125 ^g/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with multiple comparisons to R848 condition are shown. [0231] Figure 35. RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with 5 ^M oligos, prior to R848 (0.125 ^g/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with multiple comparisons to R848 condition are shown. [0232] Figure 36. RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with 5 mM oligos, prior to R848 (0.125μg/ml) stimulation overnight. Data shown are averaged from 1 experiment in biological triplicate. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM are shown. [0233] Figure 37. RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with 5 ^M of oligos, prior to R848 (0.125 ^g/ml) stimulation 1004921453 overnight. Data shown are from one experiment conducted on two independent plates. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. [0234] Figure 38. RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with 1 ^M of oligos, prior to R848 (0.125 ^g/ml) stimulation overnight. Data shown are from two independent experiments conducted in biological triplicate. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. [0235] Figure 39. TLR7 ^kika/wt BMDMs were treated overnight with 5 ^M of GGC-v1 or 200 nM Enpatoran and RNA analysed by RNAseq (using 3 mice per condition). Generally, for each sample, there were about 2.8 million counts across 18,000 genes. One non-treated sample from the Kika group was excluded from further analysis due to low counts. Statistical comparisons were made using the contrasts.fit function from the limma package (v3.48.3) and empirical Bayes moderated t-tests were performed, with p-values obtained using eBayes, and using non-treated TLR7 ^kika/wt BMDMs cells as reference. [0236] Figure 40. TLR7 ^kika/wt and WT BMDMs were treated overnight with 5 ^M of GGC-v1 or 200nM Enpatoran and RNA analysed by RTqPCR. Gene expression was normalised to 18S prior to being reported to the WT-NT condition. Each point represents data from RNA from one mouse for each condition. [0237] Figure 41. RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with 5 ^M of oligos or 50 nM of Enpatoran, prior to 0.5 μg/ml of Gardiquimod (A) and 0.5 μg/ml CL075 (B) stimulation overnight. Data shown are averaged from 3 independent experiments in biological triplicate. The ELAM-luciferase values are reported to the Guardiquimod (A) and CL075 (B) condition after background correction to NT control. All trimer and Enpatoran conditions are with Guardiquimod or CL075 co-stimulation. SEM and One-way ANOVA with multiple comparisons to the agonist conditions are shown. [0238] Figure 42. A) WT mice were injected i.v. with 200 μg of GGCv1 trimer (or PBS – Grey and black dots) conjugated with JetPei for 1h, prior to being treated or not i.p. with 25 ^g R848. Sera were collected 2h post R848 treatment and TNF levels analysed 1004921453 with beads by flow cytometry. RTqPCR analyses of indicated genes normalized to 18S were conducted on splenic mRNA. One way ANOVA comparisons are shown. B) 6 WT mice were treated per group with 20 μg trimer oligonucleotides dissolved in PBS with 30% Pluronic F-127 on the ear, or 60 μg trimer oligonucleotide on the back, prior to administration of Aldara cream, daily, for 4 days. A Vaseline group (with no Aldara) was used as control group. Thickness of the ear was measured daily with callipers, and ear redness scored along with back scaliness. On the 5 ^th day, the mice were culled and RNA from the back skin of 4 mice was collected for each group. Expression of indicated genes relative to 18S in the back skin RNA was analysed by RTqPCR and further reported to Aldara+vehicle or Vaseline conditions. One way ANOVA comparisons are shown. [0239] Figure 43. HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with 5 ^M of oligos, prior to Motolimod (600 nM) stimulation overnight. Data shown are averaged from 3 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the Motolimod condition after background correction to NT control. All trimer conditions are with Motolimod co-stimulation. SEM and One-way ANOVA with multiple comparisons to GUC condition are shown. [0240] Figure 44. A) HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre-treated ~60 min with 500 nM of oligos, prior to Motolimod (600nM) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the Motolimod condition after background correction to NT control. All trimer conditions are with Motolimod co- stimulation. SEM and One-way ANOVA with multiple comparisons to GAG-v4 condition are shown. B) HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with indicated concentration of GUC-v16 oligos, prior to Motolimod (600 nM) stimulation overnight. Data shown are averaged from 3 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the Motolimod condition after background correction to NT control. All trimer conditions are with Motolimod co-stimulation. SEM is shown. [0241] Figure 45. HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with indicated dose of oligos (A=5 μM, B=1 μM, C=1 μM and D = different doses), prior to Motolimod (600 nM) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase 1004921453 values are reported to the Motolimod condition after background correction to NT control. All trimer conditions are with Motolimod co-stimulation. SEM and One-way ANOVA with multiple comparisons to Motolimod (A, B) or parental 2′OMe GAG (C) conditions only are shown. [0242] Figure 46. HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with 1 (A) or 5 ^M of oligos (A and B), prior to Motolimod (600nM) stimulation overnight. Data shown is from two independent screens conducted in biological triplicate. The NF-κB-luciferase values are reported to the Motolimod condition after background correction to NT control. All trimer conditions are with Motolimod co-stimulation. [0243] Figure 47. HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with 1 or 5 ^M of oligos, prior to Motolimod (600 nM) stimulation overnight. Data shown is from two independent screens conducted in biological triplicate. The NF-κB-luciferase values are reported to the Motolimod condition after background correction to NT control. All trimer conditions are with Motolimod co- stimulation. GAG-v1 (mGmAdG and mGdCdC) were used as positive controls for inhibition and potentiation of TLR8, respectively). The 5′-end of all the trimers is 2′-- OMe. [0244] Figure 48. HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with 1 ^M of oligos, prior to Motolimod (600 nM) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the Motolimod condition after background correction to NT control. All trimer conditions are with Motolimod co-stimulation. SEM and One-way ANOVA with multiple comparisons to Motolimod condition are shown. [0245] Figure 49. HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with 5 ^M of oligos, prior to uridine (20 mM) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB- luciferase values are reported to the uridine condition after background correction to NT control. All trimer conditions are with uridine co-stimulation. SEM and One-way ANOVA with multiple comparisons to uridine condition are shown. 1004921453 [0246] Figure 50. HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with indicated doses of oligos, prior to Motolimod (600 nM) stimulation overnight. Data shown are averaged from 3 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the Motolimod condition after background correction to NT control. All trimer conditions are with Motolimod co- stimulation. SEM are shown. [0247] Figure 51. HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with 5 ^M of oligos, prior to uridine (20mM) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB- luciferase values are reported to the uridine condition after background correction to NT control. All trimer conditions are with uridine co-stimulation. SEM and One-way ANOVA with multiple comparisons to uridine condition are shown. [0248] Figure 52. HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre- treated ~60 min with 5 ^M of mGdCdC or 1 ^M dT20, DOTAP transfection with 5 μg total mouse RNA overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the NT control. SEM and unpaired t-test are shown. [0249] Figure 53. PMA-differentiated and IFNγ primed THP-1 cells were transfected overnight with 750 nM of indicated oligos with DOTAP, and supernatants analysed by ELISA. Data are shown averaged from 2 independent experiments in biological triplicate. SEM and One-way ANOVA with multiple comparisons to ssRNA40 condition are shown. All the bases of the sequences are RNA with PS backbone, and bold bases are 2′-OMe. [0250] Figure 54. A) Undifferentiated THP-1 cells were pre-treated ~60 min with 5 ^M of the CleanCap AG trimer (GAG-link), without serum, prior to R848 (1 ^g/ml) stimulation for 8 hours and supernatants analysed by ELISA. Data are shown averaged from 3 independent experiments in biological triplicate. B) HEK-TLR8 cells expressing an NF-κB-luciferase reporter were pre-treated ~60 min with 5 ^M of the CleanCap AG trimer, without serum, prior to R848 (1 ^g/ml) stimulation overnight. The NF-κB- luciferase values are reported to the R848 condition after background correction to NT control. Data shown are averaged from 2 (B) or 3 (A) independent experiments in 1004921453 biological triplicate. SEM and One-way ANOVA with multiple comparisons to R848 condition are shown. [0251] Figure 55. A) HEK-TLR7 cells expressing an NF-κB-luciferase reporter were pre-treated ~60 min with 5 ^M indicated oligos, without serum, prior to R848 (1 ^g/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-κB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co- stimulation. SEM and One-way ANOVA with multiple comparisons R848 condition are shown. B) RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre- treated ~60 min with 5 ^M oligos, without serum, prior to R848 (0.125 ^g/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with multiple comparisons to R848 condition are shown. [0252] Figure 56. PMA-differentiated and IFNγ primed THP-1 cells pre-treated or not with 5 μM of GUC-v16 were transfected overnight with 1 μg of CleanCap AG EGFP mRNA (Trilink) with DOTAP, and supernatants analysed by ELISA. Data are shown averaged from 2 independent experiments in biological triplicate. SEM and One-way ANOVA with multiple comparisons to EGFP condition are shown. [0253] Figure 57. HEK-TLR7 cells expressing an NF-KB-luciferase reporter were pre- treated ~60 min with 1 ^M (Fig 57. A) or 200 nM (Fig 57. B) concentration of indicated oligos, prior to R848 (1 ^g/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-KB-luciferase values are reported to the R848 condition after background correction to NT control. All oligonucleotide conditions are with R848 co-stimulation. SEM and One-way ANOVA with multiple comparisons R848 condition are shown. All internucleotide linkages are phosphorothioate. [0254] Figure 58. HEK-TLR7 cells expressing an NF-KB-luciferase reporter were pre- treated ~60 min with 5 ^M (Fig 64. A) or 200 nM (Fig 64. B) or 1 ^M (Fig 64. C) or 50 nM (Fig 64. D) concentration of indicated oligos, prior to R848 (1 ^g/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate, except for GUC-v1 in (Fig 64. C). The NF-KB-luciferase values are reported to 1004921453 the R848 condition after background correction to NT control. All oligonucleotide conditions are with R848 co-stimulation. SEM and One-way ANOVA with multiple comparisons R848 condition are shown. All internucleotide linkages are phosphorothioate except for GUC-v49 and GAG-v21 which used PMO. [0255] Figure 59. HEK-TLR7 cells expressing an NF-KB-luciferase reporter were pre- treated ~60 min with 2 ^M concentration of indicated oligos, prior to R848 (1 ^g/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-KB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co- stimulation. SEM and One-way ANOVA with multiple comparisons R848 condition are shown. All internucleotide linkages are phosphorothioate. [0256] Figure 60. RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with 1 ^M (Fig 66. A) or 200 nM (Fig 66. B) oligos, prior to R848 (0.125 ^g/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM are shown. [0257] Figure 61. RAW-ELAM stably cells expressing an ELAM-luciferase reporter were pre-treated ~60 min with 5 ^M (Fig 67. A) or 1 ^M (Fig 67. B) oligos, prior to R848 (0.125ug/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The ELAM-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM are shown. [0258] Figure 62. HEK-TLR8 cells expressing an NF-KB-luciferase reporter were pre- treated ~60 min with 1 ^M (Fig 62. A and B) or 200 nM (Fig 28. C and D) concentration of indicated oligos, prior to R848 (1 ^g/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-KB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with multiple comparisons R848 condition are shown. All internucleotide linkages are phosphorothioate. 1004921453 [0259] Figure 63. HEK-TLR8 cells expressing an NF-KB-luciferase reporter were pre- treated ~60 min with 5 ^M (Fig 63. A) or 1 ^M (Fig 63. B) concentration of indicated oligos, prior to R848 (1 ^g/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate except for GAG-v1 in (Fig 63. B). The NF-KB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with multiple comparisons R848 condition are shown. All internucleotide linkages are phosphorothioate. [0260] Figure 64. HEK-TLR8 cells expressing an NF-KB-luciferase reporter were pre- treated ~60 min with 5 ^M concentration of indicated oligos, prior to R848 (1 ^g/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-KB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co- stimulation. SEM and One-way ANOVA with multiple comparisons R848 condition are shown. All internucleotide linkages are phosphorothioate. [0261] Figure 65. Splenocytes from WT mice and mice expressing a functional human TLR8 receptor and a non-functional TLR7 (B-hTLR8/hTLR7) were pre-treated, or not, with 5 ^M of oligo 38-2 (mG*dC*dC) for 1 h before addition of 1 ^g/mL R848 overnight. TNF levels were measured in the supernatant by ELISA and are expressed as a fold increase relative to R848 alone. n = 3 mice ± SEM with one-way ANOVA shown. [0262] Figure 66. Healthy skin punch biopsies (3 mm x 3mm) inserted into Transwell filters with the epidermis facing upwards at the air-liquid interface and the dermis suspended in the culture medium were pre-treated, or not, with 5 ^M of oligo 38-2 (mG*dC*dC) for 30 min before addition 600 nM Motolimod for 24 h. IL-8 levels were measured in the supernatant by ELISA and are reported as a fold increase relative to Motolimod alone. Data show 3 independent punch biopsies from 1 human donor ± SD. [0263] Figure 67. WT 129X1/SvJ mice were injected i.v. with LNPs containing FLuc mRNA alone or FLuc mRNA and GGC-v1. A, B, Bioluminescence imaging measuring luciferase expression at 6 h (A), and 24 h (B) post-injection. C, Luciferase activity in liver homogenates at 24 h post-injection. n=5 mice/treated group and 3 naïve mice ± SEM with one-way ANOVA shown. Data are from 1 experiment. 1004921453 [0264] Figure 68. WT 129X1/SvJ mice were injected i.v. with LNPs containing FLuc mRNA alone or FLuc mRNA and GGC-v1. A, IFN- ^, B, IL-6, C, IFN- ^, D, RANTES levels were measured in the serum by (A) ELISA or (B-D) Bio-Plex. n=5 mice/treated group and 3 naïve mice ± SEM with one-way ANOVA shown. Data are from 1 experiment. [0265] Figure 69. HEK-TLR7 (A) and HEK-TLR8 (B) cells expressing an NF-KB- luciferase reporter were pre-treated ~60 min with 1 or 5 ^M concentration of indicated oligos, prior to R848 (1 ^g/ml) stimulation overnight. Data shown are averaged from 2 independent experiments in biological triplicate. The NF-KB-luciferase values are reported to the R848 condition after background correction to NT control. All trimer conditions are with R848 co-stimulation. SEM and One-way ANOVA with multiple comparisons R848 condition are shown. Detailed description of the embodiments [0266] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention. Definitions [0267] For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa. [0268] As used herein, except where the context requires otherwise, the term “comprise” and variations of the term, such as “comprising”, “comprises” and “comprised”, are not intended to exclude further additives, components, integers or steps. [0269] As used herein, the terms “treating”, “treat” or “treatment” include administering a therapeutically effective amount of a oligonucleotide(s) described herein sufficient to reduce or eliminate at least one symptom of a disease, disorder or condition. The term “treating” a subject includes delaying, slowing, stabilizing, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the disease or condition, the sign or symptom of the disease or 1004921453 condition, or the risk of (or susceptibility to) the disease or condition. The term “treating” refers to any indication of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; lessening severity of the disease; stabilization, diminishing of signs or symptoms or making the injury, pathology or condition more tolerable to the individual; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating. [0270] In particularly preferred embodiments, the methods of the present invention can be to prevent or reduce the severity, or inhibit or minimise progression, of a sign or symptom of a disease or condition as described herein. As such, the methods of the present invention have utility as treatments as well as prophylaxes. [0271] As used herein, the terms “preventing”, “prevent” or “prevention” include administering a therapeutically effective amount of a oligonucleotide(s) described herein sufficient to stop or hinder the development of at least one symptom of a disease, disorder or condition. As used herein, “preventing” is intended to refer to at least the reduction of likelihood of the risk of (or susceptibility to) acquiring a disease or disorder (i.e., causing at least one of the clinical signs or symptoms of the disease not to develop in an individual that may be exposed to or predisposed to the disease but does not yet experience or display signs or symptoms of the disease). Biological and physiological parameters for identifying such patients are provided herein and are also well known by physicians. [0272] Herein, the term “subject”, “individual” or “patient” can be used interchangeably with each other. The term “subject” refers to an animal that is treatable by the oligonucleotide and/or method, respectively. In one example, the animal is a vertebrate. For example, the animal can be a mammal, avian, chordate, amphibian or reptile. Exemplary subjects include but are not limited to human, primate, livestock (e.g. sheep, cow, chicken, horse, donkey, pig), companion animals (e.g. dogs, cats), laboratory test animals (e.g. mice, rabbits, rats, guinea pigs, hamsters), captive wild animal (e.g. fox, deer). In one example, the mammal is a human. [0273] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, in some instances ±5%, in some instances ±1%, and in some instances ±0.1% 1004921453 from the specified value, as such variations are appropriate to perform the disclosed methods. [0274] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. [0275] The terms “reduce” or “inhibit” may relate generally to the ability of one or more oligonucleotides described herein to “decrease” a relevant physiological or cellular response, such as a symptom of a disease or condition described herein, as measured according to routine techniques in the diagnostic art. Relevant physiological or cellular responses (in vivo or in vitro) will be apparent to persons skilled in the art, and may include reductions in the symptoms or pathology of a disease. A “decrease” in a response may be statistically significant as compared to the response produced by no oligonucleotide or a control composition, and may include at least about a 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% decrease, including all integers in between. [0276] As used herein, the phrase “inhibits TLR7 activity” or variations thereof means that after administration of an oligonucleotide of the invention to a subject, the subject is not able to elicit a TLR7 based immune response or is only able to elicit a reduced or partial TLR7 based immune response, such as to a pathogen or a damaged endogenous nucleic acid. In an embodiment, the TLR7 based immune response is less than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, or 20% of the response in the absence of the oligonucleotide. In an embodiment, an oligonucleotide of the invention inhibits or reduces TLR7 activity by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%. 1004921453 [0277] As used herein, the phrase “inhibits TLR8 activity” or variations thereof means that after administration of an oligonucleotide of the invention to a subject, the subject is not able to elicit a TLR8 based immune response or is only able to elicit a reduced or partial TLR8 based immune response, such as to a pathogen or a damaged endogenous nucleic acid. In an embodiment, the TLR8 based immune response is less than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, or 20% of the response in the absence of the oligonucleotide. In an embodiment, an oligonucleotide of the invention inhibits or reduces TLR8 activity by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%. [0278] As used herein the phrase “does not substantially reduce translation of the therapeutic RNA” or variations thereof means that the level of translation of the therapeutic RNA in a subject is comparable in the presence or absence of an oligonucleotide of the invention. The level of translation of the therapeutic RNA in the presence of an oligonucleotide of the invention is about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, or 80% of the level of translation of the therapeutic RNA in the absence of the oligonucleotide of the invention. The level of translation of the therapeutic RNA in the absence of an oligonucleotide of the invention may be referred to as a reference level of translation of the therapeutic RNA. The skilled person will be familiar with methods for obtaining a reference level of oligonucleotide translation. For example, the method may include obtaining data from multiple individuals to develop an appropriate reference data set. Alternatively, a reference level may be generated from the same individual, but at a different time-points for example before administration of the therapeutic RNA, after administration of the therapeutic RNA, before administration of the oligonucleotide of the invention, after administration of the oligonucleotide of the invention, or a combination thereof. [0279] The term “potentiate” refers to an increase in a functional property relative to a control condition. The term “potentiate” may relate generally to the ability of one or more oligonucleotides described herein to “increase” the effectiveness or potency of an existing immune response in a subject. This increase in effectiveness and potency may be achieved, for example, by overcoming mechanisms that suppress the endogenous host immune response or by stimulating mechanisms that enhance the endogenous host immune response. 1004921453 [0280] As used herein, the phrase “increases or potentiates TLR8 activity” or variations thereof means that after administration of an oligonucleotide of the invention to a subject, the subject is only able to elicit a TLR8 based immune response or is able to elicit an increased or elevated TLR8 based immune response, such as to a pathogen, a damaged endogenous nucleic acid or an exogenous TLR8 ligand. Potentiation of TLR8 activity may be greater than about 100%, e.g. about 2 fold, about 3 fold, about 4 fold, about 5 fold, about 6 fold, about 7 fold, about 8 fold, about 9 fold, about 10 fold, about 11 fold, about 12 fold, about 13 fold, about 14 fold, about 15 fold, about 20 fold or about 50 fold. Preferably, the level of TLR8 potentiation is between about 2 fold and 50 fold, between about 2 fold and 20 fold, and/or between about 5 fold and 20 fold greater. [0281] As used herein the terms “disease”, “disorder” or “condition” relate to any unhealthy or abnormal state. [0282] The term “disease, disorder or condition in a subject responsive to TLR7 inhibition” includes diseases, conditions, and disorders in which the inhibition of TLR7 provides a therapeutic benefit. This includes diseases, disorders and conditions associated with increased TLR7 signalling. This also includes diseases, disorders and conditions wherein TLR7 signalling exacerbates an aberrant autoimmune response. Diseases, disorders and conditions responsive to TLR7 inhibition include inflammation- related diseases, allergic diseases, infections, cancers and auto-immune diseases. [0283] The term “disease, disorder or condition in a subject responsive to TLR8 inhibition” includes diseases, conditions, and disorders in which the inhibition of TLR8 provides a therapeutic benefit. This includes diseases, disorders and conditions associated with increased TLR8 signalling. This also includes diseases, disorders and conditions wherein TLR8 signalling exacerbates an aberrant autoimmune response. Diseases, disorders and conditions responsive to TLR8 inhibition include inflammation- related diseases, allergic diseases, infections, cancers and auto-immune diseases. [0284] The term “disease, disorder or condition in a subject responsive to increased TLR8 signalling” includes diseases, conditions, and disorders in which the activation of TLR8 provides a therapeutic benefit, such as cancer, chronic viral (eg HBV) and bacterial infection. 1004921453 [0285] The term “TLR8 agonist” refers to an agent that is capable of causing a signalling response through a TLR8 signalling pathway, either as a direct ligand or indirectly through generation of endogenous or exogenous ligand. Such natural or synthetic TLR8 agonists can be used as alternative or additional adjuvants. For example the TLR8 agonist capable of causing a signalling response through TLR8 is a single stranded RNA (ssRNA), an imidazoquinoline molecule with anti-viral activity, for example resiquimod (R848). Other TLR-8 agonists which can be used include those described in WO 2004/071459 and WO2021/232099. [0286] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0287] The terms “therapeutically effective amount” and “effective amount” describe a quantity of a specified agent, such as an oligonucleotide of the invention, sufficient to achieve a desired effect in a subject or cell being treated or contacted with that agent. For example, this can be the amount of a composition comprising one or more agents that inhibit the activity of one or more nucleic acid sensors (e.g., TLR7 or TLR8) described herein, necessary to reduce, alleviate and/or prevent a disease, disorder or condition. In some embodiments, a “therapeutically effective amount” is sufficient to reduce or eliminate a symptom of a disease, disorder or condition. In other embodiments, a “therapeutically effective amount” or “effective amount” is an amount sufficient to achieve a desired biological effect, for example, an amount that is effective to decrease or prevent a senescence-associated disease, disorder or condition or inhibit or prevent senescence in a cell. [0288] Ideally, a therapeutically effective amount of an agent is an amount sufficient to induce the desired result without causing a substantial cytotoxic effect in the subject. The effective amount of an agent useful for reducing, alleviating and/or preventing a disease, disorder or condition will be dependent on the subject being treated, the type and severity of any associated symptoms and the manner of administration of the therapeutic composition. 1004921453 [0289] A sub-therapeutic dose is a dose that is unable to achieve the therapeutic goal. That goal may be for example, reducing inflammation, minimising an allergic response, a reduction in infection, a reduction in tumour size, a reduction in increase or decrease of cancer biomarker expression, stasis of tumour growth, or a reduction, alleviation or abrogation of autoimmune disease symptoms.. Preferably, a sub-therapeutic dose is one which does not cause significant adverse side effects in the subject. [0290] As used herein the term “alkyl” refers to a single bond chain of hydrocarbons ranging, in some embodiments, from 1-20 carbon atoms, ie 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 atoms, and any range therein. The terms "C1-C2 alkyl", "C1-C3 alkyl" and "C1-C6 alkyl" refer to an alkyl group, as defined herein, containing at least 1, and at most 2, 4 or 6 carbon atoms respectively, or any range in between (eg alkyl groups containing 2-5 carbon atoms are also within the range of C1- C6. Examples of alkyl as used herein include, but are not limited to, are methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, 2,2-dimethylbutyl. Preferably, alkyl is C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl. Preferably, alkyl is C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl. [0291] As used herein the term “alkenyl” refers to a straight-chain or branched-chain hydrocarbyl, which has one or more double bonds and, unless otherwise specified, contains from about 2 to about 20 carbon atoms, and ranging in some embodiments from about 2 to about 10 carbon atoms, and ranging in some embodiments from about 2 to about 8 carbon atoms, and ranging in some embodiments from about 2 to about 6 carbon atoms. Examples of alkenyl radicals include vinyl, allyl, 1,4-butadienyl, isopropenyl, and the like. Preferably, alkenyl is C2-C20 alkenyl, C2-C10 alkenyl, C2-C8 alkenyl, C2-C6 alkenyl. Preferably, alkenyl is C2 alkenyl, C3 alkenyl, C4 alkenyl, C5 alkenyl, C6 alkenyl. [0292] As used herein, the term “alkynyl” refers to a straight-chain or branched- chain hydrocarbyl, which has one or more triple bonds and, unless otherwise specified, contains from about 2 to about 20 carbon atoms, and ranging in some embodiments from about 2 to about 10 carbon atoms, and ranging in some embodiments from about 2 to about 8 carbon atoms, and ranging in some embodiments from about 2 to about 6 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl, butynyl, and the 1004921453 like. Preferably, alkenyl is C2-C20 alkynyl, C2-C10 alkynyl, C2-C8 alkynyl, C2-C6 alkynyl. Preferably, alkynyl is C2 alkynyl, C3 alkynyl, C4 alkynyl, C5 alkynyl, C6 alkynyl. [0293] As used herein, the term “amino” or “amine” refers to the group -NH ² . [0294] As used herein, the term “hydroxy” or “hydroxyl” refers to the group –OH. [0295] As used herein, the term “oxo” refers to an oxygen substituent doble bonded to the attached carbon. [0296] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) and the term "halo" refers to the halogen radicals fluoro (-F), chloro (- Cl), bromo (-Br), and iodo (-I). Preferably, ‘halo’ is fluoro, chloro or bromo. [0297] The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, ie, a compound that can be isolated, characterized and tested for biological activity. [0298] The term “substituted hydrocarbyl”, “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, refers to any of the above referenced hydrocarbyl groups, including “alkyl”, “alkenyl”, “alkynyl”, further bearing one or more substituents selected from hydroxyl, hydrocarbyloxy, substituted hydrocarbyloxy, alkylthio, substituted alkylthio, arylthio, substituted arylthio, amino, alkylamino, substituted alkylamino, carboxy, -C(S)SR, -C(O)SR, -C(S)NR2, -OR, where each R is independently hydrogen, alkyl or substituted alkyl, nitro, cyano, halo, -SO3M or -OSO3M, where M is H, Na, K, Zn, Ca, or meglumine, guanidinyl, substituted guanidinyl, hydrocarbyl, substituted hydrocarbyl, hydrocarbylcarbonyl, substituted hydrocarbylcarbonyl, hydrocarbyloxycarbonyl, substituted hydrocarbyloxycarbonyl, hydrocarbylcarbonyloxy, substituted hydrocarbylcarbonyloxy, acyl, acyloxy, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, heteroaryl-carbonyl, substituted heteroarylcarbonyl, carbamoyl, mono-alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, a carbamate group, a dithiocarbamate group, aroyl, substituted aroyl, organosulfonyl, substituted organosulfonyl, organo-sulfinyl, substituted alkylsulfinyl, alkylsulfonylamino, substituted alkylsulfonylamino, arylsulfonylamino, substituted arylsulfonylamino, a sulfonamide group, sulfuryl, and the like, including two or more of the above-described groups 1004921453 attached to the hydrocarbyl moiety by such linker/spacer moieties as -O-, -S-, -NR-, where R is hydrogen, alkyl or substituted alkyl, -C(O)-, -C(S)-, C(=NR')-, -C(=CR'2)-, where R' is alkyl or substituted alkyl, -O-C(O)-, -O-C(O)-O-, -O-C(O)-NR- (or -NR-C(O)- O-), -NR-C(O)-, -NR-C(O)-NR-, -S-C(O)-, -S-C(O)-O-, -S-C(O)-NR-, -O-S(O)2-, -O- S(O)2-O-, -O-S(O)2-NR-, -O-S(O)-, -O-S(O)-O-, -O-S(O)-NR-, -O-NR-C(O)-, -O-NR- C(O)-O-, -O-NR-C(O)-NR-, -NR-O-C(O)-, -NR-O-C(O)-O-, -NR-O-C(O)-NR-, -O-NR- C(S)-, -O-NR-C(S)-O-, -O-NR-C(S)-NR-, -NR-O-C(S)-, -NR-O-C(S)-O-, -NR-O-C(S)- NR-, -O-C(S)-, -O-C(S)-O-, -O-C(S)-NR- (or -NR-C(S)-O-), NR-C(S)-, -NR-C(S)-NR-, - S-S(O)2-, -S-S(O)2-O-, -S-S(O)2-NR-, -NR-O-S(O)-, -NR-O-S(O)-O-, -NR-O-S(O)-NR-, - NR-O-S(O)2, -NR-O-S(O)2-O-, -NR-O-S(O)2-NR-, -O-NR-S(O)-, -O-NR-S(O)-O-, -O-NR- S(O)-NR-, -O-NR-S(O)2-O-, -O-NR-S(O)2-NR-, -O-NR-S(O)-, -O-P(O)R2, -S-P(O)R2, or - NR-P(O)R2, where each R is independently hydrogen, alkyl or substituted alkyl, and the like. Preferably, the one or more substituents is selected from the group consisting of: hydroxyl, carboxyl, amino, thio, halo, and -OR, wherein R is alkyl, alkenyl or alkynyl. Even more preferably, “substituted alkyl” is “substituted C1-C6 alkyl”, “substituted alkenyl” is “substituted C2-C20 alkenyl”, and “substituted alkynyl” is “substituted C2-C20 alkynyl”. [0299] As used herein, hydrophobic lipid refers to an amphiphilic molecule that comprises a polar head group and a hydrophobic tail. The hydrophobic tail may comprise a hydrocarbon chain selected from the group consisting of: C1-C20 alkyl, C2- C20 alkenyl, C2-C20 alkynyl, substituted C1-C20 alkyl, substituted C2-C20 alkenyl, and substituted C2-C20 alkynyl. Hydrophobic lipids include, but are not limited to, phospholipids, cholesterol, cholesterol derivatives, and tocopherol. [0300] As used herein, polyethylene glycol (PEG) refers to a polyether compound. Preferably, PEG comprises H(OCH2CH2)nOH wherein n is 1 to 20, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19 or 20. Preferably, n is 1 to 6. [0301] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The oligonucleotides of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. The term “stereoisomers” refers to oligonucleotides which have identical chemical constitution, but differ with regard to the arrangement of the atoms or 1004921453 groups in space. As used herein, the term “stereoisomer” includes but is not limited to diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures. Oligonucleotides [0302] In the context of this invention, the term “oligonucleotide” refers to an oligomer or polymer of ribonucleic acid (RNA) and/or deoxyribonucleic acid (DNA), wherein the polymer or oligomer of nucleotide monomers contain any combination of nucleotides (referred to in the art and herein as simply as “base”), modified nucleotides, sugars, modified sugars, phosphate bridges, or modified phosphorus atom bridges (also referred to herein as “internucleotide linkage”). [0303] As used herein, a “target” such as “target polynucleotide” refers to a molecule upon which an oligonucleotide of the invention directly or indirectly exerts its effects. Typically, the oligonucleotide of the invention or portion thereof and the target, interact or bind under physiological conditions thereby modulating the function of the target. In the first aspect, the target is TLR7. In the second and third aspects the target is TLR8. [0304] As used herein, the term “nucleotide” includes all naturally occurring nucleotides, including all forms of nucleotide bases found in nature. Base rings most commonly found in naturally occurring nucleotides are purine and pyrimidine rings. Naturally occurring purine rings include, for example, adenine, guanine, and N ⁶ - methyladenine. Naturally occurring pyrimidine rings include, for example, cytosine, thymine, 5-methylcytosine, pseudouracil. Naturally occurring nucleotides for example include, but are not limited to, ribo, 2′-O-methyl or 2′-deoxyribose derivatives of adenosine, guanosine, thymidine, uridine, inosine, 7-methylguanosine or pseudouridine. [0305] As used herein, the term “modification group” or “modified” refers to any chemical moiety that may be attached to the oligonucleotide at locations, which include, but are not limited to, the sugar, nucleoside base, triphosphate bridge, and/or internucleotide phosphate. [0306] As used herein, the terms “nucleotide analogs”, “modified nucleotides”, or “nucleotide derivatives” include synthetic nucleotides as described herein. Nucleotide derivatives also include nucleotides having modified base and/or sugar moieties, with or without protecting groups and include, for example, 2′-deoxy-2′-fluorouridine, 5- 1004921453 fluorouridine and the like. Other nucleotide derivatives that may be utilized with the present invention include, for example, LNA nucleotides, halogen-substituted purines (eg 6-fluoropurine), halogen-substiuted pyrimidines, N ⁶ -ethyladenine, N ⁴ -(alkyl)- cytosines, 5-ethylcytosine, and the like. [0307] Typically, an oligonucleotide of the invention will be synthesized in vitro. Bases [0308] RNA nucleotides (rX) comprise 2′-OH. DNA nucleotides (dX) comprise 2′-H. [0309] Modified nucleotides may include nucleotides having modified base and/or sugar moieties. [0310] As used herein, “mX” refers to a nucleotide comprising a 2′- and/or 3′- methoxy (2′-OMe and/or 3′-OMe) modification. mX nucleotides at terminal positions of the sequence may be 2′-OMe or 3′-OMe, preferably 2′-OMe. mX nucleotides at non-terminal positions of the sequence may be 2′-OMe. In a preferred embodiment, mX is 2′-OMe. [0311] As used herein, “moX” refers to a nucleotide comprising a 2′- and/or 3′- methoxyethoxy (2′-O-CH2CH2OCH3 also known as 2′-O-(2-methoxyethyl) or 2′-MOE and/or (3′-O-CH2CH2OCH3 also known as 3′-O-(2-methoxyethyl) or 3′-MOE) modification. moX nucleotides at terminal positions of the sequence may be 2′-OMe or 3′-MOE, preferably 2′-MOE. moX nucleotides at non-terminal positions of the sequence may be 2′-MOE. In a preferred embodiment, moX is 2′-MOE. [0312] As used herein, “fX” refers to a nucleotide comprising a 2′- and/or 3′-fluoro modification. fX nucleotides at terminal positions of the sequence may be 2′-fluor or 3′- fluor, preferably 2′-fluor. fX nucleotides at non-terminal positions of the sequence may be 2′-fluor. In a preferred embodiment, fX is 2′-fluor. [0313] As used herein, “LX” refers to a nucleotide comprising a Locked Nucleic Acid (LNA) modification. LNAs are nucleic acids in which the 2′-hydroxyl group is linked to the 3′- or 4′- carbon atom of the sugar ring, thereby forming a bicyclic sugar moiety. In one embodiment, the linkage is a methylene (-CH2-)n group bridging the 2′-oxygen atom and the 4′-carbon atom, wherein n is 1 or 2, preferably 1. 1004921453 [0314] As used herein, “morpholino-X” refers to a nucleotide comprising a 1-Oxa-4- azacyclohexane ribose sugar ring (also known as a morpholine ring). Morpholine rings bear methylene groups that are bound to modified phosphates in which the anionic oxygen is replaced by a nonionic dimethylamino group. The substituted phosphate is bound through a phosphorus‐nitrogen bond to the nitrogen atom of another morpholine ring. One standard DNA or RNA nucleobase (adenine, guanine, cytosine, thymine or uracil) is bound to each morpholine ring. [0315] As used herein, “modified nucleotide”, which includes “modified dX”, “modified rX”, “modified mx”, “modified moX”, “modified fX”, ““modified LX”, refers to a nucleotide including at least one modification or substitiution. The modification or substitution may be of rX or dX, or may be an additional modification or substitution of an already modified nucleotide such as mX, moX, fX or LX. Modified nucleotides may include modifications or substitutions at positions of the base and/or sugar. For example, modified dX refers to DNA base comprising at least one modification or substitution at one or more positions of the base and/or sugar. Modified rX refers to RNA base comprising at least one modification or substitution at one or more positions of the base and/or sugar. Modified mX refers to a nucleotide including a 2′-OMe and/or 3′-OMe modification, preferably a 2′-OMe modification, and at least one additional modification or substitiution at one or more positions of the base and/or sugar. Modified moX refers to a nucleotide including a 2′-MOE and/or 3′-MOE modification, preferably a 2′-MOE modification, and at least one additional modification or substitiution at one or more positions of the base and/or sugar. Modified fX refers to a nucleotide including a 2′-fluor and/or 3′- fluor modification, preferably a 2′- fluor modification, and at least one additional modification or substitiution at one or more positions of the base and/or sugar. Modified LX refers to a nucleotide including an LNA modification, and at least one additional modification or substitiution at one or more positions of the base and/or sugar. [0316] Preferably, the modification or substitution is selected from the group consisting of: pseudouridine, 3′-deoxy, hydroxyl, des-amino, amino, thio, halo, oxo, aza, deaza, polyethylene glycol, alkyl, alkenyl, alkynyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, and combinations thereof. 1004921453 [0317] In one embodiment, the modification or substitution is at one or more positions of the sugar. The modification or substitution of the sugar may be selected from the group consisting of: 3′-deoxy, hydroxyl, amino, thio, halo, polyethylene glycol, alkyl, alkenyl, alkynyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, and combinations thereof. [0318] In one embodiment, the modification or substitution is at one or more positions of the base. The modification or substitution of the base may be selected from the group consisting of: pseudouridine, hydroxyl, des-amino, amino, thio, halo, oxo, aza, deaza, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, substituted C1-C6 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl and combinations thereof. [0319] In one embodiment, the modification or substitution is at one or more positions of the base and one or more positions of the sugar. [0320] Modified nucleotides include, for example, 2′-OMe-2,6-Diaminopurine (herein referred to as mG1), 2′-OMe-I (2′-O-methylinosine, herein interchangeably referred to as mI or mG2), 2′-OMe-5-Me-U (2′-O-methyl-5-methyluridine, herein referred to as mU1), 2′-OMe-5-Br-U (2′-O-methyl-5-bromouridine herein referred to as mU2), N3-Me-U (3- methyluridine herein referred to as mU3), 2′-OMe-5-Me-C (2′-O-methyl-5- methylcytidine, herein referred to as mC1), N7-methylated guanosine (herein referred to as ^m7 G), 5-methyl substituted deoxycytidine (herein referred to as 5-Me-dC), 5-bromo substituted deoxycytidine (herein referred to as 5-Br-dC), 5-hydroxymethyl substituted deoxycytidine (herein referred to as 5-CH2OH-dC), 2′-deoxy-3′-deoxy cytidine (herein referred to as ddC), 5-propynyl substituted deoxycytidine (herein referred to as pdC), 3- methyl deoxycytidine (herein referred to as N3-Me-dC), 5-iodo deoxycytidine (herein referred to as 5-I-dC), deoxyinosine (herein referred to as dI), 8-bromodeoxyguanosine (herein referred to as 8-Br-dG), 7-deazadeoxyguanosine (herein referred to as 7-deaza- dG), 8-bromodeoxyadenosine (herein referred to as 8-Br-dA), 8-oxodeoxyadenosine (herein referred to as 8-oxo-dA), O6-methyldeoxyguanosine (herein referred to as O6- Me-dG), 8-aminodeoxyguanosine (herein referred to as 8-NH2-dG), 2′-amino-2′- deoxyuridine (herein referred to as 2′-NH2-U), 2′-amino-2′-deoxycytidine (herein referred to as 2′-NH2-C), aracytidine (herein referred to as ara-C). [0321] As used herein, modified dG includes, but is not limited to, 2,6-diaminopurine and inosine. Modified mG includes but is not limited to: mG1, mI, and ^m7 G, wherein 1004921453 mG1 is 2′-OMe-2,6-Diaminopurine, mI or mG2 is 2′-OMe-I (2′-O-methylinosine), and ^m7 G is 3′-OMe-N7-methylated guanosine. Preferably, modified mG includes mG1 and mI. [0322] Oligonucleotides of the invention include at least one 2′-OMe or 3′-OMe- modified nucleotide, preferably 2′-OMe-modified nucleotide. [0323] Unless stated to the contrary, reference to an A, T, G, U or C can either mean a naturally occurring base or a modified version thereof. Backbones [0324] Oligonucleotides of the present disclosure include those having modified backbones or non-natural internucleoside linkages. [0325] As used herein, the term “internucleotide linkage” refers to the bond or bonds that connect two nucleotides of an oligonucleotide or nucleic acid and may be a natural phosphodiester linkage or modified linkage. Internucleotide linkages include but are not limited to: biphosphate, triphosphate, phosphorothioate, phosphodiester, thiophosphoramidate, phosphorodiamidate, methylphosphonate, and guanidinopropyl phosphoramidate. In one embodiment, each internucleotide linkage is independently selected from the group consisting of: biphosphate, triphosphate, phosphorothioate, and phosphodiester. Preferably, each internucleotide linkage is independently selected from the group consisting of: triphosphate, phosphorothioate, and phosphodiester. More preferably, each internucleotide linkage is independently selected from phosphorothioate, and phosphodiester. Even more preferably, each internucleotide linkage is phosphorothioate. [0326] Each internucleotide linkage may be the same or different. In a preferred embodiment, each internucleotide linkage is the same, preferably phosphorothioate. [0327] Internucleotide linkages can be introduced at the 2′-, 3′-, or 5′- end of a nucleotide. Each internucleotide linkage may be selected from the group consisting of: 3′-5′-, 5′-5′-, 5′-3′-, 3′-3′-, 3′-2′-, 2′-3′-, 2′-2′-, 2′-5′-, 5′-2′- linkage. Preferably each internucletodie linkage is selected from the group consisting of: 3′-5′- and 5′-5′- linkage. For example, a 3′-5′-phosphorothioate internucleotide linkage may be formed by bonding the 3′- phosphate of a first nucleotide and the 5′- hydroxyl group of a second 1004921453 nucleotide, wherein a non-bridging oxygen is substituted with a sulfur. A 3′-5′- phosphodiester internucleotide linkage may be formed by bonding the 3′- hydroxyl group of a first nucleotide and the 5′- phosphate of a second nucleotide. A 5′-5′- ,triphosphate internucloetide linkage may be formed by bonding the 5′- phosphate of a first nucleotide and the 3′- phosphate of a second nucleotide via an additional phosphate group. In one embodiment, the sequence includes a 5′-5′- linkage. Preferably, the 5′-5′- linkage connects nucleotides at a first and second position of the sequence. In one embodiment, the sequence includes a 5′-5′- linkage and a 3′-5′- linkage. Preferably, the 5′-5′- linkage connects nucleotides at a first and second position of the sequence, and the 3′-5′- linkage connects nucleotides at a second and third position of the sequence. In a preferred embodiment, each internucleotide linkage is a 3′-5′- linkage. [0328] In a particularly preferred embodiment, each internucleotide linkage is a 3′-5′- phosphorothioate linkage. [0329] Each internucleotide linkage may contain asymmetric or chiral centres and therefore exist in different stereoisomeric forms. Oligonucleotides of the invention may comprise a mixture of different oligonucleotide stereoisomers. A 3-mer oligonucleotide of the invention comprising phosphorothioate internucleotide linkages may comprise a mixture of up to 4 different oligonucleotide phosphorothioate stereoisomers, due to the chirality introduced by the two sulfur atoms in the PS internucleotide linkages. For example, 5′-[mX/modified mX]* ^y X ^A * ^z X ^B -3′ may comprise up to 4 different stereoisomers resulting from different phosphorothioate stereochemistry configurations at each internucleotide linkage, wherein * ^y and * ^z each represent a phosphorothioate internucleotide linkage, wherein * ^y and * ^z are each in the R configuration (RR), * ^y and * ^z are each in the S configuration (SS), * ^y is in the R configuration and * ^z is in the S configuration (RS), and * ^y is in the S configuration and * ^z is in the R configuration (SR). The oligonucleotides of the invention may comprise a single phosphorothioate stereoisomer, or a mixture of 2 to 4 different oligonucleotide phosphorothioate stereoisomers, preferably a 1:1:1:1 mixture of 4 different oligonucleotide phosphorothioate stereoisomers. The oligonucleotide may comprise additional chiral centres, for example on one or more ribose sugars, and therefore may comprise mixtures of, or single, stereoisomers at the additional chiral centres. Functionalised sequences 1004921453 [0330] In one embodiment, the sequence may be functionalised. Preferably, the functionalised sequence comprises a compound selected from the group consisting of: polyethylene glycol, alkyl, alkenyl, alkynyl, heterocycyl, arylalkyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heterocycyl, substituted arylalkyl, and hydrophobic lipid. Prefearbly, the compound is selected from the group consisting of: polyethylene glycol, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, heterocycyl, arylalkyl, branched C1-C20 alkyl, branched C2-C20 alkyenyl, branched C2-C20 alkynyl, substituted C1-C20 alkyl, substituted C2-C20 alkenyl, substituted C2-C20 alkynyl, substituted heterocycyl, substituted arylalkyl, and hydrophobic lipid. Prefearbly, the hydrophobic lipid is selected from cholesterol and tocopherol. Preferably, the compound is selected from the group consisting of: polyethylene glycol, cholesterol and tocopherol. [0331] In one embodiment, the compound is conjugated directly to the sequence. In another embodiment, the compound is conjugated to the sequence via a linker. The linker may be cleavable or non-cleavable. Preferably, the linker is a non-cleavable linker. [0332] Preferably, the compound is conjugated to a terminal nucleotide of the sequence, preferably the terminal 3′-nucleotide. Preferably, the compound is conjugated to the terminal 3′-nucleotide at the 3′-position. [0333] Functionalised sequences may comprise functionalised nucleotides selected from the group consisting of: dX-TEG, dX-Chol and dX-Toco, wherein dX-TEG is a DNA base with triethylene glycol covalently linked to the 3′-position via a monophosphate group, dX-Chol is a DNA base with an (N-cholesteryl-3-aminopropyl)-triethyleneglycol- glyceryl group covalently linked to the 3′-position via a monophosphate group, dX- Toco is a DNA base with a [(9-DL-α-tocopheryl)-triethyleneglycol-1-yl]-glyceryl group covalently linked to the 3′-position via a monophosphate group. Preferably, functionalised sequences may comprise functionalised nucleotides selected from the group consisting of: dC-TEG, dC-Chol, dC-Toco, wherein dC-TEG is deoxycytidine with an (N-cholesteryl-3-aminopropyl)-triethyleneglycol-glyceryl group covalently linked to the 3′-position via a monophosphate group, dC-Chol, is deoxycytidine with triethylene 1004921453 glycol covalently linked to the 3′-position via a monophosphate group, and dC-Toco is deoxycytidine with a [(9-DL-α-tocopheryl)-triethyleneglycol-1-yl]-glyceryl group covalently linked to the 3′-position via a monophosphate group. TLR7 inhibitory oligonucleotides [0334] In a first aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: [mX/modified mX]* ^y X ^A * ^z X ^B wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage, wherein at least one of * ^y and * ^z is not phosphorodiamidate; X ^A and X ^B are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, morpholino-X, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX and modified morpholino-X; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification, morpholino-X is a nucleotide comprising a morpholine ring; and wherein when [mX/modified mX] is mX, at least one of X ^A and X ^B is not mX; wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0335] Preferably, both * ^y and * ^z are not phosphorodiamidate. [0336] Preferably, X ^A is independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX, modified moX, modified LX, 1004921453 modified fX; and X ^B is independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, morpholino-X, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX and modified morpholino-X. [0337] In an embodiment of the first aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: [mX/modified mX]* ^y X ^A * ^z X ^B wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^A and X ^B are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX, modified moX, modified LX, and modified fX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification; and wherein when [mX/modified mX] is mX, at least one of X ^A and X ^B is not mX; wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0338] Preferably, at least one of * ^y and * ^z is not phosphorodiamidate. More preferably, both * ^y and * ^z are not phosphorodiamidate. [0339] Any oligonucleotide of the first aspect inhibits TLR7 activity, preferably human TLR7 activity. In one preferred embodiment, an oligonucleotide of the first aspect does not potentiate TLR8 activity, preferably human TLR8 activity. In a particularly preferred embodiment, an oligonucleotide of the first aspect further inhibits TLR8 activity, preferably human TLR8 activity. In an alternative preferred embodiment, an 1004921453 oligonucleotide of the first aspect potentiates TLR8 activity, preferably human TLR8 activity. [0340] Each internucleotide linkage may be selected from the group consisting of: 3′- 5′-, 5′-5′-, 5′-3′-, 3′-3′-, 3′-2′-, 2′-3′-, 2′-2′-, 2′-5′-, and 5′-2′- linkage. Preferably, each internucleotide linkage may be selected from: 3′-5′- and 5′-5′- linkage. Preferably, each internucletodie linkage is a 3′-5′- linkage. [0341] In one preferred embodiment of the first aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: 5′-[mX/modified mX]* ^y X ^A * ^z X ^B -3′ wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage, wherein at least one of * ^y and * ^z is not phosphorodiamidate; X ^A and X ^B are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, morpholino-X, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX and modified morpholino-X; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification, morpholino-X is a nucleotide comprising a morpholine ring; and wherein when [mX/modified mX] is mX, at least one of X ^A and X ^B is not mX; wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0342] In a particularly preferred embodiment, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: 1004921453 5′-[mX/modified mX]* ^y X ^A * ^z X ^B -3′ wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^A and X ^B are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX, modified moX, modified LX, and modified fX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification; and wherein when [mX/modified mX] is mX, at least one of X ^A and X ^B is not mX; wherein the sequence is optionally functionalised. [0343] Preferably, each internucleotide linkage is a 3′-5′ linkage. [0344] Preferably, each internucleotide linkage is independently selected from the group consisting of: biphosphate, triphosphate, phosphorothioate, and phosphodiester. Each internucleotide linkage may be the same or different. In a preferred embodiment, each internucleotide linkage is independently selected from phosphorothioate and phosphodiester. Most preferably, each internucleotide linkage is phosphorothioate. [0345] In a particularly preferred embodiment, each internucleotide linkage is a 3′-5′- phosphorothioate linkage. [0346] In one embodiment, the oligonucleotide comprises a mixture of different oligonucleotide stereoisomers, preferably a mixture of different oligonucleotide phosphorothioate stereoisomers. In another embodiment, the oligonucleotide of the first aspect comprises a single phosphorothioate stereoisomer, preferably wherein * ^y is in the S configuration. [0347] Preferably, mX is a nucleotide comprising a 2′-OMe modification. [0348] Preferably, moX, is a nucleotide comprising a 2′-MOE modification. 1004921453 [0349] Preferably, fX, is a nucleotide comprising a 2′-fluor modification. [0350] Modified dX, modified rX and modified morpholino comprise at least one modification or substitution at positions of the base and/or sugar. Modified mX, modified moX, modified LX and modified fX comprise at least one additional modification or substitution at additional positions of the base and/or sugar. Preferably, the modification or substitution is selected from the group consisting of: pseudouridine, 3′-deoxy, hydroxyl, des-amino, amino, thio, halo, oxo, aza, deaza, polyethylene glycol, alkyl, alkenyl, alkynyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl and combinations thereof. [0351] Exemplary modified mX includes but is not limited to: mG1, mI, mU1, mU2, mU3, mC1, and ^m7 G, wherein mG1 is 2′-OMe-2,6-Diaminopurine, mI is 2′-OMe-I (2′-O- methylinosine), mU1 is 2′-OMe-5-Me-U (2′-O-methyl-5-methyluridine), mU2 is 2′-OMe-5- Br-U (2′-O-methyl-5-bromouridine), mU3 is N3-Me-U (3-methyluridine), mC1 is 2′-OMe- 5-Me-C (2′-O-methyl-5-methylcytidine), and ^m7 G is 3′-OMe-N7-methylated guanosine. Preferably, modified mX is selected from the group consisting of: mG1, mI, mU1, mU2 and mC1. Most preferably, modified mX is mC1. [0352] Exemplary modified dX includes but is not limited to: 5-Me-dC, 5-Br-dC, 5- CH2OH-dC, ddC, pdC, PSU, N3-Me-dC, 5-I-dC, dI, 8-Br-dG, 7-deaza-dG, 8-Br-dA, 8- oxo-dA, O6-Me-dG, 8-NH2-dG, wherein 5-Me-dC is 5-methyl substituted deoxycytidine, 5-Br-dC is 5-bromo substituted deoxycytidine5-CH2OH-dC is 5-hydroxymethyl substituted deoxycytidine, ddC is 2′-deoxy-3′-deoxy cytidine, pdC is 5-propynyl substituted deoxycytidine, PSU is pseudo uridine, N3-Me-dC is 3-methyl deoxycytidine, 5-I-dC is 5-iodo deoxycytidine, dI is deoxyinosine, 8-Br-dG is 8-bromodeoxyguanosine, 7-deaza-dG is 7-deazadeoxyguanosine, 8-Br-dA is 8-bromodeoxyadenosine, 8-oxo-dA is 8-oxodeoxyadenosine, O6-Me-dG is O6-methyldeoxyguanosine, and 8-NH2-dG is 8- aminodeoxyguanosine. [0353] Exemplary modified rX includes but is not limited to PSU, 2′-NH2-rX, and ara- rX, wherein 2′-NH2-rX is a 2′-amino modified RNA base, and ara-rX is an arabinose modified RNA base. Exemplary 2′-NH2-rX includes but is not limited to 2′-NH2-U and 2′- NH2-C, wherein 2′-NH2-U is 2′-NH2-uridine, and 2′-NH2-C is 2′-NH2-cytidine. Exemplary ara-rX is ara-C (aracytidine). 1004921453 [0354] In one embodiment, [mX/modified mX] is selected from the group consisting of: mG, mI, mG1 and mU. Preferably, [mX/modified mX] is mG or mI. In one embodiment, [mX/modified mX] is modified mX. Preferably, modified mX is mI or mG1, preferably mI. Preferably, modified mX is not 2′-OMe-N1-Me-G (2′-O-methyl-N1- methylguanosine). In another embodiment, [mX/modified mX] is mX. Preferably, mX is mG or mU, preferably mG. [0355] In a preferred embodiment, [mX/modified mX] is [mG/modified mG]. Preferably, modified mG is not 2′-OMe-N1-Me-G (2′-O-methyl-N1-methylguanosine). Modified mG includes but is not limited to: mG1 and mI, wherein mG1 is 2′-OMe-2,6- Diaminopurine, and mI is 2′-OMe-I (2′-O-methylinosine). Preferably, [mG/modified mG] is [mG/mI]. In one embodiment, [mG/modified mG] is mG. In another embodiment, [mG/modified mG] is mI. [0356] In a preferred embodiment, X ^A and X ^B are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX and morpholino-X. In a particularly preferred embodiment, X ^A and X ^B are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, and modified dX. [0357] In one embodiment, X ^A is selected from the group consisting of: mX, dX, rX, LX, modified mX, modified dX, and modified rX. Preferably, X ^A is selected from the group consisting of: mX, dX, rX, modified mX, modified dX, and modified rX. Preferably, X ^A is selected from the group consisting of: mU, mU1, mU2, mU3, PSU, mG, mA, mC, dT, dG, dA, dC, rU, 2′-NH2-rU, 8-Br-dA, and 8-oxo-dA. In one embodiment, X ^A is selected from the group consisting of: mX, dX, rX, and modified mX. Preferably, X ^A is selected from the group consisting of: mU, mU1, mU2, PSU, mG, mA, mC, dT, dG, dA, dC, and rU. More preferably, X ^A is mU. [0358] In one embodiment, X ^B is selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX and morpholino-X. Preferably, X ^B is selected from the group consisting of: dA, dC, dG, dT, mC, mC1, mG, rC, moC, LC, , LA, LT, LG, fC, 5-Me-dC, 5-Br-dC, 5-CH2OH-dC, ddC, pdC, N3-Me-dC, 5-I-dC, 2′-NH2- C, ara-C, morpholino-C, N3-Me-mU, dI, 8-Br-dG, 7-deaza-dG, O6-Me-dG, and 8-NH2- dG. In one embodiment, X ^B is selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX and modified dX. Preferably, X ^B is selected from the group 1004921453 consisting of: dA, dC, dG, dT, mC, mC1, mG, rC, moC, LC, fC, 5-Me-dC, 5-Br-dC, 5- CH2OH-dC, ddC, and pdC. In one preferred embodiment, X ^B is selected from the group consisting of: mX, dX, LX, modified mX, modified dX and modified rX. Preferably, X ^B is selected from the group consisting of: LC, dC, 5-Me-dC, 5-Br-dC, mC, mC1, ara-C. In a particularly preferred embodiment, X ^B is selected from the group consisting of: LX, modified mX, modified dX and modified rX. Preferably, X ^B is selected from the group consisting of: LC, 5-Me-dC, 5-Br-dC, and mC1. In an even more preferred embodiment, X ^B is LX, preferably LC. [0359] In one embodiment, at least one of X ^A and X ^B is LX. In one embodiment, X ^A and X ^B are independently LX. In another embodiment, one of X ^A and X ^B is LX. Preferably, X ^B is LX. Preferably, X ^B is LX and X ^A is mX. [0360] In one embodiment, at least one of X ^A and X ^B is dX. In one embodiment, X ^A and X ^B are independently dX. In another embodiment, one of X ^A and X ^B is dX. Preferably, X ^B is dX. Preferably, X ^B is dX and X ^A is mX. More preferably, X ^B is dX and X ^A is mU. [0361] In one embodiment, at least one of X ^A and X ^B is rX. In one embodiment, X ^A and X ^B are independently rX. In another embodiment, one of X ^A and X ^B is rX. Preferably, X ^A is rX. Preferably, X ^B is mX or rX and X ^A is rX. More preferably, X ^B is mX and X ^A is rU; X ^A is rA and X ^B is rA; or X ^A is rU and X ^B is rC. Preferably, where at least one of X ^A and X ^B is rX, each internucleotide linkage is a 3′-5′- phosphorothioate linkage. [0362] In a particularly preferred embodiment, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: 5′-mG*mU*X ^B -3′ wherein: * each independently represent a 3′-5′- phosphorothioate linkage; X ^B is selected from the group consisting of: dX, rX, moX, LX, fX, morpholino-X, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX, and modified morpholino-X; 1004921453 wherein dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification, morpholino-X is a nucleotide comprising a morpholine ring; and wherein the sequence is optionally functionalised. [0363] In one embodiment, the sequence may be functionalised. Preferably, the functionalised sequence comprises a compound selected from the group consisting of: polyethylene glycol, alkyl, alkenyl, alkynyl, heterocycyl, arylalkyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heterocycyl, substituted arylalkyl, and hydrophobic lipid. Prefearbly, the hydrophobic lipid is selected from cholesterol and tocopherol. Preferably, the compound is selected from the group consisting of: polyethylene glycol, cholesterol and tocopherol. [0364] In one embodiment, the compound is conjugated directly to the sequence. In another embodiment, the compound is conjugated to the sequence via a linker. The linker may be cleavable or non-cleavable. Preferably, the linker is a non-cleavable linker. [0365] Preferably, the compound is conjugated to a terminal nucleotide of the sequence, preferably the terminal 3′- nucleotide. Preferably, the compound is conjugated to the terminal 3′-nucleotide at the 3′- position. [0366] Functionalised sequences may comprise functionalised nucleotides selected from the group consisting of: dX-TEG, dX-Chol and dX-Toco, wherein dX-TEG is a DNA base with triethylene glycol covalently linked to the 3′-position via a monophosphate group, dX-Chol is a DNA base with an (N-cholesteryl-3-aminopropyl)-triethyleneglycol- glyceryl group covalently linked to the 3′-position via a monophosphate group, dX-Toco is a DNA base with a [(9-DL-α-tocopheryl)-triethyleneglycol-1-yl]-glyceryl group covalently linked to the 3′-position via a monophosphate group. Preferably, functionalised sequences may comprise functionalised nucleotides selected from the group consisting of: dC-TEG, dC-Chol, dC-Toco, wherein dC-TEG is deoxycytidine with an (N-cholesteryl-3-aminopropyl)-triethyleneglycol-glyceryl group covalently linked to the 3′-position via a monophosphate group, dC-Chol, is deoxycytidine with triethylene 1004921453 glycol covalently linked to the 3′-position via a monophosphate group, and dC-Toco is deoxycytidine with a [(9-DL-α-tocopheryl)-triethyleneglycol-1-yl]-glyceryl group covalently linked to the 3′-position via a monophosphate group. [0367] Preferably, the oligonucleotide of the first aspect is selected from the group of oligonucleotides in Table 1. Table 1.3mer oligonucleotides that are inhibitors of TLR7 sensing. “m” indicates 2′- OMe base, * denotes the phosphorothioate backbone, “d” indicates DNA base, “r” indicates unmodified RNA base, “mo” indicates 2′-MOE, “L” indicates LNA, “f” indicates 2′-fluor. 1004921453 1004921453 [0368] In one embodiment, [mX/modified mX] is [mG/mI]; X ^A is mU; and X ^B is selected from the group consisting of: mX, dX, rX, moX, LX, fX, morpholino-X, modified mX, modified rX and modified dX, wherein the sequence is optionally functionalised. Preferably, X ^B is selected from the group consisting of: LX, mX, dX, modified mX, modified rX, and modified dX. More preferably, X ^B is selected from the group consisting of: LC, mC, ara-C, dC, mC1, and modified dC. Preferably, modified dC is selected from the group consisting of: 5-Me-dC, 5-Br-dC and 5-I-dC. Preferably, the sequence is selected from the group consisting of: mG*mU*LC, mI*mU*LC, mG*mU*mC1, 1004921453 mG*mU*5-Me-dC, mG*mU*5-Br-dC, mG*mU*dC, mG*mU*dC-TEG, mI*mU*mC, mG*mU*dC-Chol, mG*mU*dC-Toco, mG*mU*ara-C and mG*mU*5-I-dC. [0369] In another preferred embodiment, [mX/modified mX] is [mG/mI]; X ^A is mU; and X ^B is selected from the group consisting of: mX, dX, rX, LX, modified mX modified rX, and modified dX. Preferbaly, X ^B is selected from the group consisting of: LC, mC1, dC, mC, and modified dC. Preferably, modified dC is selected from the group consisting of: 5-Me-dC, 5-Br-dC and 5-I-dC. Preferably, the sequence is selected from the group consisting of: mG*mU*LC, mI*mU*LC, mG*mU*mC1, mG*mU*5-Me-dC, mG*mU*5-Br- dC and mG*mU*5-I-dC. [0370] In another preferred embodiment, [modified mX] is [mG/mI]; and X ^A and X ^B are rX. Preferably, the sequence is selected from the group consisting of: mG*rA*rA, mG*rU*rC, mG*rG*rA, mG*rU*rA, mG*rU*rU, mG*rA*rG, mG*rG*rC, mG*rA*rU, mG*rG*rG. More preferably, the sequence is selected from: mG*rA*rA, mG*rU*rC and mG*rG*rA. [0371] In another preferred embodiment, the oligonucleotide of the first aspect further inhibits TLR8 activity, preferably human TLR8 activity. Preferably, the oligonucleotide that further inhibits TLR8 activity comprises or consists of the sequence mI*mU*mC or mI*mA*dG. [0372] In one embodiment, the oligonucleotide consists of the sequence. [0373] In another embodiment, the oligonucleotide comprises the sequence. Preferably, the oligonucleotide comprising the sequence is no more than 20 bases in length, preferably 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, or 4 bases in length. Preferably, the sequence is at the terminal 5′- and/or 3′- end of the oligonucleotide, preferably the terminal 5′- end. In one preferred embodiment, the oligonucleotide comprises the sequence 5′-mG*mU*X ^B -3′, wherein X ^B is dX, preferably X ^B is dC. Even more preferably, the oligonucleotide comprises the sequence 5′- mG*mU*dC*dC*dC*dC-3′. [0374] In another embodiment of the first aspect, there is provided a method of modifying the TLR7 activity of an oligonucleotide, the method comprising modifying the oligonucleotide by adding the sequence to the terminal 5′- and/or 3′- end of the oligonucleotide, preferably the terminal 5′- end. In one embodiment, the method 1004921453 reduces the TLR7 potentiating activity of the oligonucleotide. In another embodiment, the method increases the TLR7 inhibitory activity of the oligonucleotide. TLR8 inhibitory oligonucleotides [0375] In a second aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: X ^C * ^y X ^D * ^z X ^E wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^C is selected from the group consisting of: mX, modified mX, dG, and morpholino-X; X ^D and X ^E are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, morpholino-X, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX and modified morpholino-X; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification, morpholino-X is a nucleotide comprising a morpholine ring; and wherein: when X ^C is mX, at least one of X ^D and X ^E is not mX; when X ^C is dG, at least one of X ^D and X ^E is not dX; when X ^C is mG and when: X ^D is dG, X ^E is not dA or dC; X ^D is dT or mU, X ^E is not dC or dT; X ^D is mC, X ^E is not dT, dG, or dC; and 1004921453 X ^D is mG or dC, X ^E is not dX; or when X ^C is dG, X ^E is not mG; wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0376] Preferably, X ^C is selected from the group consisting of: mX, modified mX, dG; X ^D is selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX; and X ^E is selected from the group consisting of: mX, dX, rX, moX, LX, fX, morpholino-X, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX and modified morpholino-X. [0377] In an embodiment of the second aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: X ^C * ^y X ^D * ^z X ^E wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^C is selected from the group consisting of: mX, modified mX, and dG; X ^D and X ^E are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX, modified moX, modified LX, and modified fX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification; and wherein: when X ^C is mX, at least one of X ^D and X ^E is not mX; 1004921453 when X ^C is dG, at least one of X ^D and X ^E is not dX; when X ^C is mG and when: X ^D is dG, X ^E is not dA or dC; X ^D is dT or mU, X ^E is not dC or dT; X ^D is mC, X ^E is not dT, dG, or dC; and X ^D is mG or dC, X ^E is not dX; or when X ^C is dG, X ^E is not mG; wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0378] Any oligonucleotide of the second aspect inhibits TLR8 activity, preferably human TLR8 activity. In one preferred embodiment, an oligonucleotide of the second aspect further inhibits TLR7 activity, preferably human TLR7 activtiy. In an alternative preferred embodiment, an oligonucleotide of the second aspect does not substantially inhibit TLR7 activity, preferably human TLR7 activtiy. [0379] Each internucleotide linkage may be selected from the group consisting of: 3′- 5′-, 5′-5′-, 5′-3′-, 3′-3′-, 3′-2′-, 2′-3′-, 2′-2′-, 2′-5′-, and 5′-2′- linkage. Preferably, each internucleotide linkage may be selected from: 3′-5′- and 5′-5′- linkage. Preferably, each internucletodie linkage is a 3′-5′- linkage. [0380] In a particularly preferred embodiment of the second aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: 5′-X ^C * ^y X ^D * ^z X ^E -3′ wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; 1004921453 X ^C is selected from the group consisting of: mX, modified mX, dG, and morpholino-X; X ^D and X ^E are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, morpholino-X, modified mX, modified dX, modified rX, modified moX, modified LX, modified fX and modified morpholino-X; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification, morpholino-X is a nucleotide comprising a morpholine ring; and wherein: when X ^C is mX, at least one of X ^D and X ^E is not mX; when X ^C is dG, at least one of X ^D and X ^E is not dX; when X ^C is mG and when: X ^D is dG, X ^E is not dA or dC; X ^D is dT or mU, X ^E is not dC or dT; X ^D is mC, X ^E is not dT, dG, or dC; and X ^D is mG or dC, X ^E is not dX; or when X ^C is dG, X ^E is not mG; wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0381] In a particularly preferred embodiment of the second aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: 5′-X ^C * ^y X ^D * ^z X ^E -3′ 1004921453 wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^C is selected from the group consisting of: mX, modified mX, and dG; X ^D and X ^E are each independently selected from the group consisting of: mX, dX, rX, moX, LX, fX, modified mX, modified dX, modified rX, modified moX, modified LX, and modified fX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, rX is an RNA base, moX is a nucleotide comprising a 2′-MOE and/or 3′-MOE modification, LX is a LNA modified base, fX is a nucleotide comprising a 2′-fluor and/or 3′-fluor modification; and wherein: when X ^C is mX, at least one of X ^D and X ^E is not mX; when X ^C is dG, at least one of X ^D and X ^E is not dX; when X ^C is mG and when: X ^D is dG, X ^E is not dA or dC; X ^D is dT or mU, X ^E is not dC or dT; X ^D is mC, X ^E is not dT, dG, or dC; and X ^D is mG or dC, X ^E is not dX; or when X ^C is dG, X ^E is not mG; wherein the sequence is optionally functionalised. [0382] Preferably, each internucleotide linkage is a 3′-5′ linkage. [0383] Preferably, each internucleotide linkage is independently selected from the group consisting of: biphosphate, triphosphate, phosphorothioate, phosphodiester, phosphoramidate and phosphorodiamidate. Each internucleotide linkage may be the same or different. In a preferred embodiment, each internucleotide linkage is 1004921453 independently selected from phosphorothioate and phosphodiester. Most preferably, each internucleotide linkage is phosphorothioate. [0384] In a particularly preferred embodiment, each internucleotide linkage is a 3′-5′- phosphorothioate linkage. [0385] In one embodiment, the oligonucleotide comprises a mixture of different oligonucleotide stereoisomers. In another embodiment, the oligonucleotide comprises a single stereoisomer. [0386] Preferably, mX is a nucleotide comprising a 2′-OMe modification. [0387] Preferably, moX, is a nucleotide comprising a 2′-MOE modification. [0388] Preferably, fX, is a nucleotide comprising a 2′-fluor modification. [0389] Modified dX, modified rX and modified morpholino-X comprise at least one modification or substitution at positions of the base and/or sugar. Modified mX, modified moX, modified LX and modified fX comprise at least one additional modification or substitution at additional positions of the base and/or sugar. Preferably, the modification or substitution is selected from the group consisting of: pseudouridine, 3′-deoxy, hydroxyl, des-amino, amino, thio, halo, oxo, aza, deaza, polyethylene glycol, alkyl, alkenyl, alkynyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl and combinations thereof. [0390] Exemplary modified mX includes but is not limited to: mG1, mI, mU1, mU2, mU3, mC1, and ^m7 G, wherein mG1 is 2′-OMe-2,6-Diaminopurine, mI is 2′-OMe-I (2′-O- methylinosine), mU1 is 2′-OMe-5-Me-U (2′-O-methyl-5-methyluridine), mU2 is 2′-OMe-5- Br-U (2′-O-methyl-5-bromouridine), mU3 is N3-Me-U (3-methyluridine), mC1 is 2′-OMe- 5-Me-C (2′-O-methyl-5-methylcytidine), and ^m7 G is N7-methylated guanosine. Preferably, modified mX is selected from the group consisting of: mG1, mI, mU1, mU2 and mC1. [0391] Exemplary modified dX includes but is not limited to: 5-Me-dC, 5-Br-dC, 5- CH2OH-dC, ddC, pdC, PSU, dI, 8-Br-dG, N1-Me-dG, 7-deaza-dG, 8-Br-dA, 8-oxo-dA, O6-Me-dG, and 8-NH2-dG, wherein 5-Me-dC is 5-methyl substituted deoxycytidine, 5- Br-dC is 5-bromo substituted deoxycytidine, 5-CH2OH-dC is 5-hydroxymethyl substituted deoxycytidine, ddC is 2′-deoxy-3′-deoxy cytidine, pdC is 5-propynyl 1004921453 substituted deoxycytidine, PSU is pseudo uridine, dI is deoxyinosine, 8-Br-dG is 8- bromodeoxyguanosine, N1-Me-dG is 1-methyl deoxyguanosine, 7-deaza-dG is 7- deaza-deoxyguanosine, 8-Br-dA is 8-bromo deoxyadenosine, 8-oxo-dA is 8-oxo deoxyadenosine, O6-Me-dG is O6-methyl deoxyguanosine and 8-NH2-dG is 8- aminodeoxyguanosine. [0392] Exemplary modified rX includes but is not limited to PSU, 2′-NH2-rX, and ara- rX, wherein 2′-NH2-rX is a 2′-amino modified RNA base, and ara-rX is an arabinose modified RNA base. Exemplary 2′-NH2-rX includes but is not limited to 2′-NH2-U and 2′- NH2-C, wherein 2′-NH2-U is 2′-NH2-uridine, and 2′-NH2-C is 2′-NH2-cytidine. Exemplary ara-rX is ara-C (aracytidine). [0393] In one embodiment, X ^C is selected from the group consisting of: mG, mU, mC, mI, mG1, and dG. [0394] In one embodiment, X ^C is selected from the group consisting of: mX and modified mX. Preferably, mX is selected from the group consisting of: mG, mC and mU, more preferably mG; and modified mX is mI. In a preferred embodiment, X ^C is selected from the group consisting of: mG and mI. In a particularly preferred embodiment, X ^C is mI. [0395] In one embodiment, X ^D is selected from the group consisting of: mX, dX, rX, LX, modified mX, modified dX and modified rX. Preferably, X ^D is selected from the group consisting of: mA, mU, mC, dA, dT, dG, mU1, mU2, mU3, PSU, 8-Br-dA, 8-oxo- dA, rA, rG, rU, and 2′-NH2-rU. In one embodiment, X ^D is selected from the group consisting of: mX, dX, LX, modified mX, and modified dX. Preferably, X ^D is selected from the group consisting of: mX, dX, modified mX, and modified dX. Preferably, X ^D is selected from the group consisting of: mA, mU, mC, dA, dT, dG, mU1, mU2, and PSU. More preferably, X ^D is selected from the group consisting of: mA, mU, dA, dT, and dG. [0396] In one embodiment, X ^E is selected from the group consisting of: mX, dX, rX, morpholino-X, moX, LX, fX, rX, modified mX, modified dX and modified rX. Preferably, X ^E is selected from the group consisting of: dA, dC, dG, dT, rG, mC, mC1, mG, mU3, moC, LA, LC, LG, LT, fC, 5-Me-dC, 5-Br-dC, 5-CH2OH-dC, ddC, pdC, dI, 8-Br-dG, N1- Me-dG, 7-deaza-dG, O6-Me-dG, 8-NH2-dG, morpholino-G, rA, rG, rU, rC, N3-Me-dC, 5- I-dC, 2′-NH2-C, ara-C, and morpholino-C. In one embodiment, X ^E is selected from the 1004921453 group consisting of: mX, dX, moX, LX, fX, rX, modified mX and modified dX. Preferably, X ^E is selected from the group consisting of: dA, dC, dG, dT, rG, mC, mC1, mG, moC, LA, LC, LG, LT, fC, 5-Me-dC, 5-Br-dC, 5-CH ² OH-dC, ddC, and pdC. More preferably, X ^E is selected from the group consisting of: dA, dC, dG, dT, rG, mC, mC1, mG, moC, LA, LC, LG, LT, fC, 5-Me-dC, 5-Br-dC, 5-CH2OH-dC, and pdC. In one embodiment, X ^E is selected from the group consisting of: mX, dX, rX and LX. Preferably, X ^E is selected from the group consisting of: dA, dC, dG, dT, rG, mC, LA, LC, LG, and LT. Even more preferably, X ^E is selected from the group consisting of: mX and dX. Preferably, X ^E is selected from the group consisting of: dC, dG, dT and mC. [0397] In one embodiment, at least one of X ^D and X ^E is LX. In one embodiment, X ^D and X ^E are independently LX. In another embodiment, one of X ^D and X ^E is LX. Preferably, X ^E is LX. Preferably, X ^E is LX and X ^D is mX. [0398] In one embodiment, at least one of X ^D and X ^E is dX. In one embodiment, X ^D and X ^E are independently dX. In another embodiment, one of X ^D and X ^E is dX. Preferably, X ^E is dX. Preferably, X ^E is dX and X ^D is mX. [0399] In one embodiment, at least one of X ^D and X ^E is rX. In one embodiment, one of X ^D and X ^E is rX. In another embodiment, X ^D and X ^E are each independently rX. Preferably, X ^D is selected from rA and rG, and X ^E is selected from rA, rG and rC. Preferably, X ^D is rA and X ^E is rA; X ^D is rG and X ^E is rA; X ^D is rA and X ^E is rG; X ^D is rA and X ^E is rC. Preferably, where at least one of X ^A and X ^B is rX, each internucleotide linkage is a 3′-5′- phosphorothioate linkage. [0400] In one embodiment, the sequence may be functionalised. Preferably, the functionalised sequence comprises a compound selected from the group consisting of: polyethylene glycol, alkyl, alkenyl, alkynyl, heterocycyl, arylalkyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heterocycyl, substituted arylalkyl, and hydrophobic lipid. Prefearbly, the hydrophobic lipid is selected from cholesterol and tocopherol. Preferably, the compound is selected from the group consisting of: polyethylene glycol, cholesterol and tocopherol. [0401] In one embodiment, the compound is conjugated directly to the sequence. In another embodiment, the compound is conjugated to the sequence via a linker. The 1004921453 linker may be cleavable or non-cleavable. Preferably, the linker is a non-cleavable linker. [0402] Preferably, the compound is conjugated to a terminal nucleotide of the sequence, preferably the terminal 3′- nucleotide. Preferably, the compound is conjugated to the terminal 3′-nucleotide at the 3′- position. [0403] Functionalised sequences may comprise functionalised nucleotides selected from the group consisting of: dX-TEG, dX-Chol and dX-Toco, wherein dX-TEG is a DNA base with triethylene glycol covalently linked to the 3′-position via a monophosphate group, dX-Chol is a DNA base with an (N-cholesteryl-3-aminopropyl)-triethyleneglycol- glyceryl group covalently linked to the 3′-position via a monophosphate group, dX-Toco is a DNA base with a [(9-DL-α-tocopheryl)-triethyleneglycol-1-yl]-glyceryl group covalently linked to the 3′-position via a monophosphate group. [0404] Preferably, the oligonucleotide of the second aspect is selected from the group of oligonucleotides in Table 2. Table 2.3mer oligonucleotides that are inhibitors of TLR8 sensing. “m” indicates 2′- OMe base, * denotes the phosphorothioate backbone, “d” indicates DNA base. 1004921453 1004921453 [0405] Preferably, the sequence is selected from the group consisting of: mI*mA*dG, mI*mU*mC, mG*dA*dG, mG*mA*dT, mG*mA*dG, mG*mA*dC, mG*mA*LG, mG*mA*rG, mG*mA*LT, mG*mA*LC, mU*dT*dC, mU*dA*dC, mG*mA*LA, mU*dA*dG, mC*dA*dG, mU*dT*dT, mU*dA*dT, mU*dA*dA, mC*dT*dA, mU*dG*dT, mC*dT*dC, mC*dA*dT, mU*dG*dG, mC*dT*dT, mC*dT*dG, mU*dT*dA, mU*dT*dG, mG*mA*O6- Me-dG, mG*rA*rA, mG*rG*rA, mG*rA*rG, and mG*rA*rU. [0406] More preferably, the sequence is selected from the group consisting of: mI*mA*dG, mI*mU*mC, mG*dA*dG, mG*mA*dT, mG*mA*dG, mG*mA*dC, mG*rA*rA and mG*rG*rA. Even more preferably, the sequence is selected from the group consisting of: mI*mA*dG and mI*mU*mC. 1004921453 [0407] In another preferred embodiment, the oligonucleotide of the second aspect further inhibits TLR7 activity, preferably human TLR7 activity. Preferably, the oligonucleotide that further inhibits TLR7 activity comprises or consists of the sequence of mI*mU*mC or mI*mA*dG. [0408] In one embodiment, the oligonucleotide consists of the sequence. [0409] In another embodiment, the oligonucleotide comprises the sequence. Preferably, the oligonucleotide comprising the sequence is no more than 20 bases in length, preferably 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, or 4 bases in length. Preferably, the sequence is at the terminal 5′- and/or 3′- end of the oligonucleotide, preferably the terminal 5′- end. [0410] In another embodiment of the second aspect, there is provided a method of modifying the TLR8 activity of an oligonucleotide, the method comprising modifying the oligonucleotide by adding the sequence to the terminal 5′- and/or 3′- end of the oligonucleotide, preferably the terminal 5′- end. In one embodiment, the method reduces the TLR8 potentiating activity of the oligonucleotide. In another embodiment, the method increases the TLR8 inhibitory activity of the oligonucleotide. TLR8 potentiating oligonucleotides [0411] In a third aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: [mX/modified mX]* ^y X ^F * ^z X ^G wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^F and X ^G are each independently selected from the group consisting of: mX, dX, rX, LX, modified mX, modified dX and modified LX; wherein at least one of X ^F and X ^G is dX, LX, rX, modified dX or modified LX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, LX is a LNA modified base; when mX is mC, X ^F is dG, X ^G is not mG or dG; or 1004921453 when mX is mG and when: X ^F is mU, mC or dG, X ^G is not dT, dA, dG; X ^F is dT, dA, or mA, X ^G is not dX; X ^F is dG, X ^G is not dA, dG, dT; wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0412] In an embodiment of the third aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: mX* ^y X ^F * ^z X ^G wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^F and X ^G are each independently selected from the group consisting of: mX, dX, LX, modified mX, modified dX and modified LX; wherein at least one of X ^F and X ^G is dX, LX, modified dX or modified LX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, LX is a LNA modified base; when mX is mC, X ^F is dG, X ^G is not mG or dG; or when mX is mG and when: X ^F is mU, mC or dG, X ^G is not dT, dA, dG; X ^F is dT, dA, or mA, X ^G is not dX; X ^F is dG, X ^G is not dA, dG, dT; 1004921453 wherein when [mX/modified mX] is 3′-OMe N7-methylated guanosine, * ^y is not a 5′-5′- triphosphate internucleotide linkage and * ^z is not a 3′-5′- phosphodiester internucleotide linkage; wherein the sequence is optionally functionalised. [0413] Any oligonucleotide of the third aspect potentiates TLR8 activity, preferably human TLR8 activity. In one preferred embodiment, an oligonucleotide of the third aspect does not substantially inhibit TLR7 activity, preferably human TLR7 activity. In an alternative preferred embodiment, an oligonucleotide of the third aspect inhibits TLR7 activity, preferably human TLR7 activity. [0414] Each internucleotide linkage may be selected from the group consisting of: 3′- 5′-, 5′-5′-, 5′-3′-, 3′-3′-, 3′-2′-, 2′-3′-, 2′-2′-, 2′-5′-, and 5′-2′- linkage. Preferably, each internucleotide linkage may be selected from: 3′-5′- and 5′-5′- linkage. Preferably, each internucletodie linkage is a 3′-5′- linkage. [0415] In a particularly preferred embodiment of the third aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: 5′-[mX/modified mX]* ^y X ^F * ^z X ^G -3′ wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^F and X ^G are each independently selected from the group consisting of: mX, dX, rX, LX, modified mX, modified dX and modified LX; wherein at least one of X ^F and X ^G is dX, rX, LX, modified dX or modified LX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, LX is a LNA modified base; when mX is mC, X ^F is dG, X ^G is not mG or dG; or when mX is mG and when: X ^F is mU, mC or dG, X ^G is not dT, dA, dG; X ^F is dT, dA, or mA, X ^G is not dX; 1004921453 X ^F is dG, X ^G is not dA, dG, dT; wherein the sequence is optionally functionalised. [0416] In a particularly preferred embodiment of the third aspect, there is provided an oligonucleotide comprising or consisting of a sequence consisting of: 5′-mX* ^y X ^F * ^z X ^G -3′ wherein: * ^y and * ^z each independently represent an inter-nucleotide linkage; X ^F and X ^G are each independently selected from the group consisting of: mX, dX, LX, modified mX, modified dX and modified LX; wherein at least one of X ^F and X ^G is dX, LX, modified dX or modified LX; wherein mX is a nucleotide comprising a 2′-OMe and/or 3′-OMe modification, dX is a DNA base, LX is a LNA modified base; when mX is mC, X ^F is dG, X ^G is not mG or dG; or when mX is mG and when: X ^F is mU, mC or dG, X ^G is not dT, dA, dG; X ^F is dT, dA, or mA, X ^G is not dX; X ^F is dG, X ^G is not dA, dG, dT; wherein the sequence is optionally functionalised. [0417] Preferably, each internucleotide linkage is a 3′-5′ linkage. [0418] Preferably, each internucleotide linkage is independently selected from the group consisting of: biphosphate, triphosphate, phosphorothioate, and phosphodiester. Each internucleotide linkage may be the same or different. In a preferred embodiment, each internucleotide linkage is independently selected from phosphorothioate and phosphodiester. Most preferably, each internucleotide linkage is phosphorothioate. 1004921453 [0419] In a particularly preferred embodiment, each internucleotide linkage is a 3′-5′- phosphorothioate linkage. [0420] In one embodiment, the oligonucleotide comprises a mixture of different oligonucleotide stereoisomers, preferably a mixture of different oligonucleotide phosphorothioate stereoisomers. In another embodiment, the oligonucleotide of the third aspect comprises a single phosphorothioate stereoisomer, preferably wherein * ^z is in the R configuration. [0421] Preferably, mX is a nucleotide comprising a 2′-OMe modification. [0422] Modified dX and modified rX comprise at least one modification or substitution at positions of the base and/or sugar. Modified mX, modified moX, modified LX and modified fX comprise at least one additional modification or substitution at additional positions of the base and/or sugar. Preferably, the modification or substitution is selected from the group consisting of: pseudouridine, 3′-deoxy, hydroxyl, des-amino, amino, thio, halo, oxo, aza, deaza, polyethylene glycol, alkyl, alkenyl, alkynyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl and combinations thereof. [0423] Exemplary modified mX includes but is not limited to: mG1, mI, mU1, mU2, mC1, ^m7 G, and N1-Me-G, wherein mG1 is 2′-OMe-2,6-Diaminopurine, mI is 2′-OMe-I (2′-O-methylinosine), mU1 is 2′-OMe-5-Me-U (2′-O-methyl-5-methyluridine), mU2 is 2′- OMe-5-Br-U (2′-O-methyl-5-bromouridine), mC1 is 2′-OMe-5-Me-C (2′-O-methyl-5- methylcytidine), ^m7 G is 3′-OMe-N7-methylated guanosine and N1-Me-G (1- methylguanosine). Preferably, modified mX is selected from the group consisting of: mG1, mI, mU1, mU2 and mC1. [0424] Exemplary modified dX includes but is not limited to: 5-Me-dC, 5-Br-dC, 5- CH2OH-dC, ddC, pdC, and PSU, wherein 5-Me-dC is 5-methyl substituted deoxycytidine, 5-Br-dC is 5-bromo substituted deoxycytidine, 5-CH2OH-dC is 5- hydroxymethyl substituted deoxycytidine, ddC is 2′-deoxy-3′-deoxy cytidine, pdC is 5- propynyl substituted deoxycytidine, and PSU is pseudo uridine. [0425] In one embodiment, X ^F and X ^G are each independently selected from the group consisting of: mX, dX, and LX; wherein at least one of X ^F and X ^G is dX or LX. 1004921453 [0426] In one embodiment, mX is selected from the group consisting of: mG, mC, and mU. In one preferred embodiment, mX is mG. In another preferred embodiment, mX is mC. In yet another preferred embodiment, mX is mU. [0427] In one embodiment, X ^F is selected from the group consisting of: mX and dX. Preferably, X ^F is selected from the group consisting of: dC, dG, dA, dT, mG, mC, and mU. Preferably, X ^F is selected from the group consisting of: dC, dG and mG. In a preferred embodiment, X ^F is dX, preferably dC. [0428] In one embodiment, X ^G is selected from the group consisting of: dX and LX. Preferably, X ^G is selected from the group consisting of: dC, dT, dA, dG, LG, LC, LT, and LA. More preferably, X ^G is selected from the group consisting of: dX and LG, preferably dX. [0429] In one embodiment, at least one of X ^F and X ^G is dX. In one embodiment, one of X ^F and X ^G is dX. In a preferred embodiment, X ^F and X ^G are independently dX. [0430] In one embodiment, X ^F is selected from the group consisting of: dX and mX; and X ^G is dX. In another embodiment, X ^F is mX; and X ^G is selected from the group consisting of: dX and LX. In yet another embodiment, when X ^F is dC or mG, X ^F is dX or LX. [0431] In one embodiment, the sequence may be functionalised. Preferably, the functionalised sequence comprises a compound selected from the group consisting of: polyethylene glycol, alkyl, alkenyl, alkynyl, heterocycyl, arylalkyl, branched alkyl, branched alkyenyl, branched alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heterocycyl, substituted arylalkyl, and hydrophobic lipid. Prefearbly, the hydrophobic lipid is selected from cholesterol and tocopherol. Preferably, the compound is selected from the group consisting of: polyethylene glycol, cholesterol and tocopherol. [0432] In one embodiment, the compound is conjugated directly to the sequence. In another embodiment, the compound is conjugated to the sequence via a linker. The linker may be cleavable or non-cleavable. Preferably, the linker is a non-cleavable linker. 1004921453 [0433] Preferably, the compound is conjugated to a terminal nucleotide of the sequence, preferably the terminal 3′- nucleotide. Preferably, the compound is conjugated to the terminal 3′-nucleotide at the 3′- position. [0434] Functionalised sequences may comprise functionalised nucleotides selected from the group consisting of: dX-TEG, dX-Chol and dX-Toco, wherein dX-TEG is a DNA base with triethylene glycol covalently linked to the 3′-position via a monophosphate group, dX-Chol is a DNA base with an (N-cholesteryl-3-aminopropyl)-triethyleneglycol- glyceryl group covalently linked to the 3′-position via a monophosphate group, dX-Toco is a DNA base with a [(9-DL-α-tocopheryl)-triethyleneglycol-1-yl]-glyceryl group covalently linked to the 3′-position via a monophosphate group. [0435] Preferably, the oligonucleotide is selected from the group of oligonucleotides in Table 3. Table 3.3mer oligonucleotides that are potentiators of TLR8 sensing. “m” indicates 2′- OMe base, * denotes the phosphorothioate backbone, “d” indicates DNA base. 1004921453 [0436] Preferably, the sequence is selected from the group consisting of: mG*dC*dC, mC*dC*dT, mG*dC*dA, mG*dC*dG, mC*dC*dC, mU*dC*dC, mC*dG*dC, mG*dC*dT, mG*mG*dA, mU*dC*dG, mU*mG*LG, mU*dC*dA, and mU*dC*dT. [0437] More preferably, the sequence is selected from the group consisting of: mG*dC*dC, mC*dC*dT, mU*mG*LG, mC*dC*dC, mU*dC*dC, mG*dC*dA, mG*dC*dG, and mG*dC*dT. Even more preferably the oligonucleotide is mG*dC*dC. [0438] In one embodiment, the oligonucleotide consists of the sequence. [0439] In another embodiment, the oligonucleotide comprises the sequence. Preferably, the oligonucleotide comprising the sequence is no more than 20 bases in length, preferably 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, or 4 bases in length. Preferably, the sequence is at the terminal 5′- and/or 3′- end of the oligonucleotide, preferably the terminal 5′- end. In one preferred embodiment, the oligonucleotide comprises the sequence 5′-mG*mU*dC-3′. Even more preferably, the oligonucleotide comprises the sequence 5′-mG*mU*dC*dC*dC*dC-3′. [0440] In another embodiment of the third aspect, there is provided a method of modifying the TLR8 activity of an oligonucleotide, the method comprising modifying the 1004921453 oligonucleotide by adding the sequence to the terminal 5′- and/or 3′- end of the oligonucleotide, preferably the terminal 5′- end. In one embodiment, the method increases the TLR8 potentiating activity of the oligonucleotide. In another embodiment, the method reduces the TLR8 inhibitory activity of the oligonucleotide. Fusion oligonucleotides [0441] In another aspect, there is provided a fusion oligonucleotide comprising: A-[Y-A]n wherein each A independently represents an oligonucleotide described herein, each A may be the same or different; Y represents a cleavable linker, each Y may be the same or different; and n is equal to or greater than 1. [0442] In one embodiment, each A independently represents an oligonucleotide according to the first aspect. In another embodiment, each A independently represents an oligonucleotide according to the second aspect. In another embodiment, each A independently represents an oligonucleotide according to the third aspect. In another embodiment, at least one A is an oligonucleotide according to the first aspect and at least one further A is an oligonucleotide according to the second aspect. [0443] The cleavable linker may be attached to the 5′ and/or 3′ end of the oligonucleotides, wherein the fusion oligonucleotide comprises 5′-A-3′-Y-3′-A-5′, 5′-A-3′- Y-5′-A-3′ or 3′-A-5′-Y-5′-A-3′. Preferably the fusion oligonucleotide comprises 5′-A-3′-Y- 3′-A-5′. [0444] Preferably, Y is cleavable by an enzyme. Preferably, Y is selected from the group consisting of: a TEG linker, carbon spacers (such as C3, C6, C9, C12), glycerol and PolydT. More preferably Y is a TEG linker. [0445] The term “TEG linker” refers to Triethylene Glycol linker. 1004921453 [0446] Preferably, each A is independently bound to Y by an internucleotide linkage (*). Preferably, each internucleotide linkage is independently selected from the group consisting of: biphosphate, triphosphate, phosphorothioate, and phosphodiester. Each internucleotide linkage may be the same or different. In a preferred embodiment, each internucleotide linkage is independently selected from phosphorothioate and phosphodiester. Most preferably, each internucleotide linkage is phosphorothioate. [0447] In one embodiment, the fusion oligonucleotide comprises or consists of the sequence 5′-mG*mU*dC-3′-*TEG*-3′-dC*mU*mG-5′. [0448] In another aspect, there is provided a modified oligonucleotide comprising an agent linked to an oligonucleotide or fusion oligonucleotide described herein by a linker. The agent may be a therapeutic and/or diagnostic agent. Suitable therapeutic agents include but are not limited to: monoclonal antibodies, oligonucleotides, small molecules, cholesterol, radiotherapeutics. Suitable diagnostic agents include but are not limited to: radiolabels, dyes. Preferably, the agent is a therapeutic agent, more preferably a therapeutic RNA. The therapeutic RNA may be a synthetic oligonucleotide sequence or a naturally occurring oligonucleotide sequence. A synthetic oligonucleotide sequence refers to an oligonucleotide sequence which lacks a corresponding sequence that occurs naturally. The therapeutic RNA may be synthesized in vitro. However, in some instances where modified bases and backbone are not required they can be expressed in vitro or in vivo in a suitable system such as by a recombinant virus or cell. Therapeutic RNAs include but are not limited to: DNA, RNA, mRNA, siRNA, RNA aptamers, antisense oligonucleotides, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. In one preferred embodiment, the therapeutic RNA is selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. The linker may be cleavable or non-cleavable. Preferably, the linker is a cleavable linker. Testing for inhibition of TLR7 activity [0449] Some embodiments of the methods of the present invention involve testing for inhibition of TLR7 activity which can be determined using any method known in the art. In some embodiments, TLR7 activity in cells may be measured by expression and/or secretion of one or more pro-inflammatory cytokines (e.g. TNFα), and/or activation or expression of transcription factors (e.g. NF- ^B). 1004921453 [0450] The ability of an oligonucleotide to inhibit TLR7 activity can, for example, be analysed by incubating cells which express TLR7 with an oligonucleotide, then stimulating said cells with a TLR7 agonist (e.g., R848, guanosine or an immunostimulatory ssRNA such as B-406-AS-1), and analysing the overall TLR7 response in the cell population, or analysing the proportion of cells having TLR7-positive activity after a defined period of time. [0451] In such examples, inhibition of TLR7 activity can be identified by observation of an overall decreased TLR7 response of the cell population, or a lower proportion of cells having TLR7-positive activity as compared to positive control condition in which cells are treated with TLR7 agonist in the absence of the oligonucleotide (or in the presence of an appropriate control inhibitory agent). In one example, 293XLhTLR7 (referred to as HEK-TLR7) cells are transfected with pNF- ^B-Luc4 reporter, incubated with an oligonucleotide, and then stimulated with R848. TLR7 activity can be determined by a luciferase assay, which measures activated NF- ^B by luminescence. TLR7 activity can also be analysed by measuring cytokine levels, for example by ELISA. Testing for inhibition of TLR8 activity [0452] Some embodiments of the methods of the present invention involve testing for inhibition of TLR8 activity which can be determined using any method known in the art. In some embodiments TLR8 activity in cells may be measured by expression and/or secretion of one or more pro-inflammatory cytokines (e.g. IL-6, TNFα, IP-10), and/or activation or expression of transcription factors (e.g. NF- ^B). [0453] The ability of an oligonucleotide to inhibit TLR8 activity can, for example, be analysed by incubating cells which express TLR8 with an oligonucleotide, then stimulating said cells with a TLR8 agonist, and analysing the overall TLR8 response in the cell population, or analysing the proportion of cells having TLR8-positive activity after a defined period of time. [0454] In such examples, inhibition of TLR8 activity can be identified by observation of an overall decreased TLR8 response of the cell population, or a lower proportion of cells having TLR8-positive activity as compared to a positive control condition in which cells are treated with TLR8 agonist in the absence of the oligonucleotide (or in the 1004921453 presence of an appropriate control inhibitory agent). In one example, 293XLhTLR8 (referred to as HEK-TLR8) cells are transfected with pNF- ^B-Luc4 reporter, incubated with an oligonucleotide, and then stimulated with R848. TLR8 activity can be determined by a luciferase assay, which measures activated NF- ^B by luminescence. TLR8 activity can also be analysed by measuring cytokine levels, for example by ELISA. Testing for potentiating TLR8 activity [0455] Some embodiments of the methods of the present invention involve testing for potentiation of TLR8 activity which can be determined using any method known in the art. In some embodiments TLR8 activity in cells may be measured by expression and/or secretion of one or more pro-inflammatory cytokines (e.g. IL-6, TNFα, IP-10), and/or activation or expression of transcription factors (e.g. NF- ^B). [0456] The ability of an oligonucleotide to potentiate TLR8 activity can, for example, be analysed by incubating cells which express TLR8 with an oligonucleotide, then stimulating said cells with a TLR8 agonist, and analysing the overall TLR8 response in the cell population, or analysing the proportion of cells having TLR8-positive activity after a defined period of time. [0457] In such examples, potentiation of TLR8 activity can be identified by observation of an overall increased TLR8 response of the cell population, or a higher proportion of cells having TLR8-positive activity as compared to a negative control condition in which cells are treated with TLR8 agonist in the absence of the oligonucleotide (or in the presence of an appropriate control non-potentiating agent). In one example, 293XLhTLR8 (referred to as HEK-TLR8) cells are transfected with pNF- ^B-Luc4 reporter, incubated with an oligonucleotide, and then stimulated with R848. TLR8 activity can be determined by a luciferase assay, which measures activated NF- ^B by luminescence. TLR8 activity can also be analysed by measuring cytokine levels, for example by ELISA. Uses [0458] Oligonucleotides of the invention are designed to be administered to an animal. For this purpose, the oligonucleotide can be administered in combination with another molecule, such as a further nucleic acid (e.g., a mRNA molecule, a short 1004921453 interfering RNA, an antisense oligonucleotide, a CRISPR guide RNA, etc), a peptide, a carrier agent, a therapeutic agent, and the like. In an embodiment, the oligonucleotide can be conjugated with the other molecule. [0459] Typically, the oligonucleotide is used to modify a trait of an animal, more typically to treat or prevent a disease or condition. In a preferred embodiment, the disease or condition will benefit from the animal not being able to mount a TLR7 and/or TLR8 response following administration of the oligonucleotide. In an alternative embodiment, the disease or condition will benefit from the animal being able to mount an increased TLR8 response following administration of the oligonucleotide. [0460] In an embodiment of the first aspect, there is provided a method of inhibiting TLR7 activity in a cell, the method comprising contacting the cell with an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect, thereby inhibiting TLR7 activity in the cell. [0461] In an embodiment of the first aspect, there is provided a method of inhibiting TLR7 activity in a subject, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect, thereby inhibiting TLR7 activity in the subject. [0462] In an embodiment of the first aspect, there is provided a method of treating or preventing a disease, disorder or condition in a subject is responsive to TLR7 inhibition, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the first aspect, thereby treating or preventing the disease, disorder or condition in the subject. [0463] In an embodiment of the second aspect, there is provided a method of inhibiting TLR8 activity in a cell, the method comprising contacting the cell with an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect, thereby inhibiting TLR8 activity in the cell. [0464] In an embodiment of the second aspect, there is provided a method of inhibiting TLR8 activity in a subject, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect, thereby inhibiting TLR8 activity in the subject. 1004921453 [0465] In an embodiment of the second aspect, there is provided a method of treating or preventing a disease, disorder or condition in a subject responsive to TLR8 inhibition, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the second aspect, thereby treating or preventing the disease, disorder or condition in the subject. [0466] Diseases, disorders and conditions responsive to TLR7 and/or TLR8 inhibition include immune inflammation-related diseases, allergic diseases, infections, cancers and auto-immune diseases relying on auto-antibodies. [0467] Examples of the immune inflammation-related diseases can include diseases of the connective tissue and the musculoskeletal system (such as systemic lupus erythematosus, cutaneous and subcutaneous lupus, rheumatoid arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, ankylosing spondylitis, systemic scleroderma, polymyositis, dermatomyositis, psoriatic arthritis, fibromyalgia, osteoarthritis, mixed connective tissue disease, Guillain-Barre syndrome, and muscular dystrophy), the blood system (such as autoimmune hemolytic anemia, aplastic anemia, and idiopathic thrombocytopenic purpura), the digestive tract system (such as Crohn's disease, ulcerative colitis, and ileitis), the hepatobiliary pancreatic system and the endocrine system (such as autoimmune hepatitis, viral hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, primary sclerosing cholangitis, coeliac disease, fatty liver disease, inflammatory bowel disease, pancreatitis, primary biliary cirrhosis, Sjogren's syndrome, autoimmune thyroiditis, Graves' disease, and Hashimoto's thyroiditis), the respiratory system (such as chronic obstructive pulmonary disease, cystic fibrosis, bronchitis, and interstitial pneumonia), the cranial nervous system (such as multiple sclerosis, myasthenia gravis, meningitis, encephalomyelitis, and autoimmune encephalitis, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease), the visual system (such as uveitis, trachoma, and endophthalmitis), the cardiovascular system (such as vasculitis syndrome, polyangiitis granulomatosis Wegener's granulomatosis, myocarditis, ischemic heart disease, Hypertension, stroke and atherosclerosis), the skin epidermis system (such as psoriasis, pemphigus, vitiligo, contact dermatitis, and eczema), the renal system (such as glomerulonephritis, diabetic nephropathy, IgA nephropathy, purpura nephritis, nephrosis, and interstitial cystitis), and the endocrine system (such as type 1 diabetes, type 2 diabetes, autoimmune thyroiditis, Graves' disease, and Hashimoto's thyroiditis), and systemic inflammation (such as 1004921453 Behcet's disease, antiphospholipid antibody syndrome, IgG4-related diseases, sepsis, hemorrhage, hypersensitivity, transplantation rejection, and shock symptoms caused by, for example, cancer chemotherapy). Preferably, the immune inflammation-related disease is selected from: systemic lupus erythematosus, cutaneous lupus, and psoriasis. [0468] Examples of the allergic diseases can include atopic dermatitis, hay fever, asthma, anaphylaxis, anaphylactoid reactions, food allergy, rhinitis, otitis media, drug reactions, insect sting reactions, plant reactions, latex allergy, conjunctivitis, and urticaria. [0469] Examples of the infections can include diseases caused by infections by viruses (such as a single-stranded RNA virus, a double-stranded RNA virus, a single- stranded DNA virus, and a double-stranded DNA virus), bacteria (such as gram- negative bacteria, gram-positive bacteria, acid-fast bacteria, actinomycetes, spirochetes, spiral bacteria, Rickettsia, Chlamydia, and Mycoplasma), fungi (such as Trichophyton, Candida, Cryptococcus, Aspergillus, Pneumocystis, and Malassezia), and parasites (such as filariae, trematodes, cestodes, Distoma, Echinococcus, Entamoeba histolytica, fleas, lice, mites, Ascaridida, and Oxyuridae). [0470] Examples of the cancer treatment can include treatments for blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, skin cancers (including melanoma), leukemia or lymphoid malignancies, lung cancer including small-cell lung cancer (SGLG), non-small cell lung cancer (NSGLG), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer (including metastatic breast cancer), colon cancer, rectal cancer, colorectal cancer, salivary gland carcinoma, kidney or renal cancer, prostate cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular cancer, oesophageal cancer, tumors of the biliary tract, as well as head and neck cancer. 1004921453 [0471] The present invention also provides a method of reducing or minimising a symptom associated with diseases, disorders and conditions responsive to TLR7 and/or TLR8 inhibition. Symptoms associated with diseases, disorders and conditions responsive to TLR7 and/or TLR8 inhibition include inflammation, fever, muscle aches, fatigue. In a preferred embodiment, the condition responsive to TLR7 and/or TLR8 inhibition is mRNA administration. [0472] In an embodiment of the third aspect, there is provided a method of potentiating TLR8 activity in a cell, the method comprising contacting the cell with an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect, thereby potentiating TLR8 activity in the subject. [0473] In an embodiment of the third aspect, there is provided a method of potentiating TLR8 activity in a subject, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect, thereby potentiating TLR8 activity in the subject. [0474] In an embodiment of the third aspect, there is provided a method of treating or preventing a disease, disorder or condition in a subject responsive to increased TLR8 signalling, the method comprising administering to the subject a therapeutically effective amount of an oligonucleotide, a fusion oligonucleotide, or a composition according to the third aspect, thereby treating or preventing the disease, disorder or condition in the subject. [0475] Diseases, disorders and conditions associated with decreased TLR8 signalling include cancer, viral and bacterial infections. [0476] Examples of cancers include blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, skin cancers (including basal cell carcinoma, melanoma), leukemia or lymphoid malignancies, lung cancer including small-cell lung cancer (SGLG), non-small cell lung cancer (NSGLG), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer 1004921453 including gastrointestinal cancer, pancreatic cancer, glioblastoma, ovarian cancer, cervical cancer, liver cancer, bladder cancer, hepatoma, breast cancer (including metastatic breast cancer), colon cancer, rectal cancer, colorectal cancer, salivary gland carcinoma, kidney or renal cancer, prostate cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular cancer, oesophageal cancer, tumors of the biliary tract, head and neck cancer, as well as cancers associated with a viral infection. [0477] In another form, the oligonucleotides of the first and second aspect may be used in methods of preventing or inhibiting inflammation associated with administration of a therapeutic RNA, such as those known in the art, to a subject. In particular, the oligonucleotides described herein may be used in the prevention or inhibition of inflammation mediated by one or more nucleic acid sensors (e.g., TLR7, TLR8) during or following administration of the therapeutic RNA. It is envisaged that the inflammation may involve or include any cells, tissues or organs of the body. In particular embodiments, the inflammation is or comprises hepatic inflammation. To this end, the therapeutic RNA may be conjugated to N-acetylgalactosamine (GalNAc), which enhances asialoglycoprotein receptor (ASGR)-mediated uptake into liver hepatocytes (Nair et al., 2014), and thereby enabling their specific targeting to the liver. [0478] In certain examples, the oligonucleotides of the first aspect, and more particularly those described herein that exhibit TLR7-inhibitory activity, may be utilised to prevent or inhibit a TLR7-dependent inflammatory response associated with the administration of a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof in vitro or in vivo. More particularly, the therapeutic RNA may be part of RNA-based therapeutic agent, such as an mRNA vaccine. In this regard, the oligonucleotide can at least partly inhibit the engagement or sensing of these therapeutic RNA molecules by TLR7. The oligonucleotides of the first aspect may therefore minimise the need for the use of modified bases, such as pseudo-uridines, and/or other modifications that reduce the immunogenicity of mRNA molecules for their inclusion in mRNA vaccine compositions. [0479] In certain examples, the oligonucleotides of the second aspect, and more particularly those described herein that exhibit TLR8-inhibitory activity, may be utilised to prevent or inhibit a TLR8-dependent inflammatory response associated with the administration of a therapeutic RNA selected from the group consisting of: RNA, mRNA, 1004921453 siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof in vitro or in vivo. More particularly, the therapeutic RNA may be part of RNA-based therapeutic agent, such as an mRNA vaccine. In this regard, the oligonucleotide can at least partly inhibit the engagement or sensing of these therapeutic RNA molecules by TLR8. The oligonucleotides of the second aspect may therefore minimise the need for the use of modified bases, such as pseudo-uridines, and/or other modifications that reduce the immunogenicity of mRNA molecules for their inclusion in mRNA vaccine compositions. [0480] As such, the oligonucleotides of the first and second aspects may be a component or included within an immunogenic composition, such as an RNA or mRNA vaccine composition, as are known in the art. The term “RNA vaccine” refers to vaccines comprising RNA that encodes one or more nucleotide sequences encoding antigens capable of inducing an immune response in a mammal. mRNA vaccines are described, for example, in International Patent Application Nos. PCT/US2015/027400 and PCT/US2016/044918, herein incorporated by reference in their entirety. [0481] In a particular form, the present invention provides an immunogenic composition, such as a vaccine composition, comprising a therapeutic RNA and an oligonucleotide or fusion oligonucleotide provided herein. Preferably, the therapeutic RNA is selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self-amplifying RNAs, circular RNAs and combinations thereof. Preferably, the modified oligonucleotide comprises a therapeutic RNA selected from the group consisting of: RNA, mRNA, siRNA, RNA aptamers, single guide RNA, self- amplifying RNAs, circular RNAs and combinations thereof. Suitably, the oligonucleotide of the immunogenic composition exhibits TLR7 and/or TLR8 inhibitory activity as described herein. In certain embodiments, the oligonucleotide of the immunogenic composition exhibits TLR7 inhibitory activity. In certain embodiments, the oligonucleotide of the immunogenic composition exhibits TLR8 inhibitory activity. In some embodiments, the oligonucleotide of the immunogenic composition exhibits TLR7 and TLR8 inhibitory activity. The immunogenic composition is suitably for use in a method of: (a) inducing an immune response in a subject; and/or (b) preventing, treating or ameliorating an infection, disease or condition in a subject in need thereof. [0482] It will be appreciated that mRNA vaccines provide unique therapeutic alternatives to peptide- or DNA-based vaccines. When the mRNA vaccine is delivered 1004921453 to a cell, the mRNA will be processed into a polypeptide or peptide by the intracellular machinery which can then process the polypeptide or peptide into immunogenic fragments capable of stimulating an immune response. To this end, the oligonucleotide may be included as a separate or discrete component and/or conjugated with a therapeutic RNA of the vaccine composition. Preferably the therapeutic RNA is selected from RNA or mRNA. With respect to such embodiments, the therapeutic RNA of the RNA vaccine may be unmodified or substantially unmodified (e.g., does not include any modified bases). Alternatively, the therapeutic RNA may contain one or more modifications that typically enhance stability, such as modified nucleotides, modified sugar phosphate backbones, and 5′ and/or 3′ untranslated regions (UTR). [0483] Additionally, the therapeutic RNA may be included or incorporated within a delivery, transfer or carrier system of the immunogenic composition, as are known in the art. For example, the therapeutic RNA of the immunogenic composition may be encapsulated or complexed in nanoparticles, and more particularly lipid nanoparticles. According to various embodiments, suitable nanoparticles include, but are not limited to polymer based carriers, such as polyethylenimine (PEI), lipid nanoparticles and liposomes, nanoliposomes, ceramide-containing nanoliposomes, proteoliposomes, both natural and synthetically-derived exosomes, natural, synthetic and semi-synthetic lamellar bodies, nanoparticulates, calcium phosphor-silicate nanoparticulates, calcium phosphate nanoparticulates, silicon dioxide nanoparticulates, nanocry stalline particulates, semiconductor nanoparticulates, poly(D-arginine), sol-gels, nanodendrimers, starch-based delivery systems, micelles, emulsions, niosomes, multi- domain-block polymers (vinyl polymers, polypropyl acrylic acid polymers, dynamic poly conjugates) and dry powder formulations. [0484] In some embodiments, the oligonucleotide is included in the immunogenic composition separate from the carrier system. In other embodiments, the oligonucleotide is included or incorporated within the carrier system of the immunogenic composition, such as incorporated into a lipid nanoparticle together with the therapeutic RNA of the RNA vaccine. [0485] In some embodiment, the oligonucleotide may be applied to the surface of an implantable biomaterial, such as a prosthetic. 1004921453 [0486] In particular examples, therapeutically effective amounts of the therapeutic RNA and the oligonucleotide of the invention may be administered simultaneously, concurrently, sequentially, successively, alternately or separately in any particular combination and/or order. Compositions [0487] Oligonucleotides of the disclosure may be admixed, encapsulated, conjugated (such as fused) or otherwise associated with other molecules, molecule structures or mixtures of compounds, resulting in, for example, liposomes, receptor-targeted molecules, oral, rectal, topical or other formulations, for assisting in uptake, distribution and/or absorption. [0488] Oligonucleotides of the disclosure may be administered in a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be solid or liquid. Useful examples of pharmaceutically acceptable carriers include, but are not limited to, diluents, solvents, surfactants, excipients, suspending agents, buffering agents, lubricating agents, adjuvants, vehicles, emulsifiers, absorbants, dispersion media, coatings, stabilizers, protective colloids, adhesives, thickeners, thixotropic agents, penetration agents, sequestering agents, isotonic and absorption delaying agents that do not affect the activity of the active agents of the disclosure. [0489] In one embodiment, the pharmaceutical carrier is water for injection (WFI) and the pharmaceutical composition is adjusted to pH 7.4, 7.2-7.6. In one embodiment, the salt is a sodium or potassium salt. [0490] The oligonucleotides may contain chiral (asymmetric) centres or the molecule as a whole may be chiral. Preferably, the oligonucleotides contain chiral centres at the phosphorothioate linkages. The individual stereoisomers and mixtures of these are within the scope of the present disclosure. [0491] Oligonucleotides of the disclosure may be pharmaceutically acceptable salts, esters, or salts of the esters, or any other compounds which, upon administration are capable of providing (directly or indirectly) the biologically active metabolite. The term "pharmaceutically acceptable salts" as used herein refers to physiologically and pharmaceutically acceptable salts of the oligonucleotide that retain the desired biological activities of the parent compounds and do not impart undesired toxicological 1004921453 effects upon administration. Examples of pharmaceutically acceptable salts and their uses are further described in US 6,287,860. [0492] Oligonucleotides of the disclosure may be prodrugs or pharmaceutically acceptable salts of the prodrugs, or other bioequivalents. The term "prodrugs" as used herein refers to therapeutic agents that are prepared in an inactive form that is converted to an active form (i.e., drug) upon administration by the action of endogenous enzymes or other chemicals and/or conditions. In particular, prodrug forms of the oligonucleotide of the disclosure are prepared as SATE [(S acetyl-2-thioethyl) phosphate] derivatives according to the methods disclosed in WO 93/24510, WO 94/26764 and US 5,770,713. [0493] A prodrug may, for example, be converted within the body, e. g. by hydrolysis in the blood, into its active form that has medical effects. Pharmaceutical acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol.14 of the A. C. S. Symposium Series (1976); "Design of Prodrugs" ed. H. Bundgaard, Elsevier, 1985; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". [0494] In one embodiment, oligonucleotides of the invention can be complexed with a complexing agent to increase cellular uptake of oligonucleotides. An example of a complexing agent includes cationic lipids. Cationic lipids can be used to deliver oligonucleotides to cells. [0495] The term "cationic lipid" includes lipids and synthetic lipids having both polar and non-polar domains and which are capable of being positively charged at or around physiological pH and which bind to polyanions, such as nucleic acids, and facilitate the delivery of nucleic acids into cells. In general, cationic lipids include saturated and unsaturated alkyl and alicyclic ethers and esters of amines, amides, or derivatives thereof. Straight-chain and branched alkyl and alkenyl groups of cationic lipids can contain, e.g., from 1 to about 25 carbon atoms. Preferred straight chain or branched alkyl or alkene groups have six or more carbon atoms. Alicyclic groups include 1004921453 cholesterol and other steroid groups. Cationic lipids can be prepared with a variety of counterions (anions) including, e.g., Cl-, Br-, I-, F-, acetate, trifluoroacetate, sulfate, nitrite, and nitrate. [0496] Examples of cationic lipids include polyethylenimine, polyamidoamine (PAMAM) starburst dendrimers, Lipofectin (a combination of DOTMA and DOPE), Lipofectase, LIPOFECTAMINE ^TM (e.g., LIPOFECTAMINE ^TM 2000), DOPE, Cytofectin (Gilead Sciences, Foster City, Calif.), and Eufectins (JBL, San Luis Obispo, Calif.). Exemplary cationic liposomes can be made from N-[1-(2,3-dioleoloxy)-propyl]-N,N,N- trimethylammonium chloride (DOTMA), N-[1-(2,3-dioleoloxy)-propyl]-N,N,N- trimethylammonium methylsulfate (DOTAP), 3.beta.-[N-(N′,N′- dimethylaminoethane)carbamoyl]cholesterol (DC-Chol), 2,3,-dioleyloxy-N- [2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate (DOSPA), 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide; and dimethyldioctadecylammonium bromide (DDAB). Oligonucleotides can also be complexed with, e.g., poly (L-lysine) or avidin and lipids may, or may not, be included in this mixture, e.g., steryl-poly (L-lysine). [0497] Cationic lipids have been used in the art to deliver oligonucleotides (as well as mRNA vaccines) to cells. Other lipid compositions which can be used to facilitate uptake of the instant oligonucleotides can be used in connection with the methods of the invention. In addition to those listed above, other lipid compositions are also known in the art and include, e.g., those taught in US 4,235,871; US 4,501,728; 4,837,028; 4,737,323. [0498] In one embodiment, lipid compositions can further comprise agents, e.g., viral proteins to enhance lipid-mediated transfections of oligonucleotides. In another embodiment, N-substituted glycine oligonucleotides (peptoids) can be used to optimize uptake of oligonucleotides. [0499] In another embodiment, a composition for delivering oligonucleotides of the invention comprises a peptide having from between about one to about four basic residues. These basic residues can be located, e.g., on the amino terminal, C-terminal, or internal region of the peptide. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic 1004921453 acid), uncharged polar side chains (e.g., glycine (can also be considered non-polar), asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Apart from the basic amino acids, a majority or all of the other residues of the peptide can be selected from the non-basic amino acids, e.g., amino acids other than lysine, arginine, or histidine. Preferably a preponderance of neutral amino acids with long neutral side chains are used. [0500] In one embodiment, oligonucleotides are modified by attaching a peptide sequence that transports the oligonucleotide into a cell, referred to herein as a “transporting peptide”. In one embodiment, the composition includes an oligonucleotide which is complementary to a target nucleic acid molecule encoding the protein, and a covalently attached transporting peptide. [0501] In a further embodiment, the oligonucleotide is attached to a targeting moiety such as N-acetylgalactosamine (GalNAc), an antibody, antibody-like molecule or aptamer (see, for example, Toloue and Ford (2011) and Esposito et al. (2018)). Administration [0502] In one embodiment, the oligonucleotide of the disclosure is administered systemically. In another embodiment, the oligonucleotide of the disclosure is administered topically. [0503] As used herein “systemic administration” is a route of administration that is either enteral or parenteral. [0504] As used herein “enteral” refers to a form of administration that involves any part of the gastrointestinal tract and includes oral administration of, for example, the oligonucleotide in tablet, capsule or drop form; gastric feeding tube, duodenal feeding tube, or gastrostomy; and rectal administration of, for example, the oligonucleotide in suppository or enema form. [0505] As used herein “parenteral” includes administration by injection or infusion. Examples include, intravenous (into a vein), intra-arterial (into an artery), intramuscular (into a muscle), intra-cardiac (into the heart), subcutaneous (under the skin), 1004921453 intraosseous infusion (into the bone marrow), intradermal, (into the skin itself), intrathecal (into the spinal canal), intraperitoneal (infusion or injection into the peritoneum), intra-vesical (infusion into the urinary bladder). transdermal (diffusion through the intact skin), transmucosal (diffusion through a mucous membrane), inhalational. [0506] In one embodiment, administration of the pharmaceutical composition is subcutaneous. [0507] Preferably, administration of the pharmaceutical composition is intravenously or topically, preferably intravenously. [0508] The oligonucleotide may be administered as single dose or as repeated doses on a period basis, for example, daily, once every two days, three, four, five, six seven, eight, nine, ten, eleven, twelve, thirteen or fourteen days, once weekly, twice weekly, three times weekly, every two weeks, every three weeks, every month, every two months, every three months to six months or every 12 months. [0509] In one embodiment, administration is 1 to 3 times per week, or once every week, two weeks, three weeks, four weeks, or once every two months. [0510] In one embodiment, administration is once weekly. [0511] In one embodiment, a low dose administered for 3 to 6 months, such as about 25-50mg/week for at least three to six months and then up to 12 months and chronically. [0512] Illustrative doses are between about 10 to 5,000mg. Illustrative doses include 25, 50, 100, 150, 200, 1,000, 2,000mg. Illustrative doses include 1.5 mg/kg (about 50 to 100mg) and 3 mg/kg (100-200mg), 4.5 mg/kg (150-300mg), 10 mg/kg, 20 mg/kg or 30mg/kg. In one embodiment doses are administered once per week. Thus in one embodiment, a low dose of approximately 10 to 30, or 20 to 40, or 20 to 28 mg may be administered to subjects typically weighing between about 25 and 65kg. In one embodiment the oligonucleotide is administered at a dose of less than 50 mg, or less than 30 mg, or about 25 mg per dose to produce a therapeutic effect. 1004921453 Examples Example 1 – Materials and Methods Cell Culture and Stimulation [0513] 293XL-hTLR7-HA, 293XL-hTLR8-HA stably expressing human TLR7 or TLR8 were purchased from Invivogen, and were maintained in Dulbecco’s modified Eagle’s medium plus L-glutamine supplemented with 1× antibiotic/antimycotic (Thermo Fisher Scientific) and 10% heat-inactivated foetal bovine serum (referred to as complete DMEM), with 10 μg/ml Blasticidin (Invivogen). Human acute myeloid leukemia THP-1 cells were grown in RPMI 1640 plus L-glutamine medium (Life Technologies) complemented with 1x antibiotic/antimycotic and 10% heat inactivated foetal bovine serum (referred to as complete RPMI). THP-1 cells were not differentiated with PMA in any experiments unless otherwise noted, and rather used in suspension. RAW264.7- ELAM macrophages , TLR7-deficient RAW264.7 cells and immortalized wild-type BMDMs (Ferrand et al., Frontiers in Cellular and Infection Microbiology, 2018; 8: 87) , along with TLR7/8 double-deficient immortalized BMDMs were grown in complete DMEM. All the cells were cultured at 37°C with 5% CO2. Cell lines were passaged 2-3 times a week and tested for mycoplasma contamination on routine basis by PCR or using Mycostrip (Invivogen). [0514] Indicated cells were treated with indicated concentration of oligonucleotides or Enpatoran (MedChemExpress) for 20-60 min, prior to R848 (Invivogen), uridine (Sigma) or Motolimod (MedChemExpress), as indicated. Desalted trimer and longer oligonucleotides were synthesised by Integrated DNA Technologies (IDT) or Syngenis Pty Ltd or Wuxi AppTec, and resuspended in RNase-free TE buffer, pH 8.0 (Thermo Fisher Scientific). For in vivo experiments, the oligonucleotides were HPLC-purified and confirmed to be endotoxin free by Lonza PYROGENT Ultra Limulus Amebocyte Lysate gel-clot method. Sequences and modifications are provided in Tables 1 – 3.2′-MOE is moX, 2′-MOE is mX, DNA is dX, and phosphorothioate inter-nucleotide linkages are denoted with a *. Luciferase Assays [0515] HEK293 cells stably expressing TLR8 or TLR7 were reverse-transfected with pNF-κB-Luc4 reporter (Clontech), with Lipofectamine 2000 (Thermo Fisher Scientific), 1004921453 according to the manufacturer’s protocol. Briefly, 500,000-700,000 cells were reverse- transfected with 200-400 ng of reporter with 1.2 μl of Lipofectamine 2000 per well of a 6-well plate, and incubated for 3-24 h at 37 °C with 5% CO ² . Following transfection, the cells were collected from the 6-wells and aliquoted into 96-wells, just before trimer and overnight TLR stimulation (as above described). Similarly, the RAW264.7 cells stably expressing and ELAM-Luc reporter were treated overnight. The next day, the cells were lysed in 40 μl (for a 96-well plate) of 1X Glo Lysis buffer (Promega) for 10 min at room temperature.15 μl of the lysate was then subjected to firefly luciferase assay using 40 μl of Luciferase Assay Reagent (Promega). Luminescence was quantified with a Fluostar OPTIMA (BMG LABTECH) luminometer. RNA Reverse Transcription Quantitative Real-Time PCR (RT-qPCR) [0516] Total RNA was purified from cells using the ISOLATE II RNA Mini Kit (Bioline). Random hexamer cDNA was synthesized from isolated RNA using the High-Capacity cDNA Archive kit (Thermo Fisher Scientific) according to the manufacturer’s instructions. RT-qPCR was carried out with the Power SYBR Green Master Mix (Thermo Fisher Scientific) on the QuantStudio 6 RT-PCR system (Thermo Fisher Scientific). Each PCR was carried out in technical duplicate and human 18S was used as reference gene. Each amplicon was gel-purified and used to generate a standard curve for the quantification of gene expression (used in each run). Melting curves were used in each run to confirm specificity of amplification. Detection of Cytokines [0517] Human IP-10, TNFα, and IL-6 levels were measured using supernatants from the different cultures and were quantified using IP-10 (BD Biosciences, #550926), TNFα (BD Biosciences, #555212), and IL-6 (BD Biosciences, # 555220) ELISA kits respectively, according to the manufacturers’ protocol. Tetramethylbenzidine substrate (Thermo Fisher Scientific) was used for quantification of the cytokines on a Fluostar OPTIMA (BMG LABTECH) plate-reader. Potentiation of TLR8 in humanised TLR8/TLR7 mice [0518] Spleens were harvested from 3 C57/BL6 and 3 humanised C57BL/6- Tlr8 ^tm1(TLR8) Tlr7 ^tm1(TLR7) /Bcgen (B-hTLR8/hTLR7) mice, and splenocytes isolated by passing the spleens through a 70 ^m cell strainer. Following red blood cell lysis, cells 1004921453 were washed and resuspended in RPMI 1640 (Gibco) supplemented with 10 % heat- inactivated foetal bovine serum (FBS) (ExCell) before seeding in technical triplicates at 3×10 ⁵ cells/well in a 96-well flat-bottom polystyrene TC-treated microplate. Cells were pre-treated with 5 ^M of TLR8 potentiating oligo 38-2, or a vehicle control (TE buffer) for 1 h before addition of 1 ^g/mL Resiquimod (R848) (MedChemExpress; HY-13740) overnight. The next day, supernatants were harvested for measurement of TNF levels by ELISA using the LegendMax™ Mouse TNF ELISA kit (Biolegend; 430907). Potentiation of TLR8 in human skin explants [0519] Healthy human skin tissue was obtained from surgical residual sources with full ethical consent.48 full-thickness 3 mm × 3 mm punch biopsies (including the epidermis, dermis, and hypodermis) obtained from 1 human donor were equilibrated overnight in basal skin culture medium. The following day, biopsies were inserted into Transwell filters (Corning) in 12-well culture plates, with the epidermis facing upwards at the air- liquid interface and the dermis suspended in 1 mL culture medium, and incubated at 37 ^C + 5 % CO2. The biopsies were then pre-treated with 5 ^M TLR8 potentiating oligo, 38-2, or a vehicle control (TE buffer), for 30 min before addition of 600 nM Motolimod (Cambridge Bioscience; CAY22952) or a vehicle control (DMSO) for 24 h. Media were harvested for measurement of IL-8 levels by flow cytometry beads. Co-encapsulation of GGC-v1 with mRNA inside lipid nanoparticles [0520] 1 mg of CleanCap® FLuc mRNA (TriLink; L-7602) was pre-mixed by pipetting, or not, with 0.2 mg GGC-v1 (5:1 ratio by weight) before encapsulation in lipid nanoparticles (LNPs) with the composition of III-3: IVa PEG-lipid: DSPC: Cholesterol = 47.4:10:40.9:1.7 (by molar ratio) using a Nanoassemblr Ignite (PrecisionNanoSystems). Concentrations of the LNP-formulated mRNA samples were adjusted to 0.2 g/L. LNP particle size, polydispersity index (PDI), zeta potential, and mRNA encapsulation rate were assessed. LC-MS/MS and RT-qPCR were used to quantitate GGC-v1 and mRNA, respectively, in the LNPs. Co-delivery of GGC-v1 with mRNA in vivo [0521] Female 8-week-old 129X1/SvJ mice (Jackson Laboratories) (~25 g) were injected intravenously (i.v.) with ~20 ^g FLuc mRNA (actual 20.349 ^g and 20.484 ^g) encapsulated in LNPs with, or without, GGC-v1 (see details above). Bioluminescence 1004921453 imaging was performed at 6 and 24 h post-injection using an IVIS Spectrum®. Briefly, mice were anaesthetised with 4 % isoflurane, and 3 mg/mouse d-luciferin potassium salt was administered i.v. in order to quantify luminescence expression using images recorded for 3 minutes starting 5 minutes post-luciferin injection. For bioluminescence image analysis, regions of interest encompassing the area of signal were defined using the IVIS Spectrum, and the total number of photons per second [counts/second (cps)] was recorded. Blood was sampled at 6 h post-injection by submandibular bleed and terminally at 24 h post-injection, via cardiac bleed, for serum quantification of IFN- ^ by ELISA (Invitrogen; BMS 6027) and other inflammatory cytokines by Bio-Plex Multiplex Immunoassay (BIORAD; custom 8-plex). Livers were also collected at 24 h and snap- frozen at -80 ^C until analysis. To measure luciferase activity, livers were homogenised in Luciferase Cell Culture Lysis Reagent (Promega), sonicated and vortexed, followed by centrifugation for 10 minutes at 4 °C and 15,000 rpm. Supernatant samples were then mixed with Luciferase Assay reagent, and luminescence measured using a plate reader within 5 minutes. Luciferase activity was quantified as relative light units (RLU). Statistical Analyses [0522] Statistical analyses were carried out using Prism 9 (GraphPad Software Inc.). Every experiment was repeated a minimum of two independent times (except the trimer screens for which key trimers were validated in independent experiments). One-way analyses of variance (ANOVA) were used when comparing groups of conditions, while two-tailed unpaired non-parametric Mann-Whitney U tests or unpaired two-tailed t-tests were used when comparing pairs of conditions. Symbols used: * P≤0.05, ** P≤0.01, *** P≤0.001, **** P≤0.0001 and “ns” is non-significant. Example 2 – Structure activity relationship of GUC inhibition on human TLR7 [0523] The 2′-OMe/DNA-containing C2Mut1-dC oligonucleotide (mG*mG*mU*dA*dT*dC*dC*dC*dC*dC*dC*dC*dC*dC*dC*dC*dC*dC*dC*dC where mX is a 2′-OMe modified base, dX a DNA base and * a phosphorothioate inter-nucleotide linkage) has been demonstrated to inhibit human TLR7 sensing. To determine the motif exhibiting the inhibitory effects of C2Mut1-dC the inventors investigated mutants of the 5′-end region of C2Mut1-dC, generating 3′-end variants C2Mut1-dC2 and C2Mut1-dC3 which harbor a mG*mG*mU*dA or a mG*mG*mU*dC motif. Both C2Mut1-dC2 and C2Mut1-dC3 inhibited TLR7 sensing. Conversely, changing the mG*mG*mU*dA into a 1004921453 MG*MG*MU*dA or LG*LG*LU*dA (where M is MOE and L is LNA) significantly decreased the inhibitory effect of C2Mut1-dC2 (Figure 1). [0524] Based on these observations, the inventors directly tested the effect of the 5- mer oligo mG*mG*mU*dA*dT (5-Short-Mut1-Hyb) and its associated trimers mG*mG*mU, mG*mU*dA and mU*dA*dT, as well as mG*mU*dC to reflect the motif in C2Mut1-dC3 (Figure 2). mG*mG*mU was found to be only modestly inhibiting (~25% at 5 μM), while mG*mU*dA and mG*mU*dC were as potent as the 5mer oligo (also noting that mU*dA*dT only had a marginal effect – Figure 2). [0525] These observations confirm that trimers could retain inhibitory activity on TLR7 sensing albeit containing a DNA moiety on their 3 ^rd base. To test whether other bases could tolerate DNA modification in the trimers, the inventors next assessed the activity of 6 variants of GUC with DNA moieties incorporated at different positions. As shown in Figure 3, while DNA modification at the 3 ^rd position (GUCv1) had no impact on inhibition, it significantly decreased activity at the 2nd (GUCv2) and 1st base (GUCv3). Interestingly, combining two DNA bases at 2 ^nd and 3 ^rd base (GUCv4) was more inhibitory than a single DNA modification at the 2 ^nd base – which, without being bound by theory, may be attributed to the fact that DNA modification of the 3 ^rd base is actually more inhibitory than a 2′-OMe base at this position. As such, GUCv1 was found to be more inhibitory than the native full 2′-OMe GUC trimer (see Figure 5). Critically, DNA substitution of the 1 ^st base, as seen in GUCv3, v5 and v6, had the strongest negative effect on TLR7 inhibition. [0526] Having shown that DNA modifications were compatible with TLR7 inhibition by the trimers, the inventors next investigated whether RNA modifications and inter- nucleotide modifications were also involved in the immunosuppressive effects of the trimers (Figure 4). RNA bases on phosphodiester (PO) or phosphorothioate (PS) backbone did not inhibit R848 sensing (see GUC-v7 and v9), but these trimers did not activate any response either in the absence of R848. Substitution of mU by rU in GUC- v8 was still inhibitory – although with a decreased effect compared to fully 2′-OMe GUC. mGrUrC (on PO backbone) did not inhibit nor did it activate any response. [0527] The inventors next tested whether modification of the chemistry of the 2′-OMe bases could be used to improve inhibition of the trimers. First 5 variants of mG*mU*mC, were tested including two modifications of the mG, two of the mU and one of the mC. 1004921453 [0528] As shown in Figure 5, substitution of mG with 2′-OMe-2,6-diaminopurine or 2′- OMe-I, or mU with 2′-OMe-5-Me-U or 2′-OMe-5-Br-U, retained strong inhibitory activity at 5μM, however, substitution of mG with 2′-OMe-2,6-diaminopurine or mU with 2′- OMe-5-Me-U or 2′-OMe-5-Br-U significantly decreased the inhibitory activity of GUC at 200 nM (while substitution of mG 2′-OMe-I inhibited as well as GUC at this dose). Critically, substitution of mC with with 2′-OMe-5-Me-C significantly increased TLR7 inhibition 200nM and 50nM (see GUC-v19) (Figure 5). This demonstrates that modification of the Cytosine base with an additional methyl group, as seen in GUC-v19, can improve TLR7 inhibition. It is worth noting that GUC-v19 had ~50% inhibition at 50nM, which is only seen at 200nM for the native 2′-OMe GUC. This is a ~4X improvement of IC50. [0529] Taken together with the prior finding that the deoxyribose for this base (with the dC variant) in GUC-v1 was also more potent, the inventors next tested a series of GUC variants focussing on the Cytidine. The inventors tested the selective replacement of mC and dC in mG*mU*mC with LNA, 2′-MOE, 2′-Fluor and RNA C (i.e. GUC-v11-14), or modified Cytidine (i.e. GUC-v20, 21, 23, 24, 26 – with 5-methyl modified deoxycytidine, 5-bromo modified deoxycytidine, 5-hydroxymethyl modified deoxycytidine, 2′ deoxy-3′ deoxy cytidine, and 5-propynyl modified deoxycytidine), on PS backbone. These experiments showed that the modification of Cytidine, retained strong TLR7 inhibition (Figure 7). [0530] Collectively these structure activity relationship analyses confirm that GUC trimers are very potent inhibitors of TLR7. The inventors next compared the GUC-v19, GUC-v1 and full 2′-OMe GUC trimers in head-to-head dose responses in HEK TLR7 cells (Figure 8). The trimers were clearly very potent inhibitors with GUC-v19 being the most potent with an IC50 projected below 100 nM. [0531] Importantly, screen analyses of 2′-OMe trimers suggested the strongest potency for GUX motifs, where X could be mC, mG, mU or mA. The observation that mG*mU*dA and mG*mU*dC both retained inhibitory function suggested that mG*mU*dX (where dX is a DNA base) would also be inhibiting TLR7. The inventors next tested whether the di-nucleotide mG*mU could also inhibit TLR7. As shown in Figure 9A, although clearly capable of inhibiting TLR7 sensing at high dose (5uM), 1004921453 mG*mU was a weaker inhibitor of TLR7 compared to the mG*mU*mC trimer, with most of its inhibitory activity lost below 5uM (Figure 9B). [0532] This finding confirms the importance of the 3 ^rd base for inhibition of TLR7 – also consistent with the capacity of the 3 ^rd base to increase potency of the inhibition seen with GUC-v1 and GUC-v19. However, to define whether the optimal length for inhibition is 3, 4 or 5 bases the inventors compared the inhibitory activity of mG*mU*mA, mG*mG*mU*mA and mG*mG*mU*mA*mU on TLR7 inhibition. The inventors also compared mG*mU*dC to the 5 mer mG*mG*mU*dC*dT, along with the activity of two mG*mU*dC trimers linked in 5′-3′-3′-5′ orientation with a Triethylene glycol (TEG) linker (Figure 10). [0533] Collectively, these results established the fact that while longer molecules could also inhibit TLR7 with similar potency at higher dose (e.g. with the 5-mer Short- Mut-1 at 5 μM), the GUC-v1 trimer was the optimal length for maximum inhibition at lower dose (500 nM). Critically, fusion of two GUC-v1 trimers with a TEG linker retained strong inhibitory activity even at 50 nM - concentration at which a single GUC-v1 trimer is not inhibitory. This suggests that the TEG linker is cleaved to release two molecules of GUC-v1 for each molecule of linked oligo, underlying their stronger activity. This demonstrates the potential to fuse trimers with linkers such as TEG (which could be further functionalised for specific cellular uptake), while retaining TLR7 inhibitory activity. [0534] Since trimers containing as few as a single 2′-OMe moiety combined with two DNA moieties retained inhibitory activity on TLR7 (as seen with GUC-v4), the inventors next tested all possible 64 combinations of DNA trimers on TLR7 inhibition. Comparison of inhibition at 2 μM showed that only 3 DNA trimers inhibited TLR7 by more than 20% (TCT, TTT and TTG), versus 26 for 2′-OMe (Figure 11). Similarly, the inventors tested 64 combinations of 2′-MOE trimers on TLR7 inhibition. No MOE trimers inhibited more than 20% at 5 μM, with GAA the most potent with only 19% inhibition at this high dose (Figure 11). [0535] To complement these studies, the inventors also tested 32 mG*X*X hybrid variants with the second and/or third base being DNA bases (Figure 12). These analyses, performed at 5 μM and 500 nM confirmed the capacity of mG*mU*dX variants to strongly inhibit human TLR7 sensing – with mG*mU*dC being the most potent inhibitors followed by mG*mU*dG, mG*mU*dA, mG*mG*dC and mG*mU*dT (which 1004921453 were similarly observed with fully 2′-OMe modified trimers). However, DNA modification of both 2 ^nd and 3 ^rd bases (as seen with mG*dX*dX molecules) were less inhibitory than trimers with a single DNA modification, aligning with the results from GUC variants in Figure 3. Example 3 – Trimer inhibition of mouse TLR7 [0536] Unlike the potent inhibition of TLR7 sensing seen in human cells with 2′-OMe GUC, these trimers are weak inhibitors of mouse TLR7. The inventors therefore tested a panel of 642′-OMe trimers on mTLR7 sensing in RAW 264.7 cells stably expressing an ELAM-luciferase reporter, which is activated by R848 sensing (Zamanian-Daryoush et al., J Interferon Cytokine Res, 2008; 28(4): 221-33). This screen was carried out at two doses of R848 (0.5ug/ml and 0.125ug/ml), and identified GGC, GAC and GAG as the most potent inhibitors of mouse TLR7 sensing (Figure 13). The inventors also tested the panel of 64 DNA trimers on mouse TLR7 sensing and observed a mild inhibition with 8 trimers inhibiting more than 20% at 5 μM (the maximum being 27% inhibition with ACG). At this dose however, 162′-OMe trimers inhibited mTLR7 by more than 20%, showing a clear superiority for 2′-OMe trimers (Figure 13). [0537] To define whether, like human TLR7, mouse TLR7 inhibition could be increased upon DNA substitutions of selected bases of the trimers, the inventors next tested a panel of 6 variants for 2′-OMe GGC and GAG (Figure 14). Similar to what was seen for 2′-OMe GUC variants in humans, the v1 mutation of both trimers increased inhibition, while DNA modification of the first mG ablated the activity. Critically, these experiments revealed that for both GGC and GAG, two DNA bases substitutions in v4 trimers were extremely well tolerated and rather improved inhibition compared to the full 2′-OMe trimers (Figure 14). These findings suggested that albeit closely related to human TLR7 sensing, inhibition of mouse TLR7 was slightly differently impacted by trimers – aligning with the superiority of GGC over GUC on the inhibition of mouse TLR7. [0538] The inventors also tested the dose-dependent activity of GGC, GGC-v1 and GGC-v3 head-to-head on mouse TLR7 sensing. GGC-v1 was slightly more potent than GGC, and critically GGC-v3 was devoid of any inhibitory activity (Figure 15). 1004921453 [0539] The inventors next tested whether the trimers could also inhibit TLR7 sensing driven by an immunostimulatory ssRNA, referred to as B-406-AS-1 (Sarvestani et al., Nucleic Acids Res, 2015; 43(2): 1177-88). As shown in Figure 16, GGC significantly inhibited ELAM-luc driven by transfection of B-406-AS-1 in RAW-ELAM cells. [0540] Having shown that trimers harbouring 2 DNA bases (e.g. GAG-v4 – Figure 14) were still very potent inhibitors of mouse TLR7, the inventors next assessed the inhibitory effect of the 64 DNA trimers. As shown in Figure 17, DNA trimers were only modestly inhibitory, with only 8 oligos inhibiting more than 20% (with maximum inhibition at 28% at 5 μM for ACG). There was little overlap of inhibition between the chemistries (trimers inhibiting TLR7 with 2′-OMe were not inhibitory when composed of DNA bases) and ACG was the only trimer displaying >20% inhibition for both DNA and 2′-OMe chemistries. [0541] These observations demonstrate that at least one 2′-OMe base is critical for the activity of the trimers on mouse TLR7. To define whether other combinations of mG*mX*dX or mG*dX*dX (where dX is DNA and mX is 2′-OMe) trimers could outperform the activity of mG*dA*dG or mG*mG*dC, the inventors next tested the 32 possible mG*X*X trimers on mouse TLR7. These results identified mG*mA*dC as the most potent inhibitor of TLR7, slightly outperforming the activity of GAG-v4 (mG*dA*dG) and GGC-v1 (mG*mG*dC) (Figure 18). Example 4 – Modulation of TLR8 sensing by trimers [0542] To determine whether 2′-OMe trimers could result in either potentiation or inhibition of TLR8 sensing, the inventors screened single doses of various trimers in HEK-TLR8 and THP-1 cells. As shown in Figure 19, there was a significant correlation of potentiation and inhibition in response to the two doses in each cell type (slightly better in HEK-TLR8). In both cell types, 2′-OMe CGG was the strongest potentiator of R848 or Motolimod sensing. UCG was also a top potentiator in both cells. However, AGG was very potent in HEK-TLR8 but not in THP-1 cells, and UCA/CGC being strong in THP-1 but not in HEK-TLR8. GAX were strong inhibitors of TLR8 in both cell types, with GAG the most potent in THP-1 cells at 1uM. [0543] Given the impact of DNA moieties on TLR7 inhibition, the inventors next tested the effect of successive DNA modification of CGG and GAG following the same scheme 1004921453 as with GUCv1-v6. As shown in Figure 20A and B, in both HEK-TLR8 and THP-1 cells substitution of the last base of 2′-OMe in CGG-v1 with a DNA base retained potentiation, but this was not as potent as the native 2′-OMe CGG sequence. DNA modification at other positions dwarfed the potentiation. [0544] Conversely, GAG-v1, v2, v4 and v5 all conserved a good effect on TLR8 inhibition – across both cell models (Figure 20C and D). GAG-v3 and v6 had less inhibitory effect on TLR8 in both cell types, suggesting that DNA modification of the 5′- terminal G was very important for TLR8 inhibition. [0545] Inhibition of TLR8 with the trimers, was therefore quite similar to what was observed with human and mouse TLR7 inhibition with a prevalent effect of the first 2′- OMe base for inhibition, noting however the retained effect of GAG-v5. GAG-v1 was slightly better than native 2′-OMe GAG in THP-1 and was therefore pursued in further experiments. [0546] Having shown that GAG-v4/5 with two DNA bases retained some inhibitory activity on TLR8, the inventors next assessed the immunomodulatory effect of panels of 64 DNA and 642′-MOE trimers on TLR8 sensing in HEK-TLR8 cells, testing at 1 and 5 μM. As shown in Figure 21, only one trimer (2′-MOE GGT) was increasing TLR8 sensing – and this was very modest compared to 2′-OMe CGG. Conversely, many trimers were partially inhibitory with both chemistries, noting however the low correlation between the two concentrations of 2′-MOE screens (indicating experimental variations rather than true inhibition). On the other hand, the correlation of inhibition was much better for the DNA trimers – with AGT robustly inhibiting TLR8 sensing the most (Figure 21). [0547] Based on this TLR8 inhibitory activity of DNA trimers, and given the strong inhibitory effect of GAG-v4 (mG*dA*dG), the inventors next tested whether other combinations of high dose (5 μM) mG*mX*dX or mG*dX*dX (where dX is DNA and mX is 2′OMe) could inhibit human TLR8. These studies identified mG*dA*dG as the most potent inhibitor of TLR8, while mG*dC*dC was the strongest potentiator (Figure 22A). These observations were further validated in independent experiments at low dose (500nM) of trimers, where mG*dA*dG as the most potent inhibitor of TLR8 (Figure 22B). Critically, mG*dC*dC was a stronger potentiator of TLR8 sensing than mC*mG*mG at this low dose (500nM). These results collectively establish the capacity 1004921453 to modulate the activity of the trimers on TLR8, for both inhibition and potentiation, by using DNA substitutions of selected bases in the 2′-OMe trimers. Example 5 – Alternative modifications for GUC trimers and inhibition on human TLR7 [0548] The inventors’ previous analysis demonstrated that the inhibition of human TLR7 sensing by trimer oligonucleotides could be significantly improved through modification of the 3′-cytidine of 2′-OMe-modified GUC trimer (which was the most potent inhibitor of TLR7 in the inventors previous systematic analyses of all 64 combinations of 2′-OMe trimers. In this respect, modification of the 2′-position of the sugar, for instance with use of 2′-deoxycytidine to replace the 2′-OMe-cytidine in GUC- v1, or modification of the cytosine portion in GUC-v19 (Figures 5 and 6), could both be used to improve inhibitory activity of GUC trimers. Having shown that modification to the 2′-position of cytidine of GUC-v11/v12/v13/v14, removal of the 3′-hydroxy group of cytidine in GUC-v24 or modification to the cytosine base in GUC-v20/v21/v23/v26 retained activity at 5 μM (Figure 7), the inventors next tested these trimers at 50 nM compared to parental 2′-OMe-modified GUC. [0549] These analyses identified 3 trimers which were significantly inhibiting at 50 nM: GUC-v13 (with an LNA modification of the sugar), GUC-v20 and GUC-v21 (both with modifications to the 5-position of the cytosine base) (Figure 23). Collectively with the findings from Figure 5 and the results from GUC-v19 (which is the 2′-OMe variant of GUC-v20), these results give direct insights into the positions of the cytosine base which can be used to increase TLR7 inhibition. As such, 5-methyl or 5-bromo modifications of cytosine (in GUC-v19/20 and GUC-v21) increased inhibition. However, further modification of this 5-position with a hydroxymethyl group, in GUC-v23, or with a 5-propynyl group in GUC-v26 ablated inhibition (see Figure 6 for structural details). GUC-v13, which contains an LNA modification of its sugar was the most potent in these experiments. Dose-response analyses established that its IC50 on TLR7 inhibition was as low as 18 nM versus 77 nM for parental 2′-OMe-modified GUC. Importantly the activity of GUC-v13 was close to that of Enpatoran, a small molecule inhibitor of TLR7/8 (Figure 24). [0550] However, when the inventors tested a small panel of fully modified LNA or MOE trimers, including LNA GUC, none of these significantly inhibited TLR7 even when used at the high dose of 2 ^M (Figure 25). Collectively this indicates that while full LNA 1004921453 modification of GU[X] trimers ablates inhibitory activity, selected nucleotide LNA modification can rather increase inhibition. [0551] To define how selected LNA modification of the 3′-end nucleotide of otherwise 2′-OMe modified trimers impacted their activity on TLR7, the inventors designed a panel of 16 mG*mX*LX and mU*mX*LX trimers, where the 1 ^st and 2 ^nd nucleotides are 2′-OMe modified and the 3 ^rd is LNA-modified, and tested this panel on HEK TLR7 cells (Figure 26). [0552] The experiments shown in Figure 26A revealed that in the context of LNA modification of the 3 ^rd nucleotide, GUC-v13 (i.e. mG*mU*IC) was still the most potent trimer inhibiting hTLR7. These studies also showed that trimers containing GU[X] and GA[X] are the most potent inhibitors. Critically, direct comparison of the 3 ^rd base LNA modified trimers with full 2′-OMe trimers at 400 nM confirmed a direct correlation (r=0.6335 P<0.0001) of inhibition between the two classes of trimers (Figure 26B). Nonetheless, 3 ^rd base LNA modification increased the potency of inhibition in a sequence specific manner, with 17/32 trimers inhibiting more than 20% at 400 nM, versus 5/32 for full 2′-OMe trimers (GU[X] and UUC). This was particularly evident with the mG*mA*LX trimers which were much stronger inhibitors with the LNA moiety. Importantly, the majority of the strongest inhibitors contained a 5′-mG (with 14/16 mG*mX*LX trimers inhibiting 20% or more), underlining further the importance of this base in human TLR7 inhibition. [0553] Having shown that extension of GUC-v1 with a TEG linker and another 3′-5′ GUC-v1 monomer (GUC-v1 Linked 3′-5′) strongly increased TLR7 inhibition (Figure 10), the inventors next investigated whether the TEG group alone, appended to GUC-v1 could increase TLR7 inhibition. The inventors also tested the activity of Cholesterol and Tocopherol 3′-end conjugation to GUC-v1 to define whether these groups could be later used for delivery of naked trimers (Figure 27). [0554] These experiments revealed that 3′-TEG conjugation did not significantly improve GUC-v1 driven TLR7 inhibition, suggesting that the increased activity of GUC- v1-linked, containing two moieties of GUC, is rather due to a doubling of endosomal concentration of the trimer rather than its increased resistance to nucleases (Figure 27B). Similarly, addition of a 3′ cholesterol (GUC-28) or Tocopherol (GUC-29) to GUC- v1 rather decreased its inhibitory activity, albeit clearly maintaining significant inhibitory 1004921453 function at 200 nM (Figure 27A). These results collectively suggest that increased protection from 3′-5′ end degradation is probably not why LNA (in the context of GU[X/]GA[X] trimers) has an increased inhibitory activity on TLR7. [0555] Having previously shown that substitution of 2′-OMe-guanosine with 2′-OMe- inosine in GUC-v16 was at least as good as parental GUC and GUC-v1 (Figure 5), the inventors decided to investigate the activity of GUC-v35/v36 with various 2′-OMe- inosine modifications (Figure 6). The inventors also tested whether substitution of 2′- OMe-uridine with pseudo-uridine at the second position of GUC-v1 could be used to potentiate further inhibition (Figure 28). [0556] These studies revealed that the DNA and RNA inosine modifications in GUC- v35 and v36 strongly dampened the inhibitory activity of parental 2′-OMe GUC or GUC- v16, losing nearly all inhibition even at the very high dose of 5 ^M (Figure 28A). GUC- v31, while retaining inhibitory function at high concentration was also much less inhibitory than GUC-v13/16/30 at 1 ^M, indicating that this modification limited inhibition (Figure 28B). Head-to-head dose-response analyses of GUC-v30 (mI*mU*LC) and GUC-v13 demonstrated that while both sequences displayed equivalent inhibitory activity above 125 nM, GUC-v13 was more potent at lower doses (GUC-v13 IC50 = 40 nM vs GUC-v30 IC50 = 62 nM in these experiments) (Figure 29). These results confirm the strong activity of the 3 ^rd base LNA modification in the GUC context but also reveal that 5′- end 2′OMe-inosine modification in this context does not improve further TLR7 inhibition. The results with GUC-31 suggest that pseudo-uridine modification rather decreases the activity of 2′-OMe uridine on TLR7 inhibition (confirming 2′-OMe uridine is the most potent at this position) (Figure 28 and 29). [0557] Finally, the inventors tested a panel of 32 trimers with DNA and 2′-OMe modifications to extend the findings show in Figure 12 with mG*d[X]*d[X] trimers, now using mU*d[X]*d[X] and mC*d[X]*d[X] trimers. [0558] This screen at the high dose of 5 ^M of trimer confirmed that mGmUmC was much more potent than any other oligonucleotides tested (Figure 30). mUdTdC, mUdTdA, mUdAdA, mUdGdC, mUdTdT, mUdGdT were the most potent inhibitors but only reaching ~50-75% inhibition which was rather weak at this very high dose. Interestingly all the trimers exhibiting inhibitory activity here started with mU and 1004921453 mUdTd[X] was over-represented. None of the mCd[X]d[X] trimers inhibited TLR7 sensing. Example 6 – Alternate trimers for inhibiting mouse TLR7 [0559] The inventors previous analyses of LNA- and MOE-modified 20-mer oligonucleotides in Figure 1 suggested that these modifications dampened TLR7 inhibition in human cells. To define whether this was also the case on mouse TLR7 the inventors tested the panel of Mut1-dC variants on RAW-ELAM cells. [0560] In support of the importance of the 5′-end region of C2Mut1-dC in its inhibitory effect on mouse TLR7, 3′-end variants C2Mut1-dC2 and C2Mut1-dC3 which harbor a mG*mG*mU*dA or a mG*mG*mU*dC motif, both inhibited mouse TLR7 sensing (Figure 31). Conversely, changing the mG*mG*mU*dA into a MG*MG*MT*dA or LG*LG*LT*dA (where M is MOE and L is LNA) significantly decreased the inhibitory effect of C2Mut1-dC2 (Figures 1 and 31). [0561] Based on these observations, the inventors directly tested the effect of the 5- mer oligo mG*mG*mU*dA*dT (5-Short-Mut1-Hyb) and its associated trimers mG*mG*mU, mG*mU*dA and mU*dA*dT (the inventors also included mG*mU*dC to reflect the motif in C2Mut1-dC3) on mouse TLR7 sensing (Figure 32). Consistent with the previous screen analyses (Figures 13 and 17), mG*mG*mU was only modestly inhibiting (~50% at 5 ^M), while mG*mU*dA and mG*mU*dC were more potent (as per the screen of mGd[X]d[X] oligo in Figure 17). Interestingly given that parental mG*mU*mC only had a very marginal inhibitory activity on mouse TLR7 in the screen (~18%), mG*mU*dC was the most potent trimer oligo in these experiments (Figure 32). This suggested that even in the not so favourable sequence context of GUC, 3′-end modification could be used to increase mouse TLR7 inhibition. This observation prompted the inventors to analyse the broad effect of the panel of GUC variants on mouse TLR7. [0562] As anticipated, unlike what was seen for human TLR7 where GUC is the optimal sequence context, most of the GUC variants had little activity on mouse TLR7 sensing (Figure 33). Yet, DNA modification of the cytidine in GUC-v1, GUC-v20, GUC- v21 and GUC-v26 was associated with increased inhibition compared to parental 2′OMe-modified GUC. This suggests that modification of the 2′-position of the sugar 1004921453 can improve inhibitory activity on mouse TLR7, in agreement with the findings for GGC- v1 and GAG-v1/v2/v4 (Figure 14). It should be noted that other 2′-modifications of the cytidine in GUC-v11–GUC-v14, which included 2′-hydroxy (RNA), 2′-O-MOE, LNA- modified and 2′-fluoro, did not show an improvement over 2′-OMe-cytidine. Additionally, the lack of activity in GUC-v24 with a 2′,3′-dideoxycytidine indicates that the terminal 3′- hydroxy group is important for activity. [0563] Modification of 2′-OMe-guanosine in GUC-v15/v16 increased inhibition of mouse TLR7 (Figure 33). The result of GUC-v15 with the guanine modified to a 2,6- diaminopurine demonstrates that conversion of the 6-carbonyl group to a 6-amino group improves the inhibitory activity of the 3-mer, whilst conversion to hypoxanthine in GUC- v16 through removal of the guanine’s 2-amino group, resulting in 2′-OMe-inosine, shows that the 2-amino group may be non-essential, to in vitro potency. Furthermore, this suggests that 2′-OMe-guanosine modification into 2′-OMe-inosine of the optimal sequence context, GGC, may further potentiate inhibition on mouse TLR7. [0564] Similar to the HEK TLR7 results, further modification of the 5-methyl group to 5-hydroxymethyl in GUC-v23 saw a reduction in inhibition. However, extension to a larger 5-propynyl group in GUC-v26 was more tolerated than in the HEK results with a similar response to 5-methyl. Interestingly again, GUC-v1-linked which contains two moieties of GUC was the most potent molecule which is hypothesised to be attributed to the increase molarity following endosomal uptake. [0565] Following on these results and finding that modification of LNA of the cytosine in GUC-v13 strongly increase inhibitory activity on human TLR7, the inventors synthesised an LNA variant of GGC, referred to as GGC-v7, with a 3′-LNA-modified cytosine. [0566] In accordance with the observations with GUC-v13 on human TLR7, LNA modification of the cytosine of GGC-v7 also resulted in increased potency on mouse TLR7 sensing (Figure 34). Given that mouse TLR7 recognition of trimers is clearly slightly different from human TLR7 from a structural point of view (leading to preferential binding of GGC in mouse), this converging result indicates that the molecular interactions promoted by the LNA Cytosine may be beneficial for the inhibition of human and mouse TLR7 sensing. 1004921453 [0567] Similar to the human data, and consistent with the data with longer oligos shown in Figure 30, analyses of a small panel of fully LNA modified GU[X] panel, including GGC and GUC, showed that full LNA modification of the trimers mostly abolished their inhibitory function on mouse TLR7 (noting a minor inhibitory effect with LG*LT*LC and LT*LT*LC) (Figure 35). To define how selected LNA modification of the 3′-end nucleotides of otherwise 2′-OMe modified trimers impacted their activity on mouse TLR7, the inventors next tested the panel of 32 mGm[X]L[X] and mUm[X]L[X] trimers, where the 2 ^nd nucleotide is 2′-OMe modified and the 3 ^rd is LNA modified, on RAW-ELAM cells. [0568] The experiments shown in Figure 36 revealed that in the context of LNA modification of the 3 ^rd nucleotide, GGC-v7 was the strongest inhibitor of mTLR7 followed by GA[X] trimers. [0569] Having previously shown that mG*dA*dG (GAG-v4) displayed potent mTLR7 inhibition (Figure 14), the inventors next decided to expand the mG*d[X]*d[X] hybrid screens (from Figure 18) to include mU*d[X]*d[X] and mC*d[X]*d[X]. [0570] These analyses demonstrated that, similar to what the screen on full 2′-OMe trimers indicated (Figure 14), trimers starting with a 2′-OMe uridine or cytosine were only weak inhibitors of mouse TLR7, even when DNA modifications of the 2 ^nd and 3 ^rd base were used (Figure 37). As such, mUdGdC, mCdAdA and mUdTdG were the only trimers exhibiting weak inhibitory activity at 5 ^M. [0571] The data generated thus far indicated that mouse TLR7 inhibition could be modulated by DNA modification of the 3′-end nucleotide, and 5′ inosine modification (as seen with GUC-v16). Having shown that mG*mA*mG, mG*mA*dG and mG*mA*LG were potent inhibitors of mouse TLR7, the inventors next tested the inhibitory effect of GAG-v7, containing a 5′ inosine modification (the inventors also tested GAG-v8 with an 3 ^rd LNA base). [0572] These analyses shown in Figure 38 indicate that the 5′-inosine modification of GAG-v7 increases further inhibition of mTLR7 compared to GAG and GAG-v1, confirming further the observation that modification of the 5′-end could be used to modulate inhibition suggested with GUC-v15/v16. Interestingly, the LNA modified GAG- 1004921453 v8 was less potent than the parental 2′-OMe GAG trimer, indicating that in the GAG context the 3 ^rd base being LNA was not optimal for inhibition (unlike for GGC-v7). [0573] Having established the capacity of the GGC-v1 (mG*mG*dC) trimers to potently inhibit mouse TLR7 upon stimulation with R848, the inventors next investigated its capacity to inhibit steady state inflammation driven by constitutive engagement of mouse TLR7 by guanosine in the context of Tlr7 ^Y264H (aka TLR7 ^kika ) mutant macrophages (as per 10.1038/s41586-022-04642-z). Bone marrow-macrophages from 3 TLR7 ^kika/WT female mice and 3 aged matched TLR7 ^WT/WT were differentiated for 5 days in 20% L929 conditioned medium, prior to the addition of 5 ^M of GGC-v1 or 100 nM Enpatoran for 24h and RNA collection on day 6. The RNA was purified and processed for multiplexed RNA sequencing. [0574] There were only 22 genes significantly down-regulated by GGC-v1, among which 20 were also decreased with Enpatoran (Figure 39). Critically, GGC-v1 although used at the high concentration of 5 ^M did not induce any significant transcriptional activity – confirming its specificity. To confirm further these results, 5 genes with strong basal expression were confirmed by RTqPCR. [0575] The RTqPCR analyses confirmed that the 5 genes selected for validation were significantly upregulated in TLR7 ^kika/wt mice compared to WT mice, and that these genes were normalised to WT expression upon overnight treatment of the cells with GGC-v1 or Enpatoran (Figure 40). It is noteworthy that GGC-v1 did not alter expression of these genes basally expressed in WT BMDMs. Collectively this demonstrates that GGC-v1 inhibits the constitutive activation of mouse TLR7-driven by the Kika mutation, in the context of aberrant engagement of site 1 by guanosine. [0576] Given the capacity of GGC-v1 to inhibit R848 and TLR7 driven by the Kika mutation, the inventors also tested the capacity of GGC to inhibit other site 1 agonists of TLR7 compared to Enpatoran, including CL075 and Gardiquimod. [0577] The experiments confirmed that parental 2′-OMe GGC was able to blunt mouse TLR7 signalling driven by a variety of agonists. [0578] Based on these results, the inventors next investigated the capacity of GGC- v1 to inhibit mouse TLR7 in vivo. The inventors tested injection of the trimers using 2 different routes of administration: intravenous, and topical (Figure 42). 1004921453 [0579] In a first model, the inventors tested whether systemic injection of GGC-v1 complexed with the cationic lipid invivo JetPei could dampen R848-induced inflammation in vivo. In this challenge system, the inventors found that GGC-v1 treated mice showed significantly reduced production of TNF levels in circulation in sera, and that expression of selected TLR7-driven genes was significantly reduced in the spleen of the mice. This establishes that GGC-v1 administration can directly block R848-driven TLR7 activation in mice (Figure 42). [0580] To complement these results, the inventors next investigated whether topical administration of GGC-v1 directly to the skin could help alleviate the symptoms of imiquimod (TLR7 agonist)-driven skin inflammation. For this purpose, the inventors relied on the administration of trimers formulated in PBS with Pluronic F-127 which jellifies at room temperature and was previously found to efficiently deliver PS-modified oligos to the skin (Qiu et al., Curr Biol, 2003; 13(19): 1697-703). In this animal model of TLR7-driven psoriasis (Jones et al., J Autoimmun, 2015; 61: 73-80), the inventors applied GGC-v1 just before applying the Aldara (imiquimod) cream to the back of the ear and depilated the back of the mice, for 4 consecutive days. Analyses of the ear thickness with calliper demonstrated a clear decrease of inflammation with the trimer, which was concurrent with decreased redness on the ear, and decreased scaliness of the back. In a repeat independent experiment, the inventors also analysed expression of a set of pro-inflammatory genes in the back skin and confirmed that GGC-1 significantly blunted skin inflammation. Nonetheless, the Aldara treatment did induce inflammation in GGC-v1 mice as revealed by significant splenomegaly which was similar with all Aldara-treated animals. As such, the inhibitory effect of GGC-v1 on TLR7 was localised to the skin in this topical application model (Figure 42). Example 7 – Alternate trimers for modulating human TLR8 sensing [0581] Having previously shown that TLR8 inhibition was greater with the DNA modification of its 3′-end 2′-OMe guanosine in GAG-v1, the inventors were interested to test whether the panel of GUC variants could show any improvement of selected base/sugar modification on human TLR8, even though the sequence context was not optimal. [0582] Analysis of the GUC panel in HEK TLR8 cells stimulated with Motolimod after incubation with 5 ^M of the oligonucleotides revealed that most GUC variants inhibited 1004921453 TLR8 sensing with a comparable potency as the native 2′-OMe GUC trimer (Figure 43) (~25-40%). Nonetheless, one GUC variant was clearly much more potent than the parental 2′-OMe: GUC-v16. This variant relies on the modification of 2′-OMe guanosine into 2′-OMe inosine, suggesting that TLR8 inhibition could be improved using this approach on the 5′-end of the trimers. [0583] To define whether GUC-v16 was also a potent inhibitor at lower doses, the inventors next tested its potency at 500 nM and compared it to GAG-v4 (mGdAdG) and mGmAdT which were also potent TLR8 inhibitors at 500 nM (see Figure 22). [0584] Accordingly, GUC-v16 was significantly more inhibitory than GAG-v4 at 500 nM (Figure 44). The IC50 for GUC-v16 was 190 nM – suggesting that much lower IC50 could be attained in the optimal mGmA(dG/dT) sequence context (Figure 44). [0585] To define whether 2′-OMe inosine variants could increase further the inhibitory activity of trimers on human TLR8 the inventors designed and tested a panel of GUC variants (GUC-v35/v36). The inventors also designed a variant of GAG-v1 using 2′- OMe inosine modification of the 5′-end 2′-OMe guanosine (GAG-v7), and one variant of GAG with a LNA modification of the 3′- Guanosine (GAG-v8). [0586] These experiments demonstrated that, similar to the inosine modification of GUC-v16, inosine modification of GAG-v1 (i.e. GAG-v7) led to stronger inhibition of TLR8 sensing (Figure 45). As such, GAG-v7 had an IC50 of 260 nM in these experiments – suggesting a similar activity to that of GUC-v16. Interestingly however, combination of a 5′-inosine with a 3′-LNA cytosine as in GUC-v30, rather decreased the inhibition of TLR8 (Figure 45A&B). Other inosine variants in GUC-v35-36were only poorly inhibiting TLR8 (suggesting that these modifications rather reduced the inhibitory activity of inosine in this sequence context). It is also noteworthy that 3′-end LNA modification of GAG in GAG-v8 was not as potent as the DNA modification in GAG-v1; the combination of results for GUC-v30 and GAG-v8 suggests that the LNA modification at the 3 ^rd base does not increase further TLR8 inhibition (Figure 45). [0587] To better define the importance of the 3 ^rd LNA base on TLR8 sensing the inventors next tested a panel of 32 mGm[X]L[X] and mUm[X]L[X] trimers, where the 2 ^nd nucleotide is 2′-OMe modified and the 3 ^rd is LNA modified, on HEK TLR8 cells (Figure 46). 1004921453 [0588] The screen of the 32 LNA variants confirmed that GA[X] trimers were the most potent inhibitors, independent of the LNA or 2′-OMe modification of the 3 ^rd base (Figure 46A&B). There was a significant correlation (r=0.63 p<0.0001) between the inhibition of the sequences in both chemistries (Figure 46B). As such, UCG and UGG were strong potentiators of TLR8 with both chemistries. Collectively these analyses indicated, as seen with GUC-v30 and GAG-v8, that LNA modification did not significantly improve inhibition of the trimers, unlike what was seen with these molecules on TLR7 sensing. [0589] Having previously shown that trimers with 2 DNA and a single 2′-OMe bases were potent inhibitors and potentiators of TLR8, the inventors next decided to expand the mGdXdX hybrid screens (from Figure 22) to include mU*d[X]*d[X] and mC*d[X]*d[X]. [0590] These unbiased analyses demonstrated that GAG-v1 was the most potent inhibitor in this setup, confirming that 2′-OMe modification of the 5′-end 2′-OMe guanosine of the trimers was more inhibitory on TLR8 than 2′-OMe uridine or cytosine (Figure 47). Interestingly, when considering the trimers inhibiting TLR8 by >40% at 5 ^M in this screen, these were exclusively starting with 2′-OMe uridine with preferential mUdA(dT/C/G) or mUdT(dG/A/C) sequences. [0591] Conversely, when looking at potentiation, mC*dC*dC was the strongest potentiator of TLR8 sensing, with a clear enrichment for mC*dC*d[X] variants among the top potentiators (which also included mU*dC*dA, mU*dC*dC). mG*dC*dC which was previously identified as the top potentiator could be supplanted further by several of these trimers, with mC*dC*(dC/dT) being the most potent here (Figure 47). [0592] Selected trimers were further validated at 1 ^M – which confirmed that mU*dT*dC was a robust inhibitor of TLR8, while mC*dC*(dC/dT) and mU*dC*dC trimers were robust potentiators of TLR8 at this lower dose (Figure 48). [0593] In addition to these studies, the inventors noticed during the screen of GUC variants on TLR8 (shown in Figure 43) that GUC-v1 and its two-moiety form, GUCv1- linked, rather potentiated TLR8 when compared to parental 2′-OMe GUC. [0594] The inventors therefore tested GUC-v1 and a few GUC variants (v1/v12/v13/v14) on uridine sensing in HEK TLR8 cells. These experiments revealed that GUC-v1, at this high dose, was indeed significantly potentiating sensing of uridine 1004921453 by TLR8 (Figure 49). This suggests that the DNA modification of the 2′-end of this trimer, while increasing TLR7 inhibition, also has the off-target result of increasing TLR8 potentiation – and could therefore present limitations in its therapeutic use aiming at inhibiting both receptors. Critically however, GUC-v13, which has a much stronger TLR7 inhibitory activity than GUC (Figure 24), did not potentiate TLR8 sensing. These results indicate that inhibition of TLR7 can be improved without necessarily leading to TLR8 potentiation. [0595] As shown in Figure 48, mGdCdC is one of the strongest potentiators of human TLR8 sensing. [0596] To confirm its biological relevance and that of mGmAdT (which is inhibitory on TLR8) over a range of doses, the inventors investigated their effect in HEK TLR8 cells stimulated with Motolimod. As shown in Figure 50, the potentiating effect of mGdCdC was dose-dependent, and already >2 fold at 500 nM. Conversely, mGmAdT was not as inhibitory at lower doses. [0597] Having shown the potential of mG*dC*dC in potentiating Motolimod sensing the inventors next investigated its capacity to potentiate sensing of uridine in HEK TLR8. [0598] As shown in Figure 51, mG*dC*dC and mG*dC*dT were significantly potentiating uridine sensing in HEK TLR8 cells. [0599] This inventors next tested whether mG*dC*dC could be used to sensitize TLR8 to sense otherwise non-immunostimulatory cellular RNA. To test this, total mouse RNA was transfected into HEK TLR8 cells in the presence or absence of the mG*dC*dC trimer. [0600] Analysis of HEK TLR8 cells transfected with high dose of total RNA only marginally activated TLR8-driven NF- ^B luciferase. However, this was significantly increased in the presence of the potentiating mGdCdC trimer and the 20 mer poly dT DNA (dT20). These results provide direct evidence that TLR8 potentiating trimers could have the capacity to turn otherwise immune silent RNA (due to endogenous modifications), into a TLR8 agonist (Figure 52). 1004921453 [0601] mGmAdG is one of the best trimers inhibiting TLR8 in the experiments described herein. The inventors have previously found that similar to TLR7 inhibition, modification of the 3 ^rd base of mG*mA*mG with a DNA base was tolerated. The inventors decided to investigate whether creating a 5′-end mG*mA*rG*rX motif at the end of ssRNA40, a known PS-modified ssRNA activating TLR8 (Shibata et al., Int Immunol, 2016; 28(5): 211-22), could help abrogate its TLR8 agonistic activity. [0602] As shown in Figure 53, ssRNA40 strongly activated TNF production by IFN ^ primed THP-1 cells, which depends on TLR7/8 activation (Gantier et al., Journal of Immunology, 180 (4) , pp.2117-2124). Critically, addition of a 5′-end 2′-OMe mGmA motif to ssRNA40 (creating a mGmArG motif) abolished TLR8-driven sensing, but this was not the case with a 5′-end 2′-OMe mCmA (noting that mCmAmG was not inhibiting TLR7 or 8 in the screens herein). These results provide evidence for the capacity of targeted 5′-end modification of otherwise strong TLR8 agonists, creating inhibitory trimer motifs such as mGmArG, to help prevent unintended TLR8 activation. [0603] Next the inventors tested the activity of the CleanCap AG trimer (m7G(5')ppp(5')(2′OMeA)pG) from TriLink (Trilink Biotechnologies, N-7113) in THP-1 and HEK cells at a concentration of 5 ^M. [0604] As shown in Figure 54, the inventors found that pre-treatment of the cells with the CleanCap AG trimer significantly reduced TLR8 activation by R848 in both THP-1 and HEK TLR8 cells. Interestingly, the inhibitory effect of the TriLink GAG trimer was comparable to that seen with PS-modified mG*mA*mG in HEK TLR8 cells, which was surprising given that the TriLink trimer should be much more prone to degradation prior to reaching the TLR8 containing endosome due to the PPP group and lack of PS modification. This specific observation suggests that the N7-methyl-Guanosine modification may play an important role in TLR8 inhibition. [0605] Critically, as shown in Figure 55, the TriLink GAG did not have any inhibitory activity on human or mouse TLR7 sensing of R848 when used with the same conditions as in Figure 54, while mGmAmG was modestly inhibitory in both system at this high dose of trimer. 1004921453 [0606] The finding that CleanCap AG dampens TLR8 sensing but not that of TLR7 could explain why pseudo-uridine modification is necessary, in the CleanCap AG context, to limit TLR7 engagement by mRNA. [0607] To evidence that the trimers could further inhibit TLR7/8 sensing driven by transfected mRNAs, even when containing a CleanCapAG, the inventors next tested the effect of GUC-v16 on THP-1 cells on sensing of transfected CleanCapAG EGFP mRNA. [0608] As shown in Figure 56, pre-treatment of the cells with GUC-v16 ablated the production of TNF driven by the transfection of the EGFP mRNA. These results demonstrate that trimers inhibiting TLR7/8 can be used to further dampen TLR7/8 signalling driven by capped mRNAs. Example 8 – Structure activity relationship of alternate GUC inhibition on human TLR7 [0609] Example 5 demonstrated that changing the last base of a fully 2′OMe modified mG*mU*mC (GUC) 3-mer into a DNA base (mG*mU*dC; GUC-v1) or LNA base (mG*mU*lC; GUC-v13) significantly improved hTLR7 inhibition (Figures 23 and 24). Thus, the inventors next tested whether elongating GUC-v1 and GUC-v13 to 6 bases could also increase their potency. These new sequences, namely GUC-v38 (mG*mU*dC*dC*dC*dC) and GUC-v39 (mG*mU*lC*mC*mC*mC) were tested in hTLR7 inhibition compared to native GUC at 1 ^M and 200 nM doses in HEK-TLR7 cells. The inventors compared its hTLR7 inhibiting ability with previously tested GUC-v1 Linked 3′- 5′ (Figure 57). The inventors also tested the impact of the elongation of mG*mA*mG (GAG), referred to as GAG-v10 (mG*mA*dG*dC*dC*dC) and compared its activity to that of GAG-v1 (mGmAdG), the 5′ inosine variant GAG-v7 (mI*mA*dG), and the 3′ LNA variant GAG-v8 (mGmAlG). [0610] At 1 μM concentration, GUC, GUC-v13, GUC-v38, GUC-v39, and GUC-v1 Linked 3′-5′ all strongly blunted hTLR7 sensing (Figure 57a). However, at the lower dose of 200 nM, GUC and GUC-v39 were not as potent inhibitors, indicating that elongating GUC-v13 adversely impacted activity as a 3-mer at lower concentrations (Figure 57b). On the other hand, the inosine modification of the first base of GAG-v7 was detrimental to the inhibitory effect of GAG on TLR7, and elongating GAG in GAG- 1004921453 v10 or modifying its 3 ^rd base with an LNA base in GAG-v8 did to significantly impact TLR7 inhibition (Figures 57a and 57b). [0611] These results collectively demonstrate that while elongation of GUC-v1 as in GUC-v38 can slightly improve the inhibitory effect of the GUC 3-mer, this strategy is not necessarily applicable to other sequences such as GAG, and is a function of the chemistry used, since a single LNA substitution in GUC-v39 adversely impacted the inhibitory effect of the 6-mer at lower concentrations. [0612] To obtain further insights into the structure activity relationship (SAR) of GUC and GAG 3-mers on TLR7, the inventors designed and tested a further set of 9 GUC variants (GUC-v41 to v49) and 11 GAG variants (GAG-v11 to v21) (see Figure 6), at 5 ^M, 1 ^M and 200 nM in HEK-TLR7 cells stimulated with R848 (Figure 58). [0613] At the high dose of 5 ^M, all the GUC variants strongly inhibited TLR7 sensing, except for GUC-v41 and GUC-v49 (Figure 58). As such, methylation of the N1-position of guanosine in GUC-v41 was detrimental to the activity of GUC-v1, indicating that this position should remain unsubstituted. Similarly, the results obtained with GUC-v49 showed that modification of the entire sugar backbone of GUC to a phosphorodiamidate morpholino oligo (PMO) was strongly detrimental to the TLR7 inhibitory activity even when used at 5 ^M. [0614] Conversely, methylation of the N3-position of uridine in GUC-v42 was more tolerated if slightly less active than GUC-v1 at 1 μM. Similarly, methylation of the N3- position of the cytidine in GUC-43 was also tolerated although showing a greater reduction in potency compared to GUC-v1 at 1 μM (Figure 58). [0615] Following the trend observed in GUC-v20 and -v21 (see Figure 23), substitution of the 5-position of GUC-v1 cytidine in GUC-v44 showed a potential increase in potency (Figure 58). This effect appears to be larger than that observed for GUC-v20 and -v21 with on par activity with GUC-v13 at both 200 and 50 nM. This indicates that larger substitutions at the 5-position of cytidine are potentially beneficial to more potent TLR7 inhibition. [0616] This series of compounds also revealed further SAR around the ribose sugar groups of GUC. Modifications of the ribose sugars of GUC-v1’s uridine and cytidine with a 2′-amino group in GUC-v45 and GUC-46, respectively, and to a morpholino ring in 1004921453 GUC-v48 were observed to be tolerated at 5 μM (Figure 58). However, all showed reduced activity compared to GUC-v1 at 1 μM. Modifying the deoxycytidine to aracytidine in GUC-v47 was more well tolerated, with on par activity with GUC-v1 at 1 μM and slightly reduced activity compared to GUC-v13 at 200 nM (nonetheless still active with >50% inhibition at this low dose). Although modifying the entire backbone to PMO in GUC-v49 blocked inhibition, GUC-v48 containing a mix of thiomorpholino (TMO) and phosphorothioate (PS) 2′-OMe RNA modifications retained inhibition at 5 μM, indicating that there is feasibility for incorporating morpholine in place of ribose sugars to an extent (Figure 58). [0617] The inventors also tested 11 GAG variants on TLR7 inhibition, although noting that this sequence context is not optimal for human TLR7 inhibition. GAG-v14, v16, v17, v20, and v21 were only poorly inhibiting TLR7 at 5 μM (i.e. less than ~50%), indicating that these modifications are deleterious to TLR7 inhibition. Other variants including GAG-v12, GAG-v13, GAG-v19 were inhibiting hTLR7 as potently as GAG-v7 (Figure 58). Among the new GAG variants, GAG-v11, GAG-v15, GAG-v16 and GAG-v18 were also significantly inhibiting hTLR7 at the high dose of 5 ^M, although not as much as GAG-v12, v13, v19 and GAG-v7. However, at 1 ^M all the GAG variants tested showed only weak inhibitory activity on hTLR7 (~20-30%), with GAG-v7 remaining arguably the most potent inhibitor (Figure 58). [0618] The inventors also tested a panel of 16 mG*rX*rX 3-mers where the first base is 2′OMe and the 2 ^nd and 3 ^rd base are RNA bases – to extend the data the inventors previously obtained with the mG*dX*dX series shown in Figure 12. These sequences were tested in HEK-TLR7 cells at the dose of 2 μM (Figure 59). The inventors observed that mG*rA*rA and mG*rU*rC were equally effective as tested mG*mU*dC (GUC-v1). Importantly, these analyses highlighted the TLR7 inhibiting activity of mG*rU*rX, mG*rA*rA/rG/rU and mG*rG*rC 3-mers, consistent with observations with screens in Figure 12 with DNA and 2′OMe modifications of the 2 ^nd and 3 ^rd base. These results support that single 2′OMe Guanosine modifications of RNAs are sufficient to strongly suppress TLR7 sensing, in a 3-base motif specific manner. Example 9 – Trimer inhibition of mouse TLR7 [0619] In parallel to the experiments in HEK-TLR7, the inventors tested the length variants of GUC including GUC-v38 and GUC-v39 and compared their activity to 1004921453 parental 2′OMe GUC, GUC-v13 and GUC-v1 Linked 3′-5′ on mTLR7 inhibition – noting that mGmUmC was a poor inhibitor of mouse TLR7 (see Figure 13). The inventors also tested the GAG variants (v11-21) in these experiments since mGmAmG is a potent inhibitor of mouse TLR7. The inventors included GGC-v1 as positive control. At the high dose of 1 μM, the inventors observed that GUC-v38, and GUC-v1 Linked 3′-5′ were better mTLR7 inhibitors than the parental GUC 3-mer (mGmUmC). Similar to the observations in Figure 33, at 1 μM GUC-v13 did not inhibit mTLR7 and the incorporation of an LNA base at the 3 ^rd base of GUC-v39 blunted the inhibition indicating that the LNA modification at the 3 ^rd position of GUC(X) sequences was deleterious to the activity on mouse TLR7 (Figure 60). Similarly, LNA modification of the 3 ^rd base of GAG in GAG-v8 was also detrimental to the inhibition of the mGmAmG 3-mer, while inosine modification of the 1 ^st guanosine improved the inhibitory activity (see GAG-v7). Elongation of GAG with DNA bases significantly increased inhibition, as seen with GAG-v10 which outperformed GGC-v1 at 1 μM and 200 nM, confirming that similar to human TLR7 inhibition, longer sequences containing selective 5′ end inhibitory 3-base motif (here GAG), were stronger inhibitors of mouse TLR7 than 3-mers (Figure 60). [0620] The inventors also tested the 9 GUC (GUC-v41 to GUC-v49) and 11 GAG (GAG-v11 to GAG-v21) variants at both the high (5 μM) and intermediate (1 μM) doses on mTLR7 inhibition. Among GUC variants, GUC-v42 and GUC-v44 were the strongest inhibitors of mTLR7. At 5 μM, GUC-v13 also inhibited mTLR7 by ~40%. Additional GUC variants including GUC-v43, GUC-v45 and GUC-v47 were also showing significant inhibition of mTLR7 (Figure 61). However, at 1 μM only four GUC variants including GUC-v42, GUC-v43, GUC-v44 and GUC-v47 were significantly modestly inhibiting mTLR7 (Figure 61) ~50% or less. On the other hand, 7 out of 11 GAG variants were still significantly inhibiting mTLR7 at 1 μM in addition to GAG-v7 (Figure 61). GAG-v7 and GAG-v13 were equally effective in inhibiting mTLR7 at the range of ~60% 1 μM. The decreased inhibitory activity of GAG-v19 at 1 μM suggested that unlike bromination (GAG-v13), amination of the 8-position of 3′-dG was deleterious to the interaction with mouse TLR7. It is also noteworthy that neither GUC-v49 nor GAG-v21, which contain PMO modifications, inhibited mTLR7 (Figure 61). Example 10 – Trimer modulation of human TLR8 sensing 1004921453 [0621] The inventors also tested the length variants of GUC and GAG in HEK-TLR8 cells (Figure 62). This was concordant with observations that GUC-v1 and GUC-v1 Linked 3′-5′ also potentiated TLR8 (Figures 49 and 62). GUC-v40 which comprises two consecutive GUC motif was also a significant hTLR8 potentiator (Figure 62). The inventors demonstrated that GAG-v1 (mG*mA*dG) had an improved hTLR8 inhibiting ability compared to the parental GAG (mG*mA*mG) sequence (Figure 20). The inventors observed that the inosine variant of the first base in GAG-v7 was more potent than GAG-v1 in inhibiting hTLR8 (Figure 45 and 62) at 1 μM and 200 nM. However, LNA modification of the 3 ^rd base in GAG-v8 had a similar activity to that of GAG-v1. However, 3′ dC extension of GAG-v1 with GAG-v10 (mG*mA*dG*dC*dC*dC) blunted the inhibitory of hTLR8 compared GAG-v1 (Figure 62). [0622] The inventors also tested a set of 9 GUC variants (GUC-v41 to v49) and 11 GAG variants (GAG-v11 to v21) (see Figure 6), at 5 ^M and 1 ^M in HEK-TLR8 cells stimulated with R848 (Figure 63). [0623] All new GUC variants weakly inhibited hTLR8 by ~40-50% at 5 ^M – with the exception of GUC-v41 which rather significantly potentiated TLR8, similar to what was seen with GUC-v1. GAG variants showed better inhibitory activity on TLR8 inhibition compared to GUC variants, consistent with findings described above. However, it should be noted that none of the GAG variants were as potently inhibiting TLR8 as GAG-v7 (Figure 63). [0624] Several base modifications to GAG-v1 were observed to be fairly tolerated for TLR8 inhibition at 5 μM. These included conversion of the 3′-dG to deoxyinosine (GAG- v12), bromination and amination of the 8-position of 3′-dG (GAG-v13 and GAG-v19, respectively), and methylation of the 6-oxo group of 3′-dG (GAG-v18) (Figure 63). However, each of these modifications were found to be less potent than GAG-v1 at the lower concentration of 1 μM. Other modifications including methylation of the N1- position of 3′-dG (GAG-v14), use of 7-deazadeoxyguanosine in place of 3′-dG (GAG- v15), and substitution of the 8-position of adenosine with either bromine (GAG-v16) or an oxo group (GAG-v17) all resulted in a reduction in TLR8 inhibition compared to GAG-v1. Although weak inhibition was observed with these modifications when tested at 5 μM, no significant inhibition was observed at 1 μM(Figure 63). 1004921453 [0625] As with GUC-v48, modifying the 3′-end ribose of GAG to a morpholino ring in GAG-v20 retained some TLR8 inhibition but came with a loss in potency compared to GAG-v1. Also consistent with GUC-v41, the complete conversion of the GAG trimer to PMO in GAG-v21 saw a significant reduction in potency, with only weak inhibition observed at 5 μM (Figure 63). [0626] The inventors also tested a panel of 16 mG*rX*rX 3-mers where the first base is 2′OMe and the 2 ^nd and 3 ^rd base are RNA bases – to extend the data the inventors obtained with the mG*dX*dX series shown in Figure 22. In HEK-TLR8 cells, mG*rA*rA and mG*rG*rA completely abolished hTLR8 sensing at 5 μM (Figure 64). mG*rA*rA was also inhibitory on hTLR7 (Figure 64), suggesting a potential functional activity in homeostasis since mGrArA is the most prevalent 2′OMe guanosine motif observed in human ribosomal RNA (18/28S). Some additional sequences including mG*rA*rG and mG*rA*rU also showed more than 50% inhibition of hTLR8, aligning with the inventors observations that GAX like 3-mers starting with a 2′OMe guanosine were inhibitory with DNA and 2′OMe bases. Interestingly, mG*rG*rU significantly potentiated hTLR8 sensing, supporting the concept that selected 2′OMe guanosine modified 3-base RNA fragments could also potentiate TLR8 (Figure 64). Example 11 – Potentiation of TLR8 in splenocytes derived from humanised (h)TLR8/TLR7 mice [0627] Having demonstrated that mG*dC*dC (also referred to as 38-2) was one of the strongest potentiators of TLR8 in HEK-TLR8 cells (Figure 51), the inventors next decided to test its activity on primary murine splenocytes isolated from wild-type (WT) and transgenic mice expressing the human TLR8 and TLR7 proteins (B-hTLR8/hTLR7 mice). Pre-treatment with the oligo 38-2 resulted in potentiation of TLR8 activity – measured by TNF production – in R848-treated splenocytes derived from B- hTLR8/hTLR7 mice, but not in R848-treated splenocytes from WT mice that express only the non-functional murine TLR8 protein (Figure 65). Example 12 – Potentiation of TLR8 in human skin explants [0628] The ability of 38-2 (mG*dC*dC) to potentiate TLR8 signalling was then assessed in human skin tissue using full thickness healthy skin punch biopsies in the culture medium. Pre-treatment of the medium with the oligo 38-2, followed by addition of 1004921453 the TLR8 agonist Motolimod for 24 h, resulted in a 200-fold increase in IL-8 levels in the supernatant compared with Motolimod treatment alone (Figure 66). Example 13 – Co-encapsulation of mRNA and GGC-v1 in lipis nanoparticles [0629] In order for the GGC-v1 oligo to effectively block reactogenicity arising from mRNA vaccines, it was first necessary to determine if it could be co-encapsulated with mRNA inside lipid nanoparticles (LNPs) to facilitate co-delivery to the same cells. To do this, the mRNA and GGC-v1 oligo were pre-mixed by pipetting at a ratio of 5 mRNA:1 GGC-v1 (by mass) before encapsulation. Concentrations of mRNA and GGC-v1 were then quantified by RT-qPCR and LC-MS/MS, respectively (Table 4). As expected, GGC-v1 was not detected in the control LNPs containing mRNA alone. In the LNPs containing both mRNA and GGC-v1, the measured ratio of mRNA:GGC-v1 was 8.5:1, indicating 12 % of the LNP contents were GGC-v1 oligo by weight – down from the intended 20 % at pre-mixing (Table 4). However, given the size discrepancy, this still translates to approximately 75 molecules of GGC-v1 for every 1 molecule of mRNA. Table 4. Intended and final measured concentrations of mRNA (by RT-qPCR) and GGC-v1 (by LC-MS/MS) in the LNPs formulated with mRNA alone, or mRNA and GGC- v1. Data are presented as Mean ± SD. ND, not detected. LLOQ = 10 ng/mL. [0630] In addition, the z-average, poly-dispersity index (PDI), and zeta potential were measured for both populations of LNPs to determine if inclusion of the GGC-v1 oligo affected their physico-chemical properties (Table 5). Crucially, the LNPs fell within acceptable parameters in all measured criteria, and there were no significant differences between the LNPs containing mRNA alone and the LNPs containing both mRNA and the GGC-v1 oligo (Table 5). Table 5. Physico-chemical properties of the LNPs formulated with mRNA alone, or mRNA and GGC-v1. PDI, poly-dispersity index. Data are presented as Mean ± SD. 1004921453 Example 14 – Inhibition of mRNA vaccine-induced reactogenicity [0631] Finally, to test the ability of the GGC-v1 oligo to block mRNA vaccine-induced reactogenicity in vivo, WT 129X1/SvJ mice were injected i.v. with 20 ^g of luciferase (FLuc) mRNA encapsulated in LNPs with, or without, GGC-v1. Importantly, bioluminescence imaging using an IVIS Spectrum® revealed that, as expected, both populations of LNPs delivered to the liver, and that co-encapsulation of GGC-v1 had no significant impact on mRNA expression at 6 and 24 h (Figure 67A, B). To support these observations, no significant difference in luciferase activity was detected in homogenised liver tissue at 24 h (Figure 67C). [0632] Analysis of serum cytokine levels revealed a >50 % decrease in IFN- ^ and IFN- ^ levels, as well as a significant reduction in IL-6 and RANTES, at 6 h in the mice that received the LNPs containing mRNA and GGC-v1 compared to the mice that received LNPs containing mRNA alone (Figure 68). [0633] Altogether, these data showed that GGC-v1 can be successfully co- encapsulated with mRNA in LNPs without altering their physico-chemical properties or negatively impacting the delivery and expression of mRNA in the murine liver. Co- delivery of GGC-v1 with an mRNA sequence encoding luciferase dampened the pro- inflammatory cytokine induction driven by this mRNA, i.e., its reactogenicity, presumably due to its inhibitory effect on mTLR7 sensing. Example 15 - Removing chirality of PS-modified 3-base oligonucleotides impacts their activities on TLR7 and TLR8 sensing [0634] When relying on a PS backbone, each 3-mer synthesis generates a mixture of 4 different oligonucleotide stereoisomers, due to the chirality of the two sulfur atoms in the PS internucleotide linkages. Here the inventors tested four stereopure oligonucleotides which can result from the PS backbone (referred to RR, RS, SR, and SS) from the synthesis of GUC-v1. When tested at 5 and 1 μM in HEK-TLR7 cells, the 1004921453 inventors observed that fixing the first internucleotide linkage (between mG and mU) in the S configuration was essential for inhibition as the R configuration strongly impaired the inhibitory activity in the GUC-v1-RR and GUC-v1-RS oligonucleotides at both 5 and 1 μM (Figure 69). Conversely, the configuration between the second and third nucleotide was not critical and both R and S configuration were tolerated for TLR7 inhibition at 5 and 1 μM. [0635] Critically, the impact of the stereopure isomers on TLR8 potentiation was strikingly different to the effect seen on TLR7 inhibition. As such, for potentiation at 5 μM with GUC-v1 stereopure isomers, the R configuration between the second and the third base of GUC-v1 were critical – as seen with potentiation of GUC-v1-RR and GUC- v1-SR (Figure 69). [0636] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention. 1004921453