RHYM LUKE (US)
JIANG ALLEN (US)
WITTEN JACOB (US)
RAJI IDRIS (US)
WO2021055835A1 | 2021-03-25 | |||
WO2018170306A1 | 2018-09-20 | |||
WO2015095346A1 | 2015-06-25 |
US20090006018W | 2009-11-06 |
"Handbook of Chemistry and Physics", article "Periodic Table of the Elements"
TABARA ET AL., CELL, vol. 99, 1999, pages 123
MAYS, L. E. ET AL.: "Modified Foxp3 mRNA protects against asthma through an IL-10-dependent mechanism", J. CLIN. INVEST., vol. 123, 2013, pages 1216 - 1228, XP055159538, DOI: 10.1172/JCI65351
SABNIS, S. ET AL.: "A Novel Amino Lipid Series for mRNA Delivery: Improved Endosomal Escape and Sustained Pharmacology and Safety in Non-human Primates", MOL. THER., vol. 26, 2018, pages 1509 - 1519, XP055644778, DOI: 10.1016/j.ymthe.2018.03.010
MATHIOWITZLANGER, J. CONTROLLED RELEASE, vol. 5, 1987, pages 13 - 22
BERNOIST ET AL., NATURE, vol. 290, 1981, pages 304 - 310
BERGE ET AL., J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 2725 - 19
ELIEL, E.L.: "Stereochemistry of Carbon Compounds", 1962, MCGRAW-HILL
WILEN, S.H.: "Tables of Resolving Agents and Optical Resolutions", 1972, UNIV. OF NOTRE DAME PRESS, pages: 268
STEIN ET AL., NUCL. ACIDS RES., vol. 16, 1988, pages 3209
SARIN ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 85, 1988, pages 7448 - 7451
YAMAMOTO ET AL., CELL, vol. 22, 1980, pages 787 - 797
WAGNER ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 78, 1981, pages 1441 - 1445
BRINSTER ET AL., NATURE, vol. 296, 1982, pages 39 - 42
SAMBROOK ET AL.: "Current Protocols in Molecular Biology, Current Protocols", 1989, COLD SPRING HARBOR LABORATORY PRESS
"DNA Cloning: A Practical Approach", vol. I, II, 1985, IREL PRESS
WALKER: "Cambridge Dictionary of Biology", 1990, CAMBRIDGE UNIVERSITY PRESS
"Diagnostic and Statistical Manual of Mental Disorders", 1994, AMERICAN PSYCHIATRIC ASSOCIATION
LAUBE BL ET AL., EUR. RESPIR. J., vol. 37, 2011, pages 1308 - 1311
ELBASHIR ET AL., GENES DEV., vol. 15, 2001, pages 188
FIRE ET AL., NATURE, vol. 391, 1998, pages 806 - 811
HAMMOND ET AL., NATURE, vol. 404, 2000, pages 293
ZAMORE ET AL., CELL, vol. 101, 2000, pages 25
CHAKRABORTY, CURR. DRUG TARGETS, vol. 8, 2007, pages 469
MORRISROSSI, GENE THER., vol. 13, 2006, pages 553
CROOKE: "Molecular mechanisms of action of antisense drugs", BIOCHIM. BIOPHYS. ACTA, vol. 1489, no. 1, 1999, pages 31 - 44, XP004275520, DOI: 10.1016/S0167-4781(99)00148-7
CROOKE: "Evaluating the mechanism of action of anti-proliferative antisense drugs", ANTISENSE NUCLEIC ACID DRUG DEV., vol. 10, no. 2, 2000, pages 123 - 126
METHODS IN ENZYMOLOGY, vol. 313-314, 1999
CHAN ET AL., J. MOL. MED., vol. 75, no. 4, 1997, pages 267 - 282
REYNOLDS ET AL., NAT. BIOTECHNOL., vol. 22, 2004, pages 326
NAITO ET AL., NUCLEIC ACIDS RES., vol. 34, 2006, pages W448
LI ET AL., RNA, vol. 13, 2007, pages 1765
YIU ET AL., BIOINFORMATICS, vol. 21, 2005, pages 144
JIA ET AL., BMC BIOINFORMATICS, vol. 7, 2006, pages 271
AUSUBEL ET AL.: "Current Protocols in Molecular Biology", 1999, JOHN WILEY & SONS, INC.
COTTEN ET AL., METHODS ENZYM., vol. 217, 1993, pages 618
"Microcapsules and Nanoparticles in Medicine and Pharmacy", 1992, CRC PRESS
MATHIOWITZ ET AL., REACTIVE POLYMERS, vol. 6, 1987, pages 275 - 283
MATHIOWITZ ET AL., J. APPL. POLYMER SCI., vol. 35, 1988, pages 755 - 774
WALDE, P.: "Encylopedia of Nanoscience and Nanotechnology", vol. 9, 2004, SCIENTIFIC PUBLISHERS, article "Preparation of Vesicles (Liposomes", pages: 43 - 79
SZOKA ET AL.: "Comparative Properties and Methods of Preparation of Lipid Vesicles (Liposomes", ANN. REV. BIOPHYS. BIOENG., vol. 9, 1980, pages 467 - 508, XP000600718, DOI: 10.1146/annurev.bb.09.060180.002343
NARANG ET AL.: "Cationic Lipids with Increased DNA Binding Affinity for Nonviral Gene Transfer in Dividing and Nondividing Cells", BIOCONJUGATE CHEM., vol. 16, 2005, pages 156 - 68, XP002544960, DOI: 10.1021/BC049818Q
HOFLAND ET AL.: "Formation of stable cationic lipid/DNA complexes for gene transfer", PROC. NATL. ACAD. SCI. USA, vol. 93, July 1996 (1996-07-01), pages 7305 - 7309, XP002555917, DOI: 10.1073/pnas.93.14.7305
BYK ET AL.: "Synthesis, Activity, and Structure - Activity Relationship Studies of Novel Cationic Lipids for DNA Transfer", J. MED. CHEM., vol. 41, no. 2, 1998, pages 224 - 235, XP002118261, DOI: 10.1021/jm9704964
WU ET AL.: "Cationic Lipid Polymerization as a Novel Approach for Constructing New DNA Delivery Agents", BIOCONJUGATE CHEM., vol. 12, 2001, pages 251 - 57, XP055088939, DOI: 10.1021/bc000097e
LUKYANOV ET AL.: "Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs", ADVANCED DRUG DELIVERY REVIEWS, vol. 56, 2004, pages 1273 - 1289, XP002356816, DOI: 10.1016/j.addr.2003.12.004
TRANCHANT ET AL.: "Physicochemical optimisation of plasmid delivery by cationic lipids", J. GENE MED., vol. 6, 2004, pages S24 - S35, XP002521501, DOI: 10.1002/jgm.509
VAN BALEN ET AL.: "Liposome/Water Lipophilicity: Methods, Information Content, and Pharmaceutical Applications", MEDICINAL RESEARCH REV., vol. 24, no. 3, 2004, pages 299 - 324, XP008056700, DOI: 10.1002/med.10063
NEWMAN SP.: "Principles of metered-dose inhaler design", RESPIR CARE., vol. 50, no. 9, September 2005 (2005-09-01), pages 1177 - 88, XP002725674
ROCHE NDEKHUIJEZEN R: "The evolution of pressurized metered-dose inhalers from early to modern devices", J AEROSOL MED PULM DRUG DELIV., vol. 29, no. 4, 2016, pages 311
COGAN PSSUCHER BJ: "Appropriate use of pressurized metered-dose inhalers for asthma", USPHARM, vol. 40, no. 7, 2015, pages 36 - 41
VEHRING RBALLESTEROS DLJOSHI VNOGA BDWIVEDI SK: "Co-suspensions of microcrystals and engineered microparticles for uniform and efficient delivery of respiratory therapeutics from pressurized metered dose inhalers", LANGMUIR, vol. 28, no. 42, 2012, pages 15015 - 15023, XP055121915, DOI: 10.1021/la302281n
ISLAM NGLADKI E: "Dry powder inhalers (DPIs)-a review of device reliability and innovation", INT J PHARM., 2008
DANIHER DIZHU J.: "Dry powder platform for pulmonary drug delivery", PARTICULOGY, August 2008 (2008-08-01)
DAYTON ET AL.: "Respiratory Drug Delivery", 2006, DAVIS HEALTHCARE INTERNATIONAL PUBLISHING, pages: 429 - 432
DALBY RNEICHER JZIERENBERG B.: "Development of Respimat Soft Mist inhaler and its clinical utility in respiratory disorder", MED DEVICES., August 2011 (2011-08-01)
KOWALSKI, P. S., RUDRA, A., MIAO, L., ANDERSON, D. G.: "Delivering the Messenger:Advances in Technologies for Therapeutic mRNA Delivery.", MOL. THER., vol. 27, 2019, pages 710 - 728, XP055634628, DOI: 10.1016/j.ymthe.2019.02.012
HAJJ, K. A.WHITEHEAD, K. A.: "Tools for translation: non-viral materials for therapeutic mRNA delivery", NAT. REV. MATER., vol. 2, 2017, pages 1 - 17, XP055657784, DOI: 10.1038/natrevmats.2017.56
HAN, X. ET AL.: "An ionizable lipid toolbox for RNA delivery", NAT. COMMUN., vol. 12, 2021, pages 7233, XP055938542, DOI: 10.1038/s41467-021-27493-0
QIU, M. ET AL.: "Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3", PROC. NATL. ACAD. SCI., 2021, pages 118
SWINGLE, K. L.HAMILTON, A. G.MITCHELL, M. J.: "Lipid Nanoparticle-Mediated Delivery of mRNA Therapeutics and Vaccines", TRENDS MOL. MED., vol. 27, 2021, pages 616 - 617, XP086581243, DOI: 10.1016/j.molmed.2021.03.003
MIAO, L. ET AL.: "Delivery of mRNA vaccines with heterocyclic lipids increases antitumor efficacy by STING-mediated immune cell activation", NAT. BIOTECHNOL., vol. 37, 2019, pages 1174 - 1185, XP036897247, DOI: 10.1038/s41587-019-0247-3
ZHANG, X. ET AL.: "Functionalized lipid-like nanoparticles for in vivo mRNA delivery and base editing", SCI. ADV., vol. 6, pages 2315
BILLINGSLEY, M. M. ET AL.: "Ionizable Lipid Nanoparticle-Mediated mRNA Delivery for Human CAR T Cell Engineering", NANO LETT., vol. 20, 2020, pages 1578 - 1589, XP055730997, DOI: 10.1021/acs.nanolett.9b04246
RILEY, R. S. ET AL.: "Ionizable lipid nanoparticles for in utero mRNA delivery", SCI. ADV., vol. 7, pages 1028
FENTON, O. S. ET AL.: "Synthesis and Biological Evaluation of Ionizable Lipid Materials for the In Vivo Delivery of Messenger RNA to B Lymphocytes", ADV. MATER., vol. 29, 2017, pages 1606944, XP055924544, DOI: 10.1002/adma.201606944
LIU, J. ET AL.: "Fast and Efficient CRISPR/Cas9 Genome Editing In Vivo Enabled by Bioreducible Lipid and Messenger RNA Nanoparticles", ADV. MATER., vol. 31, 2019, pages 1902575
POLACK, F.P.: "Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine", N. ENGL. J. MED., vol. 383, 2020, pages 2603 - 2615, XP055820495, DOI: 10.1056/NEJMoa2034577
BADEN, L. R. ET AL.: "Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine", N. ENGL. J. MED., vol. 384, 2021, pages 403 - 416
GILLMORE, J. D. ET AL.: "CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis", N. ENGL. J. MED., vol. 385, 2021, pages 493 - 502, XP055978811, DOI: 10.1056/NEJMoa2107454
CORNEBISE, M. ET AL.: "Discovery of a Novel Amino Lipid That Improves Lipid Nanoparticle Performance through Specific Interactions with mRNA", ADV. FUNCT. MATER., pages 2106727
BARBIER, A. J.JIANG, A. Y.ZHANG, P.WOOSTER, R.ANDERSON, D. G.: "The clinical progress of mRNA vaccines and immunotherapies", NAT. BIOTECHNOL., vol. 40, 2022, pages 840 - 854, XP037897817, DOI: 10.1038/s41587-022-01294-2
CHAKRABORTY, C., SHARMA, A. R., BHATTACHARYA, M., LEE, S.-S.: " From COVID-19 toCancer mRNA Vaccines: Moving From Bench to Clinic in the Vaccine Landscape.", IMMUNOL., vol. 12, 2021, pages 2648
CAFRI, G. ET AL.: "mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer", J. CLIN. INVEST., vol. 130, 2020, pages 5976 - 5988, XP055849485, DOI: 10.1172/JCI134915
OBERLI, M. A. ET AL.: "Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy", NANO LETT., vol. 17, 2017, pages 1326 - 1335, XP055614115, DOI: 10.1021/acs.nanolett.6b03329
ESPESETH, A. S. ET AL.: "Modified mRNA/lipid nanoparticle-based vaccines expressing respiratory syncytial virus F protein variants are immunogenic and protective in rodent models of RSV infection", NPJ VACCINES, vol. 5, 2020, pages 1 - 14
ALIPRANTIS, A. O. ET AL.: "A phase 1, randomized, placebo-controlled study to evaluate the safety and immunogenicity of an mRNA-based RSV prefusion F protein vaccine in healthy younger and older adults", HUM. VACCINES IMMUNOTHER., vol. 17, 2021, pages 1248 - 1261
BAHL, K. ET AL.: "Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses", MOL. THER., vol. 25, 2017, pages 1316 - 1327, XP055545598, DOI: 10.1016/j.ymthe.2017.03.035
FELDMAN, R. A. ET AL.: "mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials", VACCINE, vol. 37, 2019, pages 3326 - 3334, XP085695609, DOI: 10.1016/j.vaccine.2019.04.074
JOHN, S. ET AL.: "Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity", VACCINE, vol. 36, 2018, pages 1689 - 1699, XP055695626, DOI: 10.1016/j.vaccine.2018.01.029
MEDINA-MAGUES, L. G. ET AL.: "mRNA Vaccine Protects against Zika Virus", VACCINES, vol. 9, 2021, pages 1464
MU, Z., HAYNES, B. F., CAIN, D. W.: "HIV mRNA Vaccines-Progress and Future Paths", VACCINES, vol. 9, 2021, pages 134
ZABALETA, N.TORELLA, L.WEBER, N. D.GONZALEZ-ASEGUINOLAZA, G: "mRNA and gene editing: Late breaking therapies in liver diseases", HEPATOLOGY
ROBINSON, E. ET AL.: "Lipid Nanoparticle-Delivered Chemically Modified mRNA Restores Chloride Secretion in Cystic Fibrosis", MOL. THER., vol. 26, 2018, pages 2034 - 2046
DA SILVA SANCHEZ, A.PAUNOVSKA, KCRISTIAN, A.DAHLMAN, J. E.: "Treating Cystic Fibrosis with mRNA and CRISPR", HUM. GENE THER., vol. 31, 2020, pages 940 - 955
LAI, M. ET AL.: "Gene editing of DNAH1 1 restores normal cilia motility in primary ciliary dyskinesia", J. MED. GENET., vol. 53, 2016, pages 242 - 249, XP055677590, DOI: 10.1136/jmedgenet-2015-103539
PAFF, T.OMRAN, HNIELSEN, K. G.HAARMAN, E. G.: "Current and Future Treatments in Primary Ciliary Dyskinesia", INT. J. MOL. SCI., vol. 22, 2021, pages 9834
GUAN, S.DARMSTADTER, M.XU, C.ROSENECKER, J.: "In Vitro Investigations on Optimizing and Nebulization of IVT-mRNA Formulations for Potential Pulmonary-Based Alpha-1-Antitrypsin Deficiency Treatment", PHARMACEUTICS, vol. 13, 2021, pages 1281
ZEYER, F. ET AL.: "mRNA-Mediated Gene Supplementation of Toll-Like Receptors as Treatment Strategy for Asthma In Vivo", PLOS ONE, vol. 11, 2016, pages e0154001
RAKHRA, K. ET AL.: "Exploiting albumin as a mucosal vaccine chaperone for robust generation of lung-resident memory T cells", SCI. IMMUNOL., vol. 6, 2021, pages eabd8003
BIVAS-BENITA, M. ET AL.: "Pulmonary delivery of chitosan-DNA nanoparticles enhances the immunogenicity of a DNA vaccine encoding HLA-A*0201-restricted T-cell epitopes of Mycobacterium tuberculosis", VACCINE, vol. 22, 2004, pages 1609 - 1615, XP004500413, DOI: 10.1016/j.vaccine.2003.09.044
RAJAPAKSA, A. E. ET AL.: "Effective pulmonary delivery of an aerosolized plasmid DNA vaccine via surface acoustic wave nebulization", RESPIR. RES., vol. 15, 2014, pages 60
WU, M. ET AL.: "Intranasal Vaccination with Mannosylated Chitosan Formulated DNA Vaccine Enables Robust IgA and Cellular Response Induction in the Lungs of Mice and Improves Protection against Pulmonary Mycobacterial Challenge", FRONT. CELL. INFECT. MICROBIOL., vol. 7, 2017, pages 445
KING, R. G. ET AL.: "Single-Dose Intranasal Administration of AdCOVID Elicits Systemic and Mucosal Immunity against SARS-CoV-2 and Fully Protects Mice from Lethal Challenge", VACCINES, vol. 9, 2021, pages 881
AN, X. ET AL.: "Single-dose intranasal vaccination elicits systemic and mucosal immunity against SARS-CoV-2", ISCIENCE, vol. 24, 2021, pages 103037
KIM, Y. C. ET AL.: "Strategy to Enhance Dendritic Cell-Mediated DNA Vaccination in the Lung", ADV. THER., vol. 3, 2020, pages 2000013
LU, D.HICKEY, A. J.: "Pulmonary vaccine delivery", EXPERT REV. VACCINES, vol. 6, 2007, pages 213 - 226, XP009107435, DOI: 10.1586/14760584.6.2.213
SOU, T. ET AL.: "New developments in dry powder pulmonary vaccine delivery", TRENDS BIOTECHNOL., vol. 29, 2011, pages 191 - 198, XP028166085, DOI: 10.1016/j.tibtech.2010.12.009
HUANG, J. ET AL.: "A novel dry powder influenza vaccine and intranasal delivery technology: induction of systemic and mucosal immune responses in rats", VACCINE, vol. 23, 2004, pages 794 - 801, XP004637086, DOI: 10.1016/j.vaccine.2004.06.049
MINNE, A. ET AL.: "The delivery site of a monovalent influenza vaccine within the respiratory tract impacts on the immune response", IMMUNOLOGY, vol. 122, 2007, pages 316 - 325
WANG, Z. ET AL.: "Exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain as an inhalable COVID-19 vaccine", NAT. BIOMED. ENG., vol. 1-15, 2022
CHENG, Q. ET AL.: "Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing", NAT. NANOTECHNOL., vol. 15, 2020, pages 313 - 320, XP037096153, DOI: 10.1038/s41565-020-0669-6
KACZMAREK, J. C. ET AL.: "Optimization of a Degradable Polymer-Lipid Nanoparticle for Potent Systemic Delivery of mRNA to the Lung Endothelium and Immune Cells", NANO LETT., vol. 18, 2018, pages 6449 - 6454, XP055682087, DOI: 10.1021/acs.nanolett.8b02917
KACZMAREK, J. C. ET AL.: "Polymer-Lipid Nanoparticles for Systemic Delivery of mRNA to the Lungs.", ANGEW. CHEM. INT. ED., vol. 55, 2016, pages 13808 - 13812, XP055504238, DOI: 10.1002/anie.201608450
KACZMAREK, J. C. ET AL.: "Systemic Delivery of mRNA and DNA to the Lung using Polymer-Lipid Nanoparticles", BIOMATERIALS, 2021, pages 120966
KIM, N.DUNCAN, G. A.HANES, J.SUK, J. S.: "Barriers to inhaled gene therapy of obstructive lung diseases: A review", J. CONTROLLED RELEASE, vol. 240, 2016, pages 465 - 488, XP029759378, DOI: 10.1016/j.jconrel.2016.05.031
PATEL, A. K. ET AL.: "Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium", ADV. MATER., vol. 31, 2019, pages 1805116
LOKUGAMAGE, M. P. ET AL.: "Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs", NAT. BIOMED. ENG., vol. 5, 2021, pages 1059 - 1068, XP037582927, DOI: 10.1038/s41551-021-00786-x
WILSON, C.: "Future therapies for cystic fibrosis", LANCET RESPIR. MED., vol. 0, 2022
WITTEN, J.SAMAD, T.RIBBECK, K.: "Selective permeability of mucus barriers", CURR. OPIN. BIOTECHNOL., vol. 52, 2018, pages 124 - 133
WITTEN, J.RIBBECK, K.: "The particle in the spider's web: transport through biological hydrogels", NANOSCALE, vol. 9, 2017, pages 8080 - 8095
CONE, R. A.: "Barrier properties of mucus", ADV. DRUG DELIV. REV., vol. 61, 2009, pages 75 - 85, XP025950266, DOI: 10.1016/j.addr.2008.09.008
LIELEG, O.RIBBECK, K: "Biological hydrogels as selective diffusion barriers", TRENDS CELL BIOL., vol. 21, 2011, pages 543 - 551, XP028276989, DOI: 10.1016/j.tcb.2011.06.002
COYNE, C. B.KELLY, M. M.BOUCHER, R. C.JOHNSON, L. G.: "Enhanced Epithelial Gene Transfer by Modulation of Tight Junctions with Sodium Caprate", AM. J. RESPIR. CELL MOL. BIOL., vol. 23, 2000, pages 602 - 609
HOU, X., ZAKS, T., LANGER, R., DONG, Y.: "Lipid nanoparticles for mRNA delivery.", NAT. REV. MATER., vol. 6, 2021, pages 1078 - 1094, XP037634156, DOI: 10.1038/s41578-021-00358-0
ANDRIES, O. ET AL.: "Comparison of the Gene Transfer Efficiency of mRNA/GL67 and pDNA/GL67 Complexes in Respiratory Cells", MOL. PHARM., vol. 9, 2012, pages 2136 - 2145, XP055883653
PAUNOVSKA, K. ET AL.: "A Direct Comparison of in Vitro and in Vivo Nucleic Acid Delivery Mediated by Hundreds of Nanoparticles Reveals a Weak Correlation", NANO LETT., vol. 18, 2018, pages 2148 - 2157
WHITEHEAD, K. A. ET AL.: "In Vitro-In Vivo Translation of Lipid Nanoparticles for Hepatocellular siRNA Delivery", ACS NANO, vol. 6, 2012, pages 6922 - 6929
HILL, D. B.BUTTON, B.: "Mucins: Methods and Protocols", 2012, HUMANA PRESS, article "Establishment of Respiratory Air-Liquid Interface Cultures and Their Use in Studying Mucin Production, Secretion, and Function", pages: 245 - 258
RAMACHANDRAN, S. ET AL.: "Efficient delivery of RNA interference oligonucleotides to polarized airway epithelia in vitro", AM. J. PHYSIOL.-LUNG CELL. MOL. PHYSIOL., vol. 305, 2013, pages L23 - L32
PEZZULO, A. A. ET AL.: "The air-liquid interface and use of primary cell cultures are important to recapitulate the transcriptional profile of in vivo airway epithelia", AM. J. PHYSIOL.-LUNG CELL. MOL. PHYSIOL., vol. 300, 2011, pages L25 - L31
KAUFFMAN, K. J. ET AL.: "Optimization of Lipid Nanoparticle Formulations for mRNA Delivery in Vivo with Fractional Factorial and Definitive Screening Designs", NANO LETT., vol. 15, 2015, pages 7300 - 7306, XP055679418, DOI: 10.1021/acs.nanolett.5b02497
BILLINGSLEY, M. M. ET AL.: "Orthogonal Design of Experiments for Optimization of Lipid Nanoparticles for mRNA Engineering of CAR T Cells", NANO LETT., vol. 22, 2022, pages 533 - 542
KAUFFMAN, K. J. ET AL.: "Rapid, Single-Cell Analysis and Discovery of Vectored mRNA Transfection In Vivo with a loxP-Flanked tdTomato Reporter Mouse", MOL. THER. - NUCLEIC ACIDS, vol. 10, 2018, pages 55 - 63, XP055926671, DOI: 10.1016/j.omtn.2017.11.005
NUMATA, M. ET AL.: "Phosphatidylglycerol provides short-term prophylaxis against respiratory syncytial virus infection", J. LIPID RES., vol. 54, 2013, pages 2133 - 2143
BALL, R. L.BAJAJ, P.WHITEHEAD, K. A.: "Achieving long-term stability of lipid nanoparticles: examining the effect of pH, temperature, and lyophilization", INT. J., vol. 12, 2017, pages 305 - 315
EASTMAN, S. J. ET AL.: "Optimization of formulations and conditions for the aerosol delivery of functional cationic lipid:DNA complexes", HUM. GENE THER., vol. 8, 1997, pages 313 - 322
KRISHNAMURTHY, S. ET AL.: "Manipulation of Cell Physiology Enables Gene Silencing in Well-differentiated Airway Epithelia", MOL. THER. - NUCLEIC ACIDS, vol. 1, 2012, pages e41
BURGEL, P.-R.MONTANI, D.DANEL, C.DUSSER, D. J.NADEL, J. A.: "A morphometric study of mucins and small airway plugging in cystic fibrosis", THORAX, vol. 62, 2007, pages 153 - 161
RATJEN, F.: "Cystic Fibrosis: The Role of the Small Airways", J. AEROSOL MED. PULM., vol. 25, 2012, pages 261 - 264
VAN DEN BERGE, M.TEN HACKEN, N. H. T.COHEN, J.DOUMA, W. R.POSTMA, D. S.: "Small Airway Disease in Asthma and COPD: Clinical Implications", CHEST, vol. 139, 2011, pages 412 - 423
TIDDENS, H. A. W. M.DONALDSON, S. H.ROSENFELD, M.PARE, P. D.: "lung disease starts in the small airways: Can we treat it more effectively?", PEDIATR. PULMONOL., vol. 45, 2010, pages 107 - 117
TATSUTA, M. ET AL.: "Effects of cigarette smoke on barrier function and tight junction proteins in the bronchial epithelium: protective role of cathelicidin LL-37", RESPIR. RES., vol. 20, 2019, pages 251
OKUDA, K. ET AL.: "Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia", AM. J. RESPIR. CRIT. CARE MED., vol. 203, 2021, pages 1275 - 1289
CARRARO, G. ET AL.: "Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition", NAT. MED., vol. 27, 2021, pages 806 - 814, XP037452980, DOI: 10.1038/s41591-021-01332-7
MONTORO, D. T. ET AL.: "A revised airway epithelial hierarchy includes CFTR-expressing ionocytes", NATURE, vol. 560, 2018, pages 319, XP036567573, DOI: 10.1038/s41586-018-0393-7
PLASSCHAERT, L. W. ET AL.: "A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte", NATURE, vol. 560, 2018, pages 377, XP036567574, DOI: 10.1038/s41586-018-0394-6
HODGES, C. A.CONLON, R. A.: "Delivering on the promise of gene editing for cystic fibrosis", GENES DIS., vol. 6, 2019, pages 97 - 108
RYALS, R. C. ET AL.: "The effects of PEGylation on LNP based mRNA delivery to the eye", PLOS ONE, vol. 15, 2020, pages e0241006
ELTOUKHY, A. A. ET AL.: "Effect of molecular weight of amine end-modified poly(0-amino ester)s on gene delivery efficiency and toxicity.", BIOMATERIALS, vol. 33, 2012, pages 3594 - 3603, XP028461963, DOI: 10.1016/j.biomaterials.2012.01.046
CHEN, D. ET AL.: "Rapid Discovery of Potent siRNA-Containing Lipid Nanoparticles Enabled by Controlled Microfluidic Formulation", J. AM. CHEM. SOC., vol. 134, 2012, pages 6948 - 6951, XP002715254, DOI: 10.1021/ja301621z
HEYES, J.PALMER, L.BREMNER, K.MACLACHLAN, I.: "Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids", J. CONTROL. RELEASE OFF. J. CONTROL. RELEASE SOC., vol. 107, 2005, pages 276 - 287, XP005076220, DOI: 10.1016/j.jconrel.2005.06.014
MAIER, M. A.; JAYARAMAN, M.; MATSUDA, S.; LIU, J.; BARROS, S.; QUERBES, W.; TAM, Y K.; ANSELL, S. M.; KUMAR, V.; QIN, J.: "Biodegradable Lipids Enabling Rapidly Eliminated Lipid Nanoparticles for Systemic Delivery of RNAi Therapeutics", MOL. THER, vol. 21, no. 8, 2013, pages 1570 - 1578, XP055237159, Retrieved from the Internet
REDDY GUDURU, S. K.CHAMAKURI, S.RAJI, I. O.MACKENZIE, K. RSANTINI, CYOUNG, D. W.: "Synthesis of Enantiomerically Pure 3-Substituted Piperazine-2-Acetic Acid Esters as Intermediates for Library Production", J. ORG. CHEM., vol. 83, no. 19, 2018, XP093006475, Retrieved from the Internet
HAN, Z.YORIMITSU, H.SHINOKUBO, H.OSHIMA, K.: "A Highly Effective Aldol Reaction Mediated by Ti(O-n-Bu)4/t-BuOK Combined Reagent", TETRAHEDRON LETT., vol. 41, no. 22, 2000, pages 4415 - 4418, XP004205580, Retrieved from the Internet
ABDEL-MAGID, A. F.CARSON, K. G.HARRIS, B. D.MARYANOFF, C. ASHAH, R. D.: "Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Proceduresl", J. ORG. CHEM., vol. 61, no. 11, 1996, pages 3849 - 3862, XP002217704, Retrieved from the Internet
GHANEM, R.LAURENT, V.ROQUEFORT, P.HAUTE, T.RAMEL, SLE GALL, TAUBRY, T.MONTIER, T.: "Optimizations of In Vitro Mucus and Cell Culture Models to Better Predict In Vivo Gene Transfer in Pathological Lung Respiratory Airways: Cystic Fibrosis as an Example", PHARMACEUTICS, 2021, Retrieved from the Internet
YIN, H.SONG, C.-Q.SURESH, SWU, QWALSH, S.RHYM, L. HMINTZER, E.BOLUKBASI, M. F.ZHU, L. J.KAUFFMAN, K. ET AL.: "Structure-Guided Chemical Modification of Guide RNA Enables Potent Non-Viral in Vivo Genome Editing", NAT. BIOTECHNOL., vol. 35, no. 12, 2017, pages 1179 - 1187, XP055484407, Retrieved from the Internet
CLAIMS What is claimed is: 1. A compound of Formula (I): or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: R1 is -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nitrogen protecting group; R2 is -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nitrogen protecting group; or R1 and R2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl; each R3 independently is optionally substituted C6-C25 aliphatic; and each n independently is 0-15, inclusive. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each n is independently 1-10, inclusive. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each n independently is 1-6, inclusive. 4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each n is 4. 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R1 is -H, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 heteroalkyl, or a nitrogen protecting group. 6. The compound of claim 5, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R1 is -H. 7. The compound of claim 5, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R1 is optionally substituted C1-C10 alkyl or optionally substituted C1-C10 heteroalkyl. 8. The compound of claim 7, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R1 is -Me. 9. The compound of claim 7, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R1 is . 10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R2 is -H, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C3-C14 carbocyclyl, optionally substituted 3- to 14-membered heterocyclyl, or a nitrogen protecting group. 11. The compound of claim 10, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R2 is optionally substituted C1-C10 alkyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C3-C14 carbocyclyl, optionally substituted 3- to 14-membered heterocyclyl, or a nitrogen protecting group. 12. The compound of claim 11, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R2 is , 13. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R2 is optionally substituted heteroalkyl comprising one or more N atoms substituted with . 14. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R2 is 15. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R1 and R2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl. 16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R1 and R2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl comprising one or two nitrogen atoms. 17. The compound of claim 16, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein -NR1R2 is 18. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R1 and R2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl comprising two or more N atoms substituted with . 19. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R1 and R2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl comprising two N atoms substituted with . 20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R3 is optionally substituted C6-C25 alkyl, optionally substituted C6-C25 alkenyl, or optionally substituted C6- C25 alkynyl. 21. The compound of claim 20, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R3 is unsubstituted C6-C25 alkyl. 22. The compound of claim 21, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R3 is , , . 23. The compound of claim 20, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R3 is unsubstituted C6-C25 alkenyl. 24. The compound of claim 23, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R3 comprises one, two, or three double bonds. 25. The compound of claim 23 or 24, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R3 is . 26. The compound of claim 1, selected from or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. 27. The compound of claim 1, selected from , or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. 28. The compound of claim 1, selected from , or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. 29. A composition comprising a compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and an agent. 30. The composition of claim 29, wherein the agent is an organic molecule, inorganic molecule, protein, peptide, polynucleotide, targeting agent, an isotopically labeled chemical compound, vaccine, an immunological agent, or an agent useful in bioprocessing. 31. The composition of claim 29 or 30, wherein the agent is a polynucleotide. 32. The composition of claim 31, wherein the polynucleotide is an RNA. 33. The composition of claim 32, wherein the RNA is RNA is messenger RNA (mRNA), single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or lncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, or viral satellite RNA. 34. The composition of claim 33, wherein the agent is mRNA. 35. The composition of claim 31, wherein the polynucleotide is a DNA. 36. The composition of claim 35, wherein the DNA is a plasmid DNA (pDNA). 37. The composition of any one of claims 29-36, wherein the composition further comprises one or more of a PEG-lipid, sterol, phospholipid, or helper lipid. 38. The composition of any one of claims 29-37, wherein the composition further comprises a stabilizing agent. 39. The composition of any one of claims 29-38, wherein the composition further comprises a buffer. 40. The composition of any one of claims 29-39, wherein the agent and the compound, or the pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, are not covalently attached. 41. The composition of any one of claims 29-40, wherein the composition is in the form of a particle. 42. The composition of claim 41, wherein the particle is a nanoparticle or microparticle. 43. The composition of claim 41, wherein the particle is a micelle, liposome, or lipoplex. 44. The composition of any one of claims 41-43, wherein the particle encapsulates the agent. 45. A method of delivering a polynucleotide to a subject or a cell, comprising administering to the subject, or contacting the cell with, a composition comprising a polynucleotide and a compound of any one of claims 1-28. 46. The method of claim 45, wherein the delivery is to the lung or nasal epithelium of the subject, or the cell is a lung cell or nasal epithelium cell. 47. The method of claim 46, wherein the lung epithelium of the subject comprises club cells, or the lung cell is a club cell. 48. The method of any one of claims 45-47, wherein the composition is nebulized or aerosolized before the agent is delivered to the subject or the cell. 49. A method of treating or preventing a disease, disorder, or condition in a subject, comprising administering to the subject a composition of any one of claims 29-44. 50. The method of claim 49, wherein the disease, disorder, or condition is a genetic disease, proliferative disease, hematological disease, neurological disease, liver disease, spleen disease, lung disease, painful condition, psychiatric disorder, musculoskeletal disease, a metabolic disorder, inflammatory disease, or autoimmune disease. 51. The method of claim 50, wherein the disease, disorder, or condition is a lung disease. 52. The method of claim 51, wherein the lung disease is cystic fibrosis, sepsis, or lung cancer. 53. The method of any one of claims 49-52, wherein the administration is nebulized administration or IV administration. 54. A kit comprising: a compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof; or a composition of any one of claims 29-44; and instructions for using the compound, or pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or composition. 55. A method of preparing a compound of Formula (I), the method comprising reacting a compound of Formula (II): or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, with a compound of Formula (III): or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: R1 is -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nitrogen protecting group; R2 is -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nitrogen protecting group; or R1 and R2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl; each R3 independently is optionally substituted C6-C25 aliphatic; and each n independently is 0-15, inclusive. 56. The method of claim 55, wherein the compound of Formula (III), or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, is prepared by reacting one or more compounds of Formula (IV): or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, with a base or acid catalyst, wherein: each R3 independently is optionally substituted C6-C25 aliphatic; and each n independently is 0-15, inclusive. 57. The method of claim 56, wherein the base is titanium (IV) butoxide and/or potassium tert-butoxide. |
[00190] In certain embodiments, the compound of Formula (I) is
or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. [00191] In some embodiments, the compound is , or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. [00192] In some embodiments, the compound is , or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. Compositions and Administration [00193] The present disclosure provides compositions (e.g., pharmaceutical compositions) comprising a compound provided herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and an agent. [00194] In certain embodiments, the compound provided herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is an amount effective for delivering an agent to a subject or cell. In certain embodiments, the effective amount is an amount effective for delivering a polynucleotide to a subject or cell. In certain embodiments, the effective amount is an amount effective for delivering mRNA to a subject or cell. [00195] In certain embodiments, the composition further comprises one or more of a PEG- lipid, sterol, phospholipid, helper lipid, or stabilizing excipient. In certain embodiments, the composition comprises a PEG-lipid, sterol, and phospholipid. In certain embodiments, the composition comprises a PEG-lipid, sterol, phospholipid, and helper lipid. In certain embodiments, the composition comprises a PEG-lipid, sterol, phospholipid, and stabilizing excipient. In certain embodiments, the composition comprises a PEG-lipid, sterol, phospholipid, helper lipid, and stabilizing excipient. In certain embodiments, the composition comprises a PEG-lipid. In some embodiments, the composition comprises a sterol. In certain embodiments, the composition comprises a phospholipid. In some embodiments, the composition comprises a helper lipid. In some embodiments, the composition comprises a stabilizing excipient. In certain embodiments, the composition comprises one or more of a PEG-lipid, sterol, phospholipid, helper lipid, or stabilizing excipient and is formulated as a particle. In some embodiments, the composition comprises one or more of a PEG-lipid, sterol, phospholipid, helper lipid, or stabilizing excipient and is formulated as a nanoparticle or microparticle. In certain embodiments, the composition comprises one or more of a PEG-lipid, sterol, phospholipid, helper lipid, or stabilizing excipient and is formulated as a lipid nanoparticle. [00196] In some embodiments, the composition comprises approximately 30-70% of a compound of Formula (I) by mass. In certain embodiments, the composition comprises approximately 40-60% of a compound of Formula (I) by mass. In some embodiments, the composition comprises approximately 45-55% of a compound of Formula (I) by mass. In some embodiments, the composition comprises approximately 50% of a compound of Formula (I) by mass. [00197] In some embodiments, the composition comprises approximately 15-35% of a helper lipid by mass. In some embodiments, the composition comprises approximately 20- 30% of a helper lipid by mass. In some embodiments, the composition comprises approximately 25% of a helper lipid by mass. [00198] In some embodiments, the composition comprises approximately 5-25% of a sterol by mass. In some embodiments, the composition comprises approximately 10-20% of a sterol by mass. In some embodiments, the composition comprises approximately 17% of a sterol by mass. [00199] In some embodiments, the composition comprises approximately 0-20% of a PEG- lipid by mass. In some embodiments, the composition comprises approximately 5-15% of a PEG-lipid by mass. In some embodiments, the composition comprises approximately 8.5% of a PEG-lipid by mass. [00200] In some embodiments, the composition comprises approximately 50% of a compound of Formula (I), approximately 25% of a charged lipid, approximately 17% of a sterol, and approximately 8% of a PEG-lipid by mass. In some embodiments, the composition comprises approximately 50% of a compound of Formula (I), approximately 24.6% of a charged lipid, approximately 16.8% of a sterol, and approximately 8.5% of a PEG-lipid by mass. [00201] In some embodiments, the composition comprises a 10:1 weight ratio of a compound of Formula (I):agent. In some embodiments, the composition comprises a 10:1 weight ratio of a compound of Formula (I):polynucleotide. In some embodiments, the composition comprises a 10:1 weight ratio of a compound of Formula (I):mRNA. [00202] In some embodiments, the composition comprises approximately 10-50 mol % of a compound of Formula (I). In certain embodiments, the composition comprises approximately 20-40 mol % of a compound of Formula (I). In some embodiments, the composition comprises approximately 35 mol % of a compound of Formula (I). [00203] In some embodiments, the composition comprises approximately 5-35 mol % of a helper lipid. In some embodiments, the composition comprises approximately 10-20 mol % of a helper lipid. In some embodiments, the composition comprises approximately 16 mol % of a helper lipid. [00204] In some embodiments, the composition comprises approximately 30-60 mol % of a sterol. In some embodiments, the composition comprises approximately 40-50 mol % of a sterol. In some embodiments, the composition comprises approximately 46 mol % of a sterol. [00205] In some embodiments, the composition comprises approximately 0-10 mol % of a PEG-lipid. In some embodiments, the composition comprises approximately 0-5 mol % of a PEG-lipid. In some embodiments, the composition comprises approximately 2.5 mol % of a PEG-lipid. [00206] In some embodiments, the composition comprises between approximately 0.1% and 5% of a stabilizing excipient (w/v). In come embodiments, the composition comprises between approximately 1% and 3% of a stabilizing excipient (w/v). In some embodiments, the composition comprises approximately 2% of a stabilizing excipient (w/v). [00207] In certain embodiments, the composition further comprises a buffer. In certain embodiments, the composition comprises a buffer and a stabilizing excipient. [00208] In certain embodiments, the composition is formulated for aerosolization or nebulization. In certain embodiments, the composition is an aerosol. Aerosols may comprise solid particles, semi-solid particles, liquid particles (i.e., droplets), or mixtures thereof. Compounds used in the form of solid or semi-solid particles may be encapsulated or complexed in order to achieve favorable or advantageous properties such as size, weight, solubility, and dispersibility. The size of aerosol particles can be controlled by a device used to produce such particles. Particle (e.g., droplet) size and distribution and deposition in the respiratory tract will result from the device used and the inhalation pattern of the subject. See, e.g., Laube BL, et al. Eur. Respir. J.2011, 37, 1308-1311. In certain embodiments, the aerosol is produced by nebulization. In certain embodiments, the aerosol is produced by a nebulizer. [00209] In certain embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. [00210] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include bringing a compound, agent, or particle described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit. [00211] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage. [00212] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient. [00213] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents such as calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof. [00214] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor ® , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof. [00215] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [00216] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00217] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle. [00218] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient. [00219] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (II) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent. [00220] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [00221] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes. [00222] Dosage forms for topical and/or transdermal administration of a compound, agent, or particle described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel. [00223] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound, agent, or particle in powder form through the outer layers of the skin to the dermis are suitable. [00224] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein. [00225] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form. [00226] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient). [00227] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers. [00228] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares. [00229] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein. [00230] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure. [00231] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. [00232] Compounds, agents, or particles provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts. [00233] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). [00234] The exact amount of a compound, agent, or particle required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, agent or particle, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound, agent, or particle described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 µg and 1 µg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound, agent, or particle described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound, agent, or particle described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound, agent, or particle described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound, agent, or particle described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound, agent, or particle described herein. [00235] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. [00236] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that treat a disease in a subject in need thereof, prevent a disease in a subject in need thereof, or reduce the risk to develop a disease in a subject in need thereof, improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects. [00237] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, polynucleotides, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., lung disease or liver disease). Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. [00238] Additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti- inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, anesthetics, anti–coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti–pyretics, hormones, and prostaglandins. PEG-Lipid [00239] In some embodiments, the PEG-lipid is a PEG-phospholipid or PEG-glyceride lipid. In certain embodiments, the PEG-lipid is a PEG-phospholipid. In certain embodiments, the PEG-phospholipid is a PEG-phosphoethanolamine. In some embodiments, the PEG- phospholipid is a PEG-phosphatidylcholine. In certain embodiments, the PEG-lipid is 1,2- dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly ethylene glycol)-2000] (C 14 PEG2000). [00240] In certain embodiments, the PEG component has a molecular weight of about 350, about 550, about 750, about 1000, about 2000, about 3000, or about 5000. In some embodiments, the PEG component has a molecular weight of about 750, about 1000, about 2000, about 3000, or about 5000. In certain embodiments, the PEG component has a molecular weight of about 1000, about 2000, or about 3000. In some embodiments, the PEG component has a molecular weight of about 2000. [00241] In certain embodiments, the PEG-lipid is stearoyl-substituted (C 18 ). In some embodiments, the PEG-phospholipid is palmitoyl-substituted (C16). In certain embodiments, the PEG-phospholipid is myristoyl-substituted (C14). [00242] In certain embodiments, the PEG-lipid is selected from the group consisting of 1,2- distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polye thylene glycol)-5000] (C18PEG5000), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-5000] (C 16 PEG5000), 1,2-dimyristoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-5000] (C 14 PEG5000), 1,2- distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polye thylene glycol)-3000] (C18PEG3000), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-3000] (C 16 PEG3000), 1,2-dimyristoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-3000] (C14PEG3000), 1,2- distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polye thylene glycol)-2000] (C 18 PEG2000), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-2000] (C16PEG2000), 1,2-dimyristoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (C14PEG2000), 1,2- distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polye thylene glycol)-1000] (C 18 PEG1000), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-1000] (C16PEG1000), 1,2-dimyristoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-1000] (C 14 PEG1000), 1,2- distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polye thylene glycol)-750] (C18PEG750), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy( polyethylene glycol)-750] (C16PEG750), and 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-750] (C 14 PEG750). In some embodiments, the PEG-lipid is selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-2000] (C18PEG2000), 1,2-dipalmitoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (C 16 PEG2000), and 1,2- dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly ethylene glycol)-2000] (C14PEG2000). In certain embodiments, the PEG-lipid is selected from the group consisting of 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy( polyethylene glycol)- 5000] (C 14 PEG5000), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-3000] (C14PEG3000), 1,2-dimyristoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (C 14 PEG2000), 1,2- dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly ethylene glycol)-1000] (C14PEG1000), and 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-750] (C14PEG750). In certain embodiments, the PEG- phospholipid is 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-2000] (C14PEG2000). [00243] In some embodiments, the PEG-lipid is a PEG-glyceride lipid. In certain embodiments, the PEG-lipid is 1,2-distearoyl-rac-glycero-3-methoxypolyethylene glycol or 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol. In certain embodiments, the PEG-lipid is 1,2-distearoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DSG- PEG2000) or 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG- PEG2000). In some embodiments, the PEG-lipid is 1,2-distearoyl-rac-glycero-3- methoxypolyethylene glycol-2000 (DSG-PEG2000). In certain embodiments, the PEG-lipid is 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2000). Sterol [00244] In certain embodiments, the sterol is cholesterol, sitosterol, campesterol, stigmasterol, brassicasterol (including dihydrobrassicasterol), desmosterol, chalinosterol, poriferasterol, clionasterol, ergosterol, coprosterol, codisterol, isofucosterol, fucosterol, clerosterol, nervisterol, lathosterol, stellasterol, spinasterol, chondrillasterol, peposterol, avenasterol, isoavenasterol, fecosterol, pollinastasterol, or a derivative thereof. In some embodiments, the sterol is cholesterol, or a derivative thereof. In certain embodiments, the sterol is cholesterol. Helper Lipid [00245] In some embodiments, the helper lipid is a fixed cationic lipid or salt thereof. In some embodiments, the fixed cationic lipid is 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), 1,2-stearoyl-3- trimethylammonium-propane (18:0 TAP), 1,2-dipalmitoyl-3-trimethylammonium-propane (16:0 TAP), 1,2-dimyristoyl-3-trimethylammonium-propane (14:0 TAP), dimethyldioctadecylammonium (18:0 DDAB), 1,2-dimyristoleoyl-sn-glycero-3- ethylphosphocholine (14:1 EPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine (16:0-18:1 EPC), 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (18:1 EPC), 1,2- distearoyl-sn-glycero-3-ethylphosphocholine (18:0 EPC), 1,2-dipalmitoyl-sn-glycero-3- ethylphosphocholine (16:0 EPC), 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (14:0 EPC), 1,2-dilauroyl-sn-glycero-3-ethylphosphocholine (12:0 EPC), O,O’-ditetradecanoyl-N- (α-trimethylammonioacetyl)diethanolamine (DC-6-14), or N-(2-hydroxyethyl)-N,N- dimethyl-2,3-bis(oleoyloxy)propan-1-aminium. In some embodiments, the fixed cationic lipid is 1,2-dioleoyl-3-trimethylammonium propane (DOTAP). [00246] In some embodiments, the helper lipid is a salt of a fixed cationic ligand. In certain embodiments, the salt of a fixed cationic lipid is a chloride salt, bromide salt, methyl sulfate salt, or triflate salt. In some embodiments, the salt of a fixed cationic ligand is a chloride salt. [00247] In some embodiments, the helper lipid is an ionizable lipid. In certain embodiments, the ionizable lipid is 1,2-distearoyl-3-dimethylammonium-propane (18:0 DAP), 1,2-dipalmitoyl-3-dimethylammonium-propane (16:0 DAP), 1,2-dimyristoyl-3- dimethylammonium-propane (14:0 DAP), 1,2-dioleoyl-3-dimethylammonium-propane (DODAP or 18:1 DAP), or 1,2-dioleyloxy-3-dimethylaminopropane (DODMA). [00248] In some embodiments, the helper lipid is a phospholipid. In certain embodiments, the helper lipid is not a phospholipid. Phospholipid [00249] In certain embodiments, the phospholipid is a phosphoethanolamine or phosphatidylcholine. In some embodiments, the phospholipid is 1,2-distearoyl-sn-glycero-3- phosphorylethanolamine (DSPE), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). In some embodiments, the phospholipid is a phosphoethanolamine. In certain embodiments, the phospholipid is 1,2- distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE) or phospholipid is 1,2-dioleoyl-sn- glycero-3-phosphoethanolamine (DOPE). In certain embodiments, the phospholipid is 1,2- distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE). In certain embodiments, the phospholipid is 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). In some embodiments, the phospholipid is a phosphatidylcholine. In some embodiments, the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). Stabilizing Excipient [00250] In certain embodiments, the stabilizing excipient is a disaccharide lyoprotectant (e.g., trehalose, sucrose). In some embodiments, the stabilizing excipient is trehalose. In some embodiments, the stabilizing excipient is sucrose. [00251] In certain embodiments, the stabilizing excipient is an inert hydrophilic polymeric excipient (e.g., a polysaccharide (e.g., Dextran, Ficoll), linear PEG (e.g., PEG6K, PEG20k), branched PEG (e.g., bPEG20K)). In certain embodiments, the stabilizing excipient is a polysaccharide (e.g., Dextran, Ficoll). In certain embodiments, the stabilizing excipient is Dextran. In certain embodiments, the stabilizing excipient is Ficoll. In certain embodiments, the stabilizing excipient is linear PEG (e.g., PEG6K, PEG20k). In certain embodiments, the stabilizing excipient is PEG6K. In certain embodiments, the stabilizing excipient is PEG20k. In certain embodiments, the stabilizing excipient is branched PEG (e.g., bPEG20K). In certain embodiments, the stabilizing excipient is bPEG20K. In some embodiments, the stabilizing excipient is between approximately 0.1% and 5% bPEG20K (w/v). In come embodiments, the stabilizing excipient is between approximately 1% and 3% bPEG20K (w/v). In some embodiments, the stabilizing excipient is approximately 2% bPEG20K (w/v). Buffer [00252] In certain embodiments, the composition further comprises a buffer. In certain embodiments, the buffer comprises citrate buffer. In certain embodiments, the buffer comprises 10mM citrate buffer. In certain embodiments, the buffer comprises 0.9% saline. In certain embodiments, the buffer comprises 0.9% saline at pH 7.0. In certain embodiments, the buffer comprises sodium acetate (NaAc). In certain embodiments, the buffer comprises 100mM sodium acetate (NaAc). In certain embodiments, the buffer comprises 100mM sodium acetate (NaAc) at pH 5.2. [00253] In certain embodiments, the buffer reduces LNP aggregation during nebulization. In certain embodiments, the buffer attenuates the increase in LNP size following nebulization. In certain embodiments, the buffer comprises sodium acetate (NaAc) and reduces LNP aggregation during nebulization. In certain embodiments, the buffer comprises sodium acetate (NaAc) and attenuates the increase in LNP size following nebulization. [00254] In some embodiments, the composition comprises a stabilizing excipient and further comprises a buffer. In some embodiments, the stabilizing excipient is branched PEG (e.g., bPEG20K) and the buffer comprises sodium acetate. In some embodiments, the stabilizing excipient is bPEG20K and the buffer comprises sodium acetate. Agents [00255] In certain embodiments, the composition further comprises an agent. In some embodiments, the agent is an organic molecule, inorganic molecule, protein, peptide, polynucleotide, targeting agent, an isotopically labeled chemical compound, vaccine, an immunological agent, or an agent useful in bioprocessing. [00256] In some embodiments, the agent and the compound, or the pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, are not covalently attached. [00257] Agents that are delivered by the systems (e.g., compositions) described herein may be therapeutic, prophylactic, diagnostic, cosmetic, or nutraceutical agents. Any chemical compound to be administered to a subject may be delivered using the complexes, picoparticles, nanoparticles (e.g., lipid nanoparticles), microparticles, micelles, or liposomes, described herein. In some embodiments, the agent is an organic molecule, inorganic molecule, protein, peptide, polynucleotide, targeting agent, an isotopically labeled chemical compound, vaccine, an immunological agent, or an agent useful in bioprocessing (e.g., intracellular manufacturing of proteins, such as a cell’s bioprocessing of a commercially useful chemical or fuel). For example, intracellular delivery of an agent may be useful in bioprocessing by maintaining the cell’s health and/or growth, e.g., in the manufacturing of proteins. Any chemical compound to be administered to a subject or contacted with a cell may be delivered to the subject or cell using the compositions. In certain embodiments, the vaccine is a nasal vaccine. [00258] Exemplary agents that may be included in a composition described herein include, but are not limited to, small molecules, organometallic compounds, polynucleotides, proteins, peptides, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, small molecules linked to proteins, glycoproteins, steroids, nucleotides, oligonucleotides, polynucleotides, nucleosides, antisense oligonucleotides, lipids, hormones, vitamins, cells, metals, targeting agents, isotopically labeled chemical compounds, drugs (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations), vaccines, immunological agents, agents useful in bioprocessing, and mixtures thereof. The targeting agents are described in more detail herein. In certain embodiments, the agents are nutraceutical agents. In certain embodiments, the agents are pharmaceutical agents (e.g., a therapeutic or prophylactic agent). In certain embodiments, the agent is an antibiotic agent (e.g., an anti-bacterial, anti-viral, or anti-fungal agent), anesthetic, steroidal agent, anti-proliferative agent, anti-inflammatory agent, anti-angiogenesis agent, anti- neoplastic agent, anti-cancer agent, anti-diabetic agent, antigen, vaccine, antibody, decongestant, antihypertensive, sedative, birth control agent, progestational agent, anti- cholinergic, analgesic, immunosuppressant, anti-depressant, anti-psychotic, β-adrenergic blocking agent, diuretic, cardiovascular active agent, vasoactive agent, non-steroidal, nutritional agent, anti-allergic agent, or pain-relieving agent. Vaccines may comprise isolated proteins or peptides, inactivated organisms and viruses, dead organisms and viruses, genetically altered organisms or viruses, polynucleotides (e.g., mRNA), and cell extracts. Therapeutic and prophylactic agents may be combined with interleukins, interferon, cytokines, and adjuvants such as cholera toxin, alum, and Freund’s adjuvant, etc. [00259] In certain embodiments, an agent to be delivered or used in a composition described herein is a polynucleotide. In certain embodiments, the agent is plasmid DNA (pDNA). In certain embodiments, the agent is single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, or viral DNA. In certain embodiments, the agent is RNA. In certain embodiments, the agent is small interfering RNA (siRNA). In certain embodiments, the agent is messenger RNA (mRNA). In certain embodiments, the agent is single-stranded RNA (ssRNA), double- stranded RNA (dsRNA), small interfering RNA (siRNA), precursor messenger RNA (pre- mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or lncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, or viral satellite RNA. In certain embodiments, the agent is an RNA that carries out RNA interference (RNAi). The phenomenon of RNAi is discussed in greater detail, for example, in the following references: Elbashir et al., 2001, Genes Dev., 15:188; Fire et al., 1998, Nature, 391:806; Tabara et al., 1999, Cell, 99:123; Hammond et al., Nature, 2000, 404:293; Zamore et al., 2000, Cell, 101:25; Chakraborty, 2007, Curr. Drug Targets, 8:469; and Morris and Rossi, 2006, Gene Ther., 13:553. In certain embodiments, upon delivery of an RNA into a subject, tissue, or cell, the RNA is able to interfere with the expression of a specific gene in the subject, tissue, or cell. In certain embodiments, the agent is a pDNA, siRNA, mRNA, or a combination thereof. [00260] In certain embodiments, the polynucleotide may be provided as an antisense agent or RNAi. See, e.g., Fire et al., Nature 391:806-811, 1998. Antisense therapy is meant to include, e.g., administration or in situ provision of single- or double-stranded polynucleotides, or derivatives thereof, which specifically hybridize, e.g., bind, under cellular conditions, with cellular mRNA and/or genomic DNA, or mutants thereof, so as to inhibit the expression of the encoded protein, e.g., by inhibiting transcription and/or translation. See, e.g., Crooke, “Molecular mechanisms of action of antisense drugs,” Biochim. Biophys. Acta 1489(1):31-44, 1999; Crooke, “Evaluating the mechanism of action of anti-proliferative antisense drugs,” Antisense Nucleic Acid Drug Dev.10(2):123-126, discussion 127, 2000; Methods in Enzymology volumes 313-314, 1999. The binding may be by conventional base pair complementarity, or, for example, in the case of binding to DNA duplexes, through specific interactions in the major groove of the double helix (i.e., triple helix formation). See, e.g., Chan et al., J. Mol. Med.75(4):267-282, 1997. [00261] In some embodiments, pDNA, siRNA, dsRNA, shRNA, miRNA, mRNA, tRNA, asRNA, and/or RNAi can be designed and/or predicted using one or more of a large number of available algorithms. To give but a few examples, the following resources can be utilized to design and/or predict polynucleotides: algorithms found at Alnylum Online; Dharmacon Online; OligoEngine Online; Molecula Online; Ambion Online; BioPredsi Online; RNAi Web Online; Chang Bioscience Online; Invitrogen Online; LentiWeb Online GenScript Online; Protocol Online; Reynolds et al., 2004, Nat. Biotechnol., 22:326; Naito et al., 2006, Nucleic Acids Res., 34:W448; Li et al., 2007, RNA, 13:1765; Yiu et al., 2005, Bioinformatics, 21:144; and Jia et al., 2006, BMC Bioinformatics, 7: 271. [00262] The polynucleotide included in a composition may be of any size or sequence, and they may be single- or double-stranded. In certain embodiments, the polynucleotide includes at least about 30, at least about 100, at least about 300, at least about 1,000, at least about 3,000, or at least about 10,000 base pairs. In certain embodiments, the polynucleotide includes less than about 10,000, less than about 3,000, less than about 1,000, less than about 300, less than about 100, or less than about 30 base pairs. Combinations of the above ranges (e.g., at least about 100 and less than about 1,000) are also within the scope of the invention. The polynucleotide may be provided by any means known in the art. In certain embodiments, the polynucleotide is engineered using recombinant techniques. See, e.g., Ausubel et al., Current Protocols in Molecular Biology (John Wiley & Sons, Inc., New York, 1999); Molecular Cloning: A Laboratory Manual, 2nd Ed., ed. by Sambrook, Fritsch, and Maniatis (Cold Spring Harbor Laboratory Press: 1989). The polynucleotide may also be obtained from natural sources and purified from contaminating components found normally in nature. The polynucleotide may also be chemically synthesized in a laboratory. In certain embodiments, the polynucleotide is synthesized using standard solid phase chemistry. The polynucleotide may be isolated and/or purified. In certain embodiments, the polynucleotide is substantially free of impurities. In certain embodiments, the polynucleotide is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% free of impurities. [00263] The polynucleotide may be modified by physical, chemical, and/or biological means. The modifications include methylation, phosphorylation, and end-capping, etc. In certain embodiments, the modifications lead to increased stability of the polynucleotide. [00264] Wherever a polynucleotide is employed in the composition, a derivative of the polynucleotide may also be used. These derivatives include products resulted from modifications of the polynucleotide in the base moieties, sugar moieties, and/or phosphate moieties of the polynucleotide. Modified base moieties include, but are not limited to, 2- aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5- methylcytidine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine. Modified sugar moieties include, but are not limited to, 2 ^-fluororibose, ribose, 2 ^-deoxyribose, 3 ^-azido- 2 ^,3 ^-dideoxyribose, 2 ^,3 ^-dideoxyribose, arabinose (the 2 ^-epimer of ribose), acyclic sugars, and hexoses. The nucleosides may be strung together by linkages other than the phosphodiester linkage found in naturally occurring DNA and RNA. Modified linkages include, but are not limited to, phosphorothioate and 5 ^-N-phosphoramidite linkages. Combinations of the various modifications may be used in a single polynucleotide. These modified polynucleotides may be provided by any means known in the art; however, as will be appreciated by those of skill in the art, the modified polynucleotides may be prepared using synthetic chemistry in vitro. [00265] The polynucleotide described herein may be in any form, such as a circular plasmid, a linearized plasmid, a cosmid, a viral genome, a modified viral genome, and an artificial chromosome. [00266] The polynucleotide described herein may be of any sequence. In certain embodiments, the polynucleotide encodes a protein or peptide. The encoded protein may be an enzyme, structural protein, receptor, soluble receptor, ion channel, active (e.g., pharmaceutically active) protein, cytokine, interleukin, antibody, antibody fragment, antigen, coagulation factor, albumin, growth factor, hormone, and insulin, etc. The polynucleotide may also comprise regulatory regions to control the expression of a gene. These regulatory regions may include, but are not limited to, promoters, enhancer elements, repressor elements, TATA boxes, ribosomal binding sites, and stop sites for transcription, etc. In certain embodiments, the polynucleotide is not intended to encode a protein. For example, the polynucleotide may be used to fix an error in the genome of the cell being transfected. [00267] In certain embodiments, the polynucleotide described herein comprises a sequence encoding an antigenic peptide or protein. A composition containing the polynucleotide can be delivered to a subject to induce an immunologic response sufficient to decrease the chance of a subsequent infection and/or lessen the symptoms associated with such an infection. The polynucleotide of these vaccines may be combined with interleukins, interferon, cytokines, and/or adjuvants described herein. [00268] The antigenic protein or peptides encoded by the polynucleotide may be derived from bacterial organisms, such as Streptococccus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes, Corynebacterium diphtheriae, Listeria monocytogenes, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Neisseria meningitidis, Neisseria gonorrhoeae, Streptococcus mutans, Pseudomonas aeruginosa, Salmonella typhi, Haemophilus parainfluenzae, Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibrio cholerae, Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium leprae, Treponema pallidum, Leptospirosis interrogans, Borrelia burgdorferi, and Camphylobacter jejuni; from viruses, such as smallpox virus, influenza A virus, influenza B virus, respiratory syncytial virus, parainfluenza virus, measles virus, HIV virus, varicella-zoster virus, herpes simplex 1 virus, herpes simplex 2 virus, cytomegalovirus, Epstein-Barr virus, rotavirus, rhinovirus, adenovirus, papillomavirus, poliovirus, mumps virus, rabies virus, rubella virus, coxsackieviruses, equine encephalitis virus, Japanese encephalitis virus, yellow fever virus, Rift Valley fever virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis E virus; and from fungal, protozoan, or parasitic organisms, such as Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, Candida tropicalis, Nocardia asteroides, Rickettsia ricketsii, Rickettsia typhi, Mycoplasma pneumoniae, Chlamydial psittaci, Chlamydial trachomatis, Plasmodium falciparum, Trypanosoma brucei, Entamoeba histolytica, Toxoplasma gondii, Trichomonas vaginalis, and Schistosoma mansoni. [00269] In certain embodiments, the agent is erythropoietin (EPO), e.g., recombinant human erythropoietin (rhEPO). Erythropoietin is an essential hormone for red blood cell production, and may be used in treating hematological diseases, e.g., anemia., such as anemia resulting from chronic kidney disease, chemotherapy induced anemia in patients with cancer, inflammatory bowel disease (Crohn's disease and ulcerative colitis) and myelodysplasia from the treatment of cancer (chemotherapy and radiation). Recombinant human erythropoietins available for use include EPOGEN/PROCRIT (Epoetin alfa, rINN) and ARANESP (Darbepoetin alfa, rINN). [00270] An agent described herein may be non-covalently (e.g., complexed or encapsulated) attached to a compound as described herein, or included in a composition described herein. In certain embodiments, upon delivery of the agent into a cell, the agent is able to interfere with the expression of a specific gene in the cell. [00271] In certain embodiments, the agent in a composition that is delivered to a subject in need thereof may be a mixture of two or more agents that may be useful as, e.g., combination therapies. The compositions including the two or more agents can be administered to achieve a synergistic effect. In certain embodiments, the compositions including the two or more agents can be administered to improve the activity and/or bioavailability, reduce and/or modify the metabolism, inhibit the excretion, and/or modify the distribution within the body of a subject, of each one of the two or more agents. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. [00272] The compositions (e.g., pharmaceutical compositions) can be administered concurrently with, prior to, or subsequent to the one or more agents (e.g., pharmaceutical agents). The two or more agents may be useful for treating and/or preventing a same disease or different diseases described herein. Each one of the agents may be administered at a dose and/or on a time schedule determined for that agent. The agents may also be administered together with each other and/or with the composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the agents and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. Targeting Agents [00273] Since it is often desirable to target a particular cell, collection of cells, or tissue, compounds provided herein, and the complexes, liposomes, micelles, and particles (e.g., microparticles and nanoparticles) thereof, may be modified to include targeting moieties. For example, a compound provided herein may include a targeting moiety. A variety of agents or regions that target particular cells are known in the art. See, e.g., Cotten et al., Methods Enzym.217:618, 1993. The targeting agent may be included throughout a particle of a compound provided herein or may be only on the surface of the particle. The targeting agent may be a protein, peptide, carbohydrate, glycoprotein, lipid, small molecule, or polynucleotide, etc. The targeting agent may be used to target specific cells or tissues or may be used to promote endocytosis or phagocytosis of the particle. Examples of targeting agents include, but are not limited to, antibodies, fragments of antibodies, proteins, peptides, carbohydrates, receptor ligands, sialic acid, and aptamers, etc. If the targeting agent is included throughout a particle, the targeting agent may be included in the mixture that is used to form the particle. If the targeting agent is only on the surface of a particle, the targeting agent may be associated with (e.g., by covalent or non-covalent (e.g., electrostatic, hydrophobic, hydrogen bonding, van der Waals, ^- ^ stacking) interactions) the formed particle using standard chemical techniques. Particles [00274] In some embodiments, a composition including a compound provided herein and an agent is in the form of a particle. In certain embodiments, the compound provided herein and agent form a complex, and the complex is in the form of a particle. In certain embodiments, the compound provided herein encapsulates the agent and is in the form of a particle. In certain embodiments, the compound provided herein is mixed with the agent, and the mixture is in the form of a particle. In some embodiments, the particle encapsulates the agent. [00275] In certain embodiments, a complex of a compound provided herein and an agent in a composition of is in the form of a particle. In some embodiments, the particle is a nanoparticle or a microparticle. In certain embodiments, the particle is a microparticle (i.e., particle having a characteristic dimension of less than about 1 millimeter and at least about 1 micrometer, where the characteristic dimension of the particle is the smallest cross-sectional dimension of the particle). In certain embodiments, the particle is a nanoparticle (i.e., a particle having a characteristic dimension of less than about 1 micrometer and at least about 1 nanometer, where the characteristic dimension of the particle is the smallest cross- sectional dimension of the particle). In certain embodiments, the average diameter of the particle is at least about 10 nm, at least about 30 nm, at least about 100 nm, at least about 300 nm, at least about 1 µm, at least about 3 µm, at least about 10 µm, at least about 30 µm, at least about 100 µm, at least about 300 µm, or at least about 1 mm. In certain embodiments, the average diameter of the particle is less than about 1 mm, less than about 300 µm, less than about 100 µm, less than about 30 µm less than about 10 µm, less than about 3 µm, less than about 1 µm, less than about 300 nm, less than about 100 nm, less than about 30 nm, or less than about 10 nm. Combinations of the above ranges (e.g., at least about 100 nm and less than about 1 µm) are also within the scope of the present invention. [00276] The particles described herein may include additional materials such as polymers (e.g., synthetic polymers (e.g., PEG, PLGA) and natural polymers (e.g., phospholipids)). In certain embodiments, the additional materials are approved by a regulatory agency, such as the U.S. FDA, for human and veterinary use. [00277] The particles may be prepared using any method known in the art, such as precipitation, milling, spray drying, single and double emulsion solvent evaporation, solvent extraction, phase separation, and simple and complex coacervation. In certain embodiments, methods of preparing the particles are the double emulsion process and spray drying. The conditions used in preparing the particles may be altered to yield particles of a desired size or property (e.g., hydrophobicity, hydrophilicity, external morphology, “stickiness”, shape, polydispersity, etc.). The method of preparing the particle and the conditions (e.g., solvent, temperature, concentration, and air flow rate, etc.) used may also depend on the agent being complexed, encapsulated, or mixed, and/or the composition of the matrix. [00278] Methods developed for making particles for delivery of agents that are included in the particles are described in the literature. See, e.g., Doubrow, M., Ed., “Microcapsules and Nanoparticles in Medicine and Pharmacy,” CRC Press, Boca Raton, 1992; Mathiowitz and Langer, J. Controlled Release 5:13-22, 1987; Mathiowitz et al., Reactive Polymers 6:275- 283, 1987; Mathiowitz et al., J. Appl. Polymer Sci.35:755-774, 1988. [00279] If the particles prepared by any of the above methods have a size range outside of the desired range, the particles can be sized, for example, using a sieve. The particles may also be coated. In certain embodiments, the particles are coated with a targeting agent. In certain embodiments, the particles are coated with a surface-altering agent. In some embodiments, the particles are coated to achieve desirable surface properties (e.g., a particular charge). [00280] In certain embodiments, the polydispersity index (PDI, determined by dynamic light scattering) of the particles described herein (e.g., particles included in a composition described herein) is between 0.01 and 0.9, between 0.1 and 0.9, between 0.1 and 0.7, between 0.1 and 0.5, between 0.01 and 0.4, between 0.03 and 0.4, between 0.1 and 0.4, between 0.01 and 0.3, between 0.03 and 0.3, or between 0.1 and 0.3. Micelles and Liposomes [00281] A composition including one or more compounds provided herein and an agent may be in the form of a micelle, liposome, or lipoplex. In certain embodiments, the compound provided herein is in the form of a micelle or liposome. In certain embodiments, the agent is in the form of a micelle or liposome. In certain embodiments, the compound provided herein and agent form a complex, and the complex is in the form of a micelle or liposome. In certain embodiments, the compound provided herein encapsulates the agent and is in the form of a micelle or liposome. In certain embodiments, the compound provided herein is mixed with the agent, and the mixture is in the form of a micelle or liposome. Micelles and liposomes are particularly useful in delivering an agent, such as a hydrophobic agent. When the micelle or liposome is complexed with (e.g., encapsulates or covers) a polynucleotide, the resulting complex may be referred to as a “lipoplex.” Many techniques for preparing micelles and liposomes are known in the art, and any such method may be used herein to make micelles and liposomes. [00282] In certain embodiments, liposomes are formed through spontaneous assembly. In some embodiments, liposomes are formed when thin lipid films or lipid cakes are hydrated and stacks of lipid crystalline bilayers become fluid and swell. The hydrated lipid sheets detach during agitation and self-close to form large, multilamellar vesicles (LMV). This prevents interaction of water with the hydrocarbon core of the bilayers at the edges. Once these liposomes have formed, reducing the size of the liposomes can be modified through input of sonic energy (sonication) or mechanical energy (extrusion). See, e.g., Walde, P. “Preparation of Vesicles (Liposomes)” In Encylopedia of Nanoscience and Nanotechnology; Nalwa, H. S. Ed. American Scientific Publishers: Los Angeles, 2004; Vol.9, pp.43-79; Szoka et al., “Comparative Properties and Methods of Preparation of Lipid Vesicles (Liposomes)” Ann. Rev. Biophys. Bioeng.9:467-508, 1980; each of which is incorporated herein by reference. The preparation of lipsomes may involve preparing a compound provided herein for hydration, hydrating the compound with agitation, and sizing the vesicles to achieve a homogenous distribution of liposomes. A compound provided herein may be first dissolved in an organic solvent in a container to result in a homogeneous mixture. The organic solvent is then removed to form a polymer-derived film. This polymer- derived film is thoroughly dried to remove residual organic solvent by placing the container on a vacuum pump for a period of time. Hydration of the polymer-derived film is accomplished by adding an aqueous medium and agitating the mixture. Disruption of LMV suspensions using sonic energy typically produces small unilamellar vesicles (SUV) with diameters in the range of 15-50 nm. Lipid extrusion is a technique in which a lipid/polymer suspension is forced through a polycarbonate filter with a defined pore size to yield particles having a diameter near the pore size of the filter used. Extrusion through filters with 100 nm pores typically yields large, unilamellar polymer-derived vesicles (LUV) with a mean diameter of 120-140 nm. In certain embodiments, the amount of a compound provided herein in the liposome ranges from about 30 mol% to about 80 mol%, from about 40 mol% to about 70 mol%, or from about 60 mol% to about 70 mol%. In certain embodiments, the compound provided herein employed further complexes an agent, such as a polynucleotide. In such embodiments, the application of the liposome is the delivery of the polynucleotide. [00283] The following scientific papers described other methods for preparing liposomes and micelles: Narang et al., “Cationic Lipids with Increased DNA Binding Affinity for Nonviral Gene Transfer in Dividing and Nondividing Cells,” Bioconjugate Chem.16:156- 68, 2005; Hofland et al., “Formation of stable cationic lipid/DNA complexes for gene transfer,” Proc. Natl. Acad. Sci. USA 93:7305-7309, July 1996; Byk et al., “Synthesis, Activity, and Structure – Activity Relationship Studies of Novel Cationic Lipids for DNA Transfer,” J. Med. Chem.41(2):224-235, 1998; Wu et al., “Cationic Lipid Polymerization as a Novel Approach for Constructing New DNA Delivery Agents,” Bioconjugate Chem. 12:251-57, 2001; Lukyanov et al., “Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs,” Advanced Drug Delivery Reviews 56:1273-1289, 2004; Tranchant et al., “Physicochemical optimisation of plasmid delivery by cationic lipids,” J. Gene Med.6:S24-S35, 2004; van Balen et al., “Liposome/Water Lipophilicity: Methods, Information Content, and Pharmaceutical Applications,” Medicinal Research Rev.24(3):299-324, 2004. Kits [00284] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a composition or compound described herein. In some embodiments, the composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form. [00285] Thus, in one aspect, provided are kits including a first container comprising a compound or composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., genetic disease, proliferative disease, hematological disease, neurological disease, liver disease, spleen disease, lung disease, painful condition, psychiatric disorder, musculoskeletal disease, a metabolic disorder, inflammatory disease, or autoimmune disease) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., genetic disease, proliferative disease, hematological disease, neurological disease, liver disease, spleen disease, lung disease, painful condition, psychiatric disorder, musculoskeletal disease, a metabolic disorder, inflammatory disease, or autoimmune disease) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease (e.g., genetic disease, proliferative disease, hematological disease, neurological disease, liver disease, spleen disease, lung disease, painful condition, psychiatric disorder, musculoskeletal disease, a metabolic disorder, inflammatory disease, or autoimmune disease) in a subject in need thereof. In certain embodiments, the kits are useful for delivering an agent to a subject or cell. In certain embodiments, the kits are useful for delivering a polynucleotide to a subject or cell. In certain embodiments, the kits are useful for delivering mRNA to a subject or cell. [00286] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., genetic disease, proliferative disease, hematological disease, neurological disease, liver disease, spleen disease, lung disease, painful condition, psychiatric disorder, musculoskeletal disease, a metabolic disorder, inflammatory disease, or autoimmune disease)in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., genetic disease, proliferative disease, hematological disease, neurological disease, liver disease, spleen disease, lung disease, painful condition, psychiatric disorder, musculoskeletal disease, a metabolic disorder, inflammatory disease, or autoimmune disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g., genetic disease, proliferative disease, hematological disease, neurological disease, liver disease, spleen disease, lung disease, painful condition, psychiatric disorder, musculoskeletal disease, a metabolic disorder, inflammatory disease, or autoimmune disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for delivering an agent to a subject or cell. In certain embodiments, the kits and instructions provide for delivering a polynucleotide to a subject or cell. In certain embodiments, the kits and instructions provide for delivering mRNA to a subject or cell. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition. Methods of Treatment and Uses [00287] Also provided herein are methods for treating and/or preventing a disease, disorder, or condition in a subject, comprising administering to the subject a composition provided herein, e.g., a composition comprising an agent and a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. [00288] In certain embodiments, the disease, disorder, or condition is a genetic disease, proliferative disease, hematological disease, neurological disease, liver disease, spleen disease, lung disease, painful condition, psychiatric disorder, musculoskeletal disease, a metabolic disorder, inflammatory disease, or autoimmune disease. In some embodiments, the disease, disorder, or condition is a genetic disease. In some embodiments, the disease, disorder, or condition is a proliferative disease. In some embodiments, the disease, disorder, or condition is a hematological disease. In some embodiments, the disease, disorder, or condition is a neurological disease. In some embodiments, the disease, disorder, or condition is a liver disease. In some embodiments, the disease, disorder, or condition is a spleen disease. In some embodiments, the disease, disorder, or condition is a lung disease. In some embodiments, the disease, disorder, or condition is a painful condition. In some embodiments, the disease, disorder, or condition is a psychiatric disorder. In some embodiments, the disease, disorder, or condition is a musculoskeletal disease. In some embodiments, the disease, disorder, or condition is a metabolic disorder. In some embodiments, the disease, disorder, or condition is an inflammatory disease. In some embodiments, the disease, disorder, or condition is an autoimmune disease. [00289] In some embodiments, the lung disease is cystic fibrosis, sepsis, or lung cancer. In some embodiments, the lung disease is cystic fibrosis. In some embodiments, the lung disease is sepsis. In some embodiments, the lung disease is lung cancer. [00290] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile. [00291] In some embodiments, the agent is any agent provided herein. In certain embodiments, the agent is a polynucleotide. In some embodiments, the agent is mRNA. [00292] In some embodiments, the composition is administered by any method provided herein. In certain embodiments, the composition is administered by nebulized administration or IV administration. In some embodiments, the composition is administered by nebulized administration. In certain embodiments, the composition is administered by IV administration. [00293] In certain embodiments, the administration comprises inducing increased expression of a protein. In certain embodiments, the administration comprises inducing increased expression of a protein in the nose and/or lungs. In certain embodiments, the administration comprises inducing increased expression of a protein in the nose. In certain embodiments, the administration comprises inducing increased expression of a protein in the lungs. In certain embodiments, the increased expression of the protein lasts for at least 1 hour. In certain embodiments, the increased expression of the protein lasts for at least 4 hours. In certain embodiments, the increased expression of the protein lasts for at least 12 hours. In certain embodiments, the increased expression of the protein lasts for at least 24 hours. In certain embodiments, the increased expression of the protein lasts for at least 48 hours. In certain embodiments, the increased expression of the protein lasts for at least 72 hours. In certain embodiments, the increased expression of the protein lasts for at least 96 hours. [00294] In certain embodiments, the composition is administered to the subject more than once. In certain embodiments, the composition is administered to the subject at least once daily. In certain embodiments, the composition is administered to the subject at least once every 2 days. In certain embodiments, the composition is administered to the subject at least once every 3 days. In certain embodiments, the composition is administered to the subject at least once every 5 days. In certain embodiments, the composition is administered to the subject at least once every 7 days. Additional Methods and Uses [00295] Also provided herein are methods of delivering an agent (e.g., a polynucleotide), comprising administering a composition comprising a polynucleotide and a compound provided herein (e.g., a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. In certain embodiments, the method is for delivering an agent to a subject, cell, collection of cells, or tissue. In some embodiments, the method is for delivering an agent to a subject or cell. In certain embodiments, the method is for delivering an agent to a subject. In some embodiments, the method is for delivering an agent to a cell. [00296] In some embodiments, the agent is any agent provided herein. In certain embodiments, the agent is a polynucleotide. In some embodiments, the agent is mRNA. [00297] In some embodiments, the agent is delivered to a subject. In some embodiments, the agent is delivered to the lung or nasal epithelium of the subject. In certain embodiments, the agent is delivered to the lung of the subject. In certain embodiments, the agent is delivered to the lung epithelium of the subject. In certain embodiments, the agent is delivered to the lung endothelium of the subject. In some embodiments, the agent is delivered to the nasal epithelium of the subject. In certain embodiments, the polynucleotide is delivered to a subject. In some embodiments, the polynucleotide is delivered to the lung or nasal epithelium of the subject. In certain embodiments, the polynucleotide is delivered to the lung of the subject. In certain embodiments, the polynucleotide is delivered to the lung epithelium of the subject. In some embodiments, the lung epithelium of the subject comprises club cells. In some embodiments, the polynucleotide is delivered to club cells in the lung epithelium of the subject. In certain embodiments, the polynucleotide is delivered to the lung endothelium of the subject. In some embodiments, the polynucleotide is delivered to the nasal epithelium of the subject. In certain embodiments, the mRNA is delivered to a subject. In some embodiments, the mRNA is delivered to the lung or nasal epithelium of the subject. In certain embodiments, the mRNA is delivered to the lung of the subject. In certain embodiments, the mRNA is delivered to the lung epithelium of the subject. In some embodiments, the mRNA is delivered to club cells in the lung epithelium of the subject. In certain embodiments, the mRNA is delivered to the lung endothelium of the subject. In some embodiments, the mRNA is delivered to the nasal epithelium of the subject. In some embodiments, the composition is nebulized or aerosolized before the agent is delivered to the subject. In some embodiments, the composition is nebulized before the agent is delivered to the subject. In some embodiments, the composition is aerosolized before the agent is delivered to the subject. [00298] In certain embodiments, the agent is delivered to a cell. In some embodiments, the agent is delivered to a lung cell or nasal epithelial cell. In certain embodiments, the agent is delivered to a lung cell. In some embodiments, the agent is delivered to a nasal epithelial cell. In certain embodiments, the polynucleotide is delivered to a cell. In some embodiments, the polynucleotide is delivered to a lung cell or nasal epithelial cell. In certain embodiments, the polynucleotide is delivered to a lung cell. In some embodiments, the polynucleotide is delivered to a nasal epithelial cell. In certain embodiments, the mRNA is delivered to a cell. In some embodiments, the mRNA is delivered to a lung cell or nasal epithelial cell. In certain embodiments, the mRNA is delivered to a lung cell. In some embodiments, the mRNA is delivered to a nasal epithelial cell. In certain embodiments, the agent is delivered to a club cell. In certain embodiments, the polynucleotide is delivered to a club cell. In certain embodiments, the mRNA is delivered to a club cell. In some embodiments, the composition is nebulized or aerosolized before the agent is delivered to the cell. In some embodiments, the composition is nebulized before the agent is delivered to the cell. In some embodiments, the composition is aerosolized before the agent is delivered to the cell. [00299] In some embodiments, the lung cell is an endothelium cell. In certain embodiments, the lung cell is a lung epithelial cell. In some embodiments, the cell is an A549 cell. In certain embodiments, the lung cell is a human bronchial epithelial cell. In some embodiments, the lung cell is a pulmonary endothelial cell. In some embodiments, the lung cell is a club cell. [00300] In some embodiments, the cell is in vivo, e.g., in an organism. In certain embodiments, the cell is in vitro, e.g., in cell culture. In some embodiments, the cell culture is an air-liquid interface (ALI) culture. In some embodiments, the composition is nebulized before the agent is delivered to the ALI culture. In some embodiments, the cell is ex vivo, meaning the cell is removed from an organism prior to the delivery. [00301] In some embodiments, the composition is administered by any method provided herein. In certain embodiments, the composition is administered by nebulized administration, aerosolized administration, or IV administration. In some embodiments, the composition is administered by nebulized administration. In some embodiments, the composition is administered by aerosolized administration. In some embodiments, when the composition is administered by nebulized administration, there is microscale heterogeneity in transfection. In some embodiments, microscale heterogeneity is due to differences in transfectability and/or particle deposition. In some embodiments, when the composition is administered by nebulized administration, there is at least one stretch of airway with near-complete transfection. In certain embodiments, the composition is administered by IV administration. [00302] In some embodiments, the composition is administered by a device for delivering to a subject via inhalation or exhalation (e.g., oral or nasal) an aerosol as described herein, i.e., an aerosolized form of a pharmaceutical composition as described herein. In certain embodiments, the device is a nebulizer (e.g., jet or ultrasonic), atomizer, vaporizer, or electrospray. In certain embodiments, the device is propellant-driven, breath-actuated, or pump-actuated. In certain embodiments, the device comprises a metering valve. In certain embodiments, the device is configured to control or regulate aerosol droplet or particle size. In certain embodiments, the device is configured to produce the aerosol for a duration in the range of 5 seconds to 30 minutes. In certain embodiments, the device is configured to control or regulate aerosol velocity. [00303] In certain embodiments, the device is configured to deliver an amount of the composition in the range of 0.1-130 mg, e.g., 0.1-1 mg, 1-5 mg, 5-10 mg, 10-20 mg, 10-50 mg, 25-75 mg, 50-75 mg, 75-100 mg, 75-130 mg, or 100-130 mg. In certain embodiments, a dose of compound in the range of 1-130 mg, e.g., 1-5 mg, 5-10 mg, 10-20 mg, 10-50 mg, 25- 75 mg, 50-75 mg, 75-100 mg, 75-130 mg, or 100-130 mg. In certain embodiments, the device is configured to deliver the composition to the respiratory tract with an efficiency (i.e., percent agent delivered) of at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 99%. [00304] In certain embodiments, the device is a metered-dose inhaler. See, e.g., Newman SP. “Principles of metered-dose inhaler design.” Respir Care.2005 Sep; 50(9):1177-88; Roche N, Dekhuijezen R. “The evolution of pressurized metered-dose inhalers from early to modern devices.” J Aerosol Med Pulm Drug Deliv.2016; 29(4):311. [00305] In certain embodiments, the device comprises a non-pressurized reservoir containing the composition. In certain embodiments, the device a pressurized reservoir containing the composition. See, e.g., Cogan PS, Sucher BJ. “Appropriate use of pressurized metered-dose inhalers for asthma.” US Pharm.2015; 40(7), 36-41; Vehring R, Ballesteros DL, Joshi V, Noga B, Dwivedi SK. “Co-suspensions of microcrystals and engineered microparticles for uniform and efficient delivery of respiratory therapeutics from pressurized metered dose inhalers.” Langmuir 201228(42), 15015-15023. [00306] In certain embodiments, the device is a breath-actuated inhaler. In certain embodiments, the device is dry powder inhaler. See, e.g., Islam N, Gladki E. “Dry powder inhalers (DPIs)-a review of device reliability and innovation.” Int J Pharm.2008; Daniher DI, Zhu J. “Dry powder platform for pulmonary drug delivery.” Particulogy.2008 Aug. Dry powder inhalers may be breath-actuated, may deliver particles having a mean mass aerodynamic diameter (MMAD) of less than 5 microns, and may produce inspiratory flow rates of 30-60 L/min. Other soft mist inhalers such as AERx and Medspray have been in development based on extrusion of liquids through arrays of nozzles (Dayton et al., Respiratory Drug Delivery 2006, Davis Healthcare International Publishing, River Grove, IL, USA, pp.429-432). In certain embodiments, the device is a soft mist inhaler. See, e.g., Dalby RN, Eicher J, Zierenberg B. “Development of Respimat Soft Mist inhaler and its clinical utility in respiratory disorder.” Med Devices.2011 Aug. In certain embodiments, the device is a Respimat® Soft Mist inhaler. In certain embodiments, the device is an Aerogen® Ultra/Aerogen® Solo nebulizer. The device is manufactured by Aerogen Ltd. Aerogen® Ultra is an accessory specific to the Aerogen® Solo nebulizer. This device facilitates intermittent and continuous nebulization and optional supply of supplemental oxygen to pediatric (29 days or older) and adult patients in hospital use environments via mouthpiece or aerosol face mask. The Aerogen® Ultra is a single patient use device. In certain embodiments, the device is used intermittently for a maximum of 20 treatments, which is based upon a typical usage profile of four 3 ml doses per day over 5 days, with an average treatment time of 9 minutes. In other embodiments, the device is used continuously for a maximum of 3 hours. In other embodiments the device uses a volume of approximately 0.5 mL that can be delivered in about 1 minute. In certain embodiments, the device is a PARI LC Sprint, used in conjunction with a compressor. The PARI LC Sprint is manufactured by PARI Respiratory Equipment, Inc. In certain embodiments, the device is a soft mist inhaler manufactured by Medspray (Enschede, Twente, Netherlands). Such devices include the following: ADI/Colistair (puff size 50 μL, capacity 1 mL); PFSI (puff size 30 μL, capacity 90 μL); Ecomyst90 (puff size 25 μL, capacity 5 or 10 mL); and Pulmospray, Pulmospray ICU devices (patient breaths in through mouth and out through nose). [00307] The present disclosure contemplates specific combinations of the compositions and devices disclosed herein. [00308] In another aspect, the disclosure provides a method of preparing a compound of Formula (I), the method comprising reacting a compound of Formula (II): or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, with a compound of Formula (III): or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: R 1 is -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nitrogen protecting group; R 2 is -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nitrogen protecting group; or R 1 and R 2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl; each R 3 independently is optionally substituted C6-C25 aliphatic; and each n independently is 0-15, inclusive. [00309] In some embodiments, the compound of Formula (III), or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, is prepared by reacting one or more compounds of Formula (IV): or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, with a base or acid catalyst, wherein: each R 3 independently is optionally substituted C6-C25 aliphatic; and each n independently is 0-15, inclusive. [00310] In some embodiments, the one or more compounds of Formula (IV) comprise at least two equivalents of the same compound. In certain embodiments, the compound of Formula (III) is prepared via Aldol dimerization of a compound of Formula (IV). [00311] In some embodiments, the base is titanium (IV) butoxide and/or potassium tert- butoxide. In some embodiments, the base is titanium (IV) butoxide and potassium tert- butoxide. In some embodiments, the base is titanium (IV) butoxide. In some embodiments, the base is potassium tert-butoxide. [00312] In some embodiments, the compound of Formula (II) is an amine provided in FIG. 2. [00313] As defined herein, R 1 is -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nitrogen protecting group; or R 1 and R 2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl. [00314] In some embodiments, R 1 is -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nitrogen protecting group. In certain embodiments, R 1 is -H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted C 1 -C 20 heteroalkyl, optionally substituted C 1 -C 20 heteroalkenyl, optionally substituted C1-C20 heteroalkynyl, optionally substituted C6-C14 aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C3-C14 carbocyclyl, optionally substituted 3- to 14-mmbered heterocyclyl, or a nitrogen protecting group. In certain embodiments, R 1 is -H, optionally substituted C 1 -C 10 alkyl, optionally substituted C1-C10 alkenyl, optionally substituted C1-C10 alkynyl, optionally substituted C1- C 10 heteroalkyl, optionally substituted C 1 -C 10 heteroalkenyl, optionally substituted C 1 -C 10 heteroalkynyl, optionally substituted C 6 -C 14 aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C3-C14 carbocyclyl, optionally substituted 3- to 14- membered heterocyclyl, or a nitrogen protecting group. [00315] In certain embodiments, R 1 is -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, or a nitrogen protecting group. In some embodiments, R 1 is -H, optionally substituted C 1 -C 10 alkyl, optionally substituted C1-C10 alkenyl, optionally substituted C1-C10 alkynyl, optionally substituted C1- C10 heteroalkyl, optionally substituted C1-C10 heteroalkenyl, optionally substituted C1-C10 heteroalkynyl, or a nitrogen protecting group. In certain embodiments, R 1 is -H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 heteroalkyl, or a nitrogen protecting group. [00316] In some embodiments, R 1 is -H or a nitrogen protecting group. In certain embodiments, R 1 is -H. In some embodiments, R 1 is a nitrogen protecting group. In certain embodiments, the nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts. [00317] In certain embodiments, R 1 is optionally substituted C 1 -C 10 alkyl or optionally substituted C1-C10 heteroalkyl. In some embodiments, R 1 is optionally substituted C1-C10 alkyl. In certain embodiments, R 1 is unsubstituted C1-C10 alkyl. In some embodiments, R 1 is substituted C 1 -C 10 alkyl. In certain embodiments, R 1 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 1 is unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 1 is substituted C1-C6 alkyl. In some embodiments, R 1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, R 1 is methyl, ethyl, propyl, or butyl. In some embodiments, R 1 is methyl, ethyl, or propyl. In certain embodiments, R 1 is propyl. In some embodiments, R 1 is - Et. In certain embodiments, R 1 is -Me. [00318] In some embodiments, R 1 is optionally substituted C1-C10 heteroalkyl. In certain embodiments, R 1 is unsubstituted C 1 -C 10 heteroalkyl. In some embodiments, R 1 is substituted C1-C10 heteroalkyl. In certain embodiments, R 1 is optionally substituted C1-C6 heteroalkyl. In some embodiments, R 1 is unsubstituted C1-C6 heteroalkyl. In certain embodiments, R 1 is substituted C 1 -C 6 heteroalkyl. In some embodiments, R 1 is optionally substituted heteroalkyl comprising one or more nitrogen atoms. In some embodiments, R 1 is optionally substituted C1-C10 heteroalkyl comprising one or more nitrogen atoms. In some embodiments, R 1 is optionally substituted C 1 -C 6 heteroalkyl comprising one or more nitrogen atoms. In certain embodiments, R 1 is [00319] In certain embodiments, R 1 is optionally substituted aryl. In some embodiments, R 1 is optionally substituted C6-C14 aryl. In some embodiments, R 1 is substituted C6-C14 aryl. In some embodiments, R 1 is unsubstituted C6-C14 aryl. In certain embodiments, R 1 is optionally substituted C 6 -C 10 aryl. In certain embodiments, R 1 is substituted C 6 -C 10 aryl. In certain embodiments, R 1 is unsubstituted C6-C10 aryl. In some embodiments, R 1 is optionally substituted phenyl or optionally substituted naphthyl. In certain embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is optionally substituted naphthyl. [00320] In certain embodiments, R 1 is optionally substituted heteroaryl. In some embodiments, R 1 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R 1 is substituted 5- to 14-membered heteroaryl. In some embodiments, R 1 is unsubstituted 5- to 14-membered heteroaryl. In some embodiments, R 1 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R 1 is substituted 5- to 10- membered heteroaryl. In some embodiments, R 1 is unsubstituted 5- to 10-membered heteroaryl. [00321] In some embodiments, R 1 is optionally substituted carbocyclyl. In some embodiments, R 1 is optionally substituted C3-C14 carbocyclyl. In some embodiments, R 1 is substituted C3-C14 carbocyclyl. In some embodiments, R 1 is unsubstituted C3-C14 carbocyclyl. In some embodiments, R 1 is optionally substituted C 3 -C 8 carbocyclyl. In some embodiments, R 1 is substituted C 3 -C 8 carbocyclyl. In some embodiments, R 1 is unsubstituted C 3 -C 8 carbocyclyl. In some embodiments, R 1 is C3-C8 carbocyclyl substituted with optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl. [00322] In some embodiments, R 1 is optionally substituted heterocyclyl. In some embodiments, R 1 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R 1 is substituted 3- to 14-membered heterocyclyl. In some embodiments, R 1 is unsubstituted 3- to 14-membered heterocyclyl. In some embodiments, R 1 is optionally substituted 3- to 8-membered heterocyclyl. In some embodiments, R 1 is substituted 3- to 8- membered heterocyclyl. In some embodiments, R 1 is unsubstituted 3- to 8-membered heterocyclyl. In some embodiments, R 1 is 3- to 8-membered heterocyclyl substituted with optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl. [00323] As defined herein, R 2 is -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nitrogen protecting group; or R 1 and R 2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl. [00324] In some embodiments, R 2 is -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nitrogen protecting group. In certain embodiments, R 2 is -H, optionally substituted C 1 -C 20 alkyl, optionally substituted C 1 -C 20 alkenyl, optionally substituted C 1 -C 20 alkynyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C1-C20 heteroalkenyl, optionally substituted C1-C20 heteroalkynyl, optionally substituted C6-C14 aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C3-C14 carbocyclyl, optionally substituted 3- to 14-mmbered heterocyclyl, or a nitrogen protecting group. In certain embodiments, R 2 is -H, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkenyl, optionally substituted C1-C10 alkynyl, optionally substituted C1- C 10 heteroalkyl, optionally substituted C 1 -C 10 heteroalkenyl, optionally substituted C 1 -C 10 heteroalkynyl, optionally substituted C 6 -C 14 aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C3-C14 carbocyclyl, optionally substituted 3- to 14- membered heterocyclyl, or a nitrogen protecting group. [00325] In some embodiments, R 2 is -H, optionally substituted optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nitrogen protecting group. In certain embodiments, R 2 is -H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nitrogen protecting group. In some embodiments, R 2 is -H, optionally substituted C 1 -C 20 alkyl, optionally substituted C 1 -C 20 heteroalkyl, optionally substituted C 3 - C14 carbocyclyl, optionally substituted 3- to 14-membered heterocyclyl, or a nitrogen protecting group. In certain embodiments, R 2 is -H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 heteroalkyl, optionally substituted C 3 -C 14 carbocyclyl, optionally substituted 3- to 14-membered heterocyclyl, or a nitrogen protecting group. [00326] In some embodiments, R 2 is optionally substituted optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nitrogen protecting group. In certain embodiments, R 2 is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nitrogen protecting group. In some embodiments, R 2 is optionally substituted C 1 -C 20 alkyl, optionally substituted C 1 -C 20 heteroalkyl, optionally substituted C 3 - C 14 carbocyclyl, optionally substituted 3- to 14-membered heterocyclyl, or a nitrogen protecting group. In certain embodiments, R 2 is optionally substituted C1-C10 alkyl, optionally substituted C 1 -C 10 heteroalkyl, optionally substituted C 3 -C 14 carbocyclyl, optionally substituted 3- to 14-membered heterocyclyl, or a nitrogen protecting group. [00327] In some embodiments, R 2 is -H or a nitrogen protecting group. In certain embodiments, R 2 is -H. In some embodiments, R 2 is not -H. In certain embodiments, R 2 is a nitrogen protecting group. In certain embodiments, the nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts. [00328] In certain embodiments, R 2 is optionally substituted C1-C10 alkyl or optionally substituted C 1 -C 10 heteroalkyl. In some embodiments, R 2 is optionally substituted C 1 -C 10 alkyl. In certain embodiments, R 2 is unsubstituted C 1 -C 10 alkyl. In some embodiments, R 2 is substituted C1-C10 alkyl. In certain embodiments, R 2 is optionally substituted C1-C6 alkyl. In some embodiments, R 2 is unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 2 is substituted C 1 -C 6 alkyl. In some embodiments, R 2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, R 2 is methyl, ethyl, propyl, or butyl. In some embodiments, R 2 is methyl, ethyl, or propyl. In certain embodiments, R 2 is propyl. In some embodiments, R 2 is - Et. In certain embodiments, R 2 is -Me. [00329] In some embodiments, R 2 is optionally substituted C1-C10 heteroalkyl. In certain embodiments, R 2 is unsubstituted C1-C10 heteroalkyl. In some embodiments, R 2 is substituted C 1 -C 10 heteroalkyl. In certain embodiments, R 2 is optionally substituted C 1 -C 6 heteroalkyl. In some embodiments, R 2 is unsubstituted C 1 -C 6 heteroalkyl. In certain embodiments, R 2 is substituted C1-C6 heteroalkyl. In some embodiments, R 2 is optionally substituted heteroalkyl comprising one or more nitrogen atoms. In some embodiments, R 2 is optionally substituted C 1 -C 10 heteroalkyl comprising one or more nitrogen atoms. In some embodiments, R 2 is optionally substituted C1-C6 heteroalkyl comprising one or more nitrogen atoms. In certain embodiments, R 2 is [00330] In certain embodiments, R 2 is optionally substituted heteroalkyl comprising one or more N atoms substituted with . In some embodiments, R 2 is [00331] In certain embodiments, R 2 is optionally substituted aryl. In some embodiments, R 2 is optionally substituted C 6 -C 14 aryl. In some embodiments, R 2 is substituted C 6 -C 14 aryl. In some embodiments, R 2 is unsubstituted C6-C14 aryl. In certain embodiments, R 2 is optionally substituted C6-C10 aryl. In certain embodiments, R 2 is substituted C6-C10 aryl. In certain embodiments, R 2 is unsubstituted C 6 -C 10 aryl. In some embodiments, R 2 is optionally substituted phenyl or optionally substituted naphthyl. In certain embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is optionally substituted naphthyl. [00332] In certain embodiments, R 2 is optionally substituted heteroaryl. In some embodiments, R 2 is optionally substituted 5- to 14-membered heteroaryl. In some embodiments, R 2 is substituted 5- to 14-membered heteroaryl. In some embodiments, R 2 is unsubstituted 5- to 14-membered heteroaryl. In some embodiments, R 2 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R 2 is substituted 5- to 10- membered heteroaryl. In some embodiments, R 2 is unsubstituted 5- to 10-membered heteroaryl. [00333] In some embodiments, R 2 is optionally substituted carbocyclyl. In some embodiments, R 2 is optionally substituted C3-C14 carbocyclyl. In some embodiments, R 2 is substituted C3-C14 carbocyclyl. In some embodiments, R 2 is unsubstituted C3-C14 carbocyclyl. In some embodiments, R 2 is optionally substituted C 3 -C 8 carbocyclyl. In some embodiments, R 2 is substituted C 3 -C 8 carbocyclyl. In some embodiments, R 2 is unsubstituted C 3 -C 8 carbocyclyl. In some embodiments, R 2 is C3-C8 carbocyclyl substituted with optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl. [00334] In some embodiments, R 2 is optionally substituted heterocyclyl. In some embodiments, R 2 is optionally substituted 3- to 14-membered heterocyclyl. In some embodiments, R 2 is substituted 3- to 14-membered heterocyclyl. In some embodiments, R 2 is unsubstituted 3- to 14-membered heterocyclyl. In some embodiments, R 2 is optionally substituted 3- to 8-membered heterocyclyl. In some embodiments, R 2 is substituted 3- to 8- membered heterocyclyl. In some embodiments, R 2 is unsubstituted 3- to 8-membered heterocyclyl. In some embodiments, R 2 is 3- to 8-membered heterocyclyl substituted with optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl. [00335] In certain embodiments, R 1 and R 2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl. In some embodiments, R 1 and R 2 are joined together with the intervening atoms to form a substituted heterocyclyl. In certain embodiments, R 1 and R 2 are joined together with the intervening atoms to form an unsubstituted heterocyclyl. [00336] In some embodiments, R 1 and R 2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl comprising one or two nitrogen atoms. In certain embodiments, R 1 and R 2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl comprising one nitrogen atoms. In some embodiments, R 1 and R 2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl comprising two nitrogen atoms. In certain embodiments, R 1 and R 2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl comprising two or more nitrogen atoms. [00337] In some embodiments, -NR 1 R 2 is [00338] In certain embodiments, R 1 and R 2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl comprising two or more N atoms substituted with some embodiments, R 1 and R 2 are joined together with the intervening atoms to form an optionally substituted heterocyclyl comprising two N atoms substituted with . [00339] As defined herein, each R 3 independently is optionally substituted C 6 -C 25 aliphatic. In some embodiments, R 3 is optionally substituted C 6 -C 25 alkyl, optionally substituted C 6 -C 25 alkenyl, or optionally substituted C6-C25 alkynyl. In certain embodiments, R 3 is optionally substituted C6-C25 alkyl or optionally substituted C6-C25 alkenyl. In some embodiments, R 3 is optionally substituted C 6 -C 25 alkyl or optionally substituted C 6 -C 25 alkynyl. In certain embodiments, R 3 is optionally substituted C6-C25 alkenyl or optionally substituted C6-C25 alkynyl. In some embodiments, R 3 is substituted C6-C25 alkyl, substituted C6-C25 alkenyl, or substituted C 6 -C 25 alkynyl. In certain embodiments, R 3 is substituted C 6 -C 25 alkyl or substituted C 6 -C 25 alkenyl. In some embodiments, R 3 is substituted C 6 -C 25 alkyl or substituted C6-C25 alkynyl. In certain embodiments, R 3 is substituted C6-C25 alkenyl or substituted C 6 -C 25 alkynyl. In some embodiments, R 3 is unsubstituted C 6 -C 25 alkyl, unsubstituted C 6 -C 25 alkenyl, or unsubstituted C 6 -C 25 alkynyl. In certain embodiments, R 3 is unsubstituted C6-C25 alkyl or unsubstituted C6-C25 alkenyl. In some embodiments, R 3 is unsubstituted C 6 -C 25 alkyl or unsubstituted C 6 -C 25 alkynyl. In certain embodiments, R 3 is unsubstituted C 6 -C 25 alkenyl or unsubstituted C 6 -C 25 alkynyl. In each of the foregoing embodiments, the aliphatic, alkyl, alkenyl, or alkynyl group may have 6-12 carbon atoms, 12- 18 carbon atoms, or 18-25 carbon atoms. [00340] In some embodiments, R 3 is optionally substituted C 6 -C 25 alkyl. In certain embodiments, R 3 is substituted C6-C25 alkyl. In some embodiments, R 3 is unsubstituted C6- C25 alkyl. In certain embodiments, R 3 is , , , , . [00341] In certain embodiments, R 3 is optionally substituted C6-C25 alkenyl. In some embodiments, R 3 is substituted C6-C25 alkenyl. In certain embodiments, R 3 is unsubstituted C 6 -C 25 alkenyl. In some embodiments, R 3 comprises one or more double bonds. In certain embodiments, R 3 comprises two or more double bonds. In some embodiments, R 3 comprises three or more double bonds. In certain embodiments, R 3 comprises one, two, or three double bonds. In some embodiments, R 3 comprises one double bond. In certain embodiments, R 3 comprises two double bonds. In some embodiments, R 3 comprises three double bonds. In . [00342] In some embodiments, R 3 is optionally substituted C6-C25 alkynyl. In some embodiments, R 3 is substituted C 6 -C 25 alkynyl. In certain embodiments, R 3 is unsubstituted C 6 -C 25 alkynyl. In some embodiments, R 3 comprises one or more triple bonds. In certain embodiments, R 3 comprises two or more triple bonds. In some embodiments, R 3 comprises three or more triple bonds. In certain embodiments, R 3 comprises one, two, or three triple bonds. In some embodiments, R 3 comprises one triple bond. In certain embodiments, R 3 comprises two triple bonds. In some embodiments, R 3 comprises three triple bonds. [00343] As defined herein, each n independently is 0-15, inclusive. In some embodiments, each n is independently 1-10, inclusive. In certain embodiments, each n is independently 1-8, inclusive. In some embodiments, each n is independently 1-6, inclusive. In certain embodiments, each n is different. In certain embodiments, each n is different, and n is 1-10, inclusive. In certain embodiments, each n is different, and n is 1-8, inclusive. In some embodiments, each n is different, and n is 1-6, inclusive. In some embodiments, n is 1. In certain embodiments, n is 2. In some embodiments, n is 3. In certain embodiments, n is 4. In some embodiments, n is 5. In certain embodiments, n is 6. In some embodiments, n is 7. In certain embodiments, n is 8. In some embodiments, n is 9. In certain embodiments, n is 10. In some embodiments, n is 11. In certain embodiments, n is 12. In some embodiments, n is 13. In certain embodiments, n is 14. In some embodiments, n is 15. In some embodiments, each n is the same. In certain embodiments, each n is the same, and n is 1-10, inclusive. In certain embodiments, each n is the same, and n is 1-8, inclusive. In some embodiments, each n is the same, and n is 1-6, inclusive. In some embodiments, each n is 1. In certain embodiments, each n is 2. In some embodiments, each n is 3. In certain embodiments, each n is 4. In some embodiments, each n is 5. In certain embodiments, each n is 6. In some embodiments, each n is 7. In certain embodiments, each n is 8. In some embodiments, each n is 9. In certain embodiments, each n is 10. In some embodiments, each n is 11. In certain embodiments, each n is 12. In some embodiments, each n is 13. In certain embodiments, each n is 14. In some embodiments, each n is 15. [00344] In some embodiments, the compound of Formula (III) is a linker compound with lipid tail provided in FIG.2. EXAMPLES [00345] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, compositions, and methods provided herein and are not to be construed in any way as limiting in their scope. [00346] In vivo delivery of messenger RNA is a rapidly expanding field with the promise to treat and prevent a wide variety of genetic, infectious, or other diseases. 1–17 Notably, intramuscularly delivered lipid nanoparticle (LNP)-based mRNA vaccines have showed excellent efficacy against the SARS-CoV-2 virus driving the COVID19 pandemic. 13,14 Numerous other therapies including vaccines against cancer 6,18–20 and non-SARS-CoV-2 infectious diseases, 21–27 protein replacement therapy, 28 and gene editing 15 are in various stages of clinical trials or preclinical investigation. [00347] The respiratory epithelium is a target for mRNA delivery for a range of these applications. Protein replacement therapy and/or gene editing could treat single-gene disorders such as cystic fibrosis (CF), 29,29,30 primary ciliary dyskinesia (PCD), 31,32 or alpha-1 antitrypsin deficiency (AATD). 33 mRNA-based delivery of cytokines or other inflammatory mediators is also a promising strategy for treating asthma. 34,35 For vaccines, in addition to inducing systemic immunity, mucosal vaccination induces a localized mucosal immune response that is particularly promising for vaccines against respiratory infections. 36–46 While nasal spray-based vaccines may provide some benefits of pulmonary vaccination, antigen delivery to the deep lung may further enhance mucosal or even systemic immunity. 46,47 [00348] The two primary approaches to lung mRNA delivery are intravenous (IV) and topical delivery of nanoparticles (NPs). 48–51 IV lung targeting formulations typically preferentially deliver cargo to the endothelium rather than the epithelium 48,49 . However, the epithelium is the therapeutically relevant cellular target for the treatment of many diseases, including CF, PCD, and asthma. 52 Topical delivery of mRNA to the epithelium of the lung has been reported with both nebulized hyperbranched poly(beta amino ester) (hPBAE) based nanoparticles 53 and lipid nanoparticles (LNPs). 54 While polymer-based delivery systems are promising for inhaled delivery of mRNA, LNPs remain the more clinically advanced method of delivery. 17 However, a recent clinical trial for CF gene therapy using nebulized mRNA LNPs did not show notable efficacy, suggesting that further improvements are necessary for this delivery modality. 55 [00349] The difficulty of LNP-based nebulized mRNA delivery is related to several nebulization- and lung-specific barriers. First, nebulization itself induces powerful shear forces that can disrupt nanoparticle structure and induce aggregation. 54 Second, transfecting the lung can be difficult, in particular because access to bronchial epithelial cells involves penetration of a mucus layer that is a steric and chemical barrier to diffusion. 56–59 This barrier is particularly difficult to penetrate in muco-obstructive lung diseases such as asthma and CF. 56–58 Furthermore, the lung epithelium itself is a challenging target because NP uptake is more efficient on the basolateral side of polarized lung epithelial cells, but the basolateral side can be rendered inaccessible to apically delivered LNPs by tight junctions. 52,60 Lastly, there is a NP challenge of endosomal escape and mRNA release from the nanoformulation. 1 [00350] These factors are addressed by first optimizing the LNP formulation. An mRNA- LNP contains 5 components: an ionizable lipid (the component with the most chemical diversity), cholesterol, a helper lipid, a PEG-lipid, and mRNA. 1,3,61 To improve nebulized delivery, screened a range of component ratios, or formulations, were screened to identify one with maximal stability to nebulization. This stability to nebulization was further enhanced by rational design of buffer conditions and excipients. [00351] To avoid toxicity due to accumulation of ionizable lipids in target organs, incorporation of biodegradable ester bonds into the structures of ionizable lipids have been explored, and shown to be successful at mitigating toxicity in target organs. The studies provided herein focused on creating a library of biodegradable ionizable lipids for mRNA encapsulation into LNPs and delivery to the lungs. Lipids were identified that were particularly effective for nebulized delivery of mRNA to the lung and nasal epithelium. A subset of lipids were effective at delivering mRNA to the lung endothelium upon IV administration. These lipids will be useful for the delivery of therapeutic mRNA in the form of LNPs to treat diseases affecting the lungs such as cystic fibrosis, sepsis, and lung cancer. [00352] To date lung mRNA delivery has not generally been focused on developing lipids for apical delivery to the lung epithelium in particular. Instead, lipids have been adapted from IV or intramuscular use 54 or from DNA delivery formulations. 62 Herein an in vitro mRNA delivery assay was developed based on primary airway cell air-liquid interface (ALI) cultures to screen for lung delivery. While in vitro evaluation of novel lipids for RNA delivery can be a poor predictor of in vivo delivery, screens using primary cells perform better than immortalized cells. 63,64 It was hypothesized that primary fully differentiated, air-liquid interface (ALI) cultures would provide an improved in vitro cellular model for in vivo lung delivery, as they retain key qualities of the lung: mucus secretion, mRNA delivery was therefore screened in ALI cultures, showing that the top performing formulation did indeed perform excellently in vivo. [00353] Two candidates, IR-117-17 and IR-19-Py, when formulated using the nebulization optimized formulation and delivered with nebulization optimized buffer and excipient, significantly outperform state-of-the-art mRNA delivery formulations to the lung and nose respectively. Nebulized IR-117-17 LNPs had a 300-fold improvement in lung mRNA delivery over the top previously described LNP, 54 and a twofold improvement over a previously identified top polymeric NP (PNP). 53 Example 1: Formulation optimization of LNPs for nebulized delivery using DOE. [00354] Given the vast chemical space available for LNP formulations and the material- intensive nature of nebulization experiments, a design-of-experiment (DOE) approach 68,69 was used to optimize LNPs for stability to the harsh conditions of nebulization. Initial experiments with a liver-optimized C12-200 based LNP formulation 68 showed that LNPs collected after nebulization using an Aeroneb vibrating mesh nebulizer had reduced in vitro transfection ability in A549 cells, loss of mRNA encapsulation, and increased size (FIGs. 17A-17C). Using these three measurements as readouts for LNP structural disruption post nebulization, formulations with maximal post nebulization stability were screened for. [00355] To identify a starting LNP delivery baseline, an in vivo pilot experiment was performed comparing two LNP formulations previously developed for systemic delivery of mRNA via i.v. administration. As previously described for delivery of PNPs, 0.5mg of firefly luciferase (FFL) mRNA was delivered to mice via nebulization to a whole-body exposure chamber, and luminescence was measured in excised lungs 6h after delivery. 53 It was found that the C12-200 based liver-targeting formulation resulted in a higher lung luminescence than the cKK-E12 based lung-targeting formulation (FIG.18) 70 and the C12-200 based formulation was therefore selected as the central formulation for screening. This result also showed that LNPs developed for lung-specific i.v. administration are not necessarily superior for nebulized delivery of mRNA to the lung epithelium. [00356] For the mixture-constrained DOE screen, the molar ratios of the ionizable lipid, helper phospholipid, and cholesterol were varied, while also varying the identity of the ionizable lipid and helper phospholipid (FIG.10A). cKK-E12 was included as a second ionizable lipid in the screen given that the ionizable lipid identity has been shown to significantly impact LNP transfection efficiencies. Additionally, helper phospholipids DSPC and DOTAP were included to test the effect of saturated alkyl chains and positive charge respectively on LNP stability during nebulization. In total, 19 formulations were prepared, including the initial liver-targeting C12-200 formulation (T1-1), encapsulating FFL mRNA via microfluidic mixing for evaluation (FIG.10B). [00357] The formulations were then evaluated for in vitro transfection ability, encapsulation efficiency, and size before and after nebulization (FIGs.10C-10D, 19). Of the 19, one formulation (T1-5) was identified with high transfection efficiency in A549 cells both before and after nebulization and no loss in encapsulation efficiency due to nebulization (FIG.10C). Like the other formulations, T1-5 showed a substantial post-nebulization size increase (FIG. 19), but was nevertheless considered a promising formulation. It was also tested whether POPG, a primary component of pulmonary surfactant that has been reported to destabilize liposomes, inhibited transfection. POPG inhibited both commercial lipofection reagent RNAiMAX and the original formulation T1-1 in a concentration dependent manner, but formulation T1-5 showed minimal loss in transfection efficiency even at concentrations similar to the physiologically highest levels found in alveolar spaces 71 (FIG.20). [00358] Based on these promising characteristics of T1-5, its in vivo performance was evaluated in delivering FFL mRNA to mice via nebulization. Luminescence was significantly higher in lungs transfected with T1-5 (1.88x10 4 p s -1 cm -2 sr -1 ) compared to T1-1 (1.18x10 4 p s -1 cm -2 sr -1 ) (FIG.10E). Although promising, the potential of the T1-5 formulation was hindered by its increase in size following nebulization. Such an increase was observed for all the LNPs tested but not for a hPBAE PNP that was the first published, nebulized mRNA delivery formulation for the lungs (FIG.19). 53 This nebulization induced aggregation of LNPs suggested further opportunities to improve LNP stability during nebulization and potentially improve in vivo efficacy. Example 2: Excipients and buffer modifications for improved LNP stability and delivery. [00359] A rationally designed screen of stabilizing excipients and buffer modifications was performed (FIG.11A). To evaluate the effects of additional excipients on nebulized delivery efficiency, excipients were added to T1-5 LNP formulations following overnight dialysis in PBS and immediately before nebulization. Based on previous data demonstrating that the addition of disaccharide lyoprotectants such as trehalose and sucrose helped to prevent LNP aggregation and loss of LNP efficacy following multiple freeze-thaw cycles, 72 these two sugars were evaluated in our LNP formulation at a final concentration of 20% (w/v) before nebulized delivery of the resultant LNP solution to mice. However, it was found that neither sugar improved the nebulized performance of T1-5 in mice when compared to T1-5 nebulized without any excipient (FIG.11B). It was reasoned that addition of an inert hydrophilic polymeric excipient could provide steric hindrance between LNPs that could prevent LNP aggregation and improve nebulized LNP performance in vivo. Polysaccharides (Dextran and Ficoll) were evaluated, as well as linear (PEG6K and PEG20k) and branched (bPEG20K) PEGs by adding these polymers to the LNP formulation at a final concentration of 2% (w/v) before nebulizing. All polymers evaluated were able to improve the nebulized performance of T1-5 in mice, with all three PEGs significantly improving luminescence in the lung over T1-5 with no excipient (FIG.11B). bPEG20K in particular led to a ~13-fold increase in lung luminescence when compared to T1-5 with no excipient. To evaluate whether bPEG20K improved in vivo performance of T1-5 due to changes in lung physiology upon exposure to bPEG20K, a solution of 2% bPEG20K without LNPs was nebulized to mice immediately followed by T1-5 LNPs without an excipient. Pre-treatment of the mice with the bPEG20K solution did not improve T1-5 performance compared to T1-5 delivered without pre-treatment (FIG.21), suggesting that the effect of bPEG20K on in vivo nebulized performance is directly related to its presence in the nebulization formulation. [00360] While performing nebulization experiments, mice would sometimes huddle together while in the whole-body chamber, which may lead to varied exposure to aerosol. To remove this potential issue, mRNA formulations were administered to mice that are restrained such that only their noses are exposed to a central chamber. Aerosol generated from the nebulizer is directed into this chamber via air flow. Using this nose-only exposure system, nebulized delivery of T1-5 with 2% bPEG20K leads to significantly higher lung luminescence when compared to the same formulation delivered in the whole-body exposure chamber (FIG. 11C). The nose-only exposure system was used for all subsequent experiments. [00361] During the process of excipient evaluation, all nebulization experiments were performed in PBS. It was hypothesized that modifications to the LNP buffer may further improve the in vivo nebulized delivery efficacy of the T1-5 formulation with bPEG20K excipient. Two additional buffers were tested: 0.9% saline, pH 7.0, which has been previously explored in nebulized delivery of liposomal formulations, 73 and 100mM sodium acetate (NaAc) at pH 5.2. It was reasoned that the slightly acidic NaAc buffer would protonate the ionizable lipids present in LNPs. This would lead both to tighter mRNA binding which could improve resistance to nebulization-based shear forces, and to a more positive surface charge that could reduce LNP aggregation via electrostatic repulsion. Additionally, 100mM NaAc buffer has been used in the nebulized delivery of hPBAEs with no observed toxicity. 53 To evaluate the buffers, T1-5 LNPs were microfluidically mixed, 68 initially dialyzed into PBS before overnight dialysis in the selected buffer, and 2% bPEG20K excipient was added before nebulization to mice in the nose only exposure system. NaAc buffer, but not 0.9% saline, significantly improved nebulized delivery efficacy compared to PBS (FIG.11D). [00362] To test the hypothesis that addition of the bPEG20K stabilizing excipient and use of the NaAc buffer improved nebulized delivery of T1-5 through reduction of LNP aggregation during nebulization, the size of LNPs was measured before and after nebulization in the presence or absence of the excipient and buffer modification. From DLS measurements, incorporating bPEG20K into the PBS buffer attenuated the increase in LNP size following nebulization. An even greater reduction was observed for LNPs nebulized with bPEG20K in NaAc buffer when comparing both nebulization formulations to PBS buffer without excipient (FIG.11E) These sequential reductions in LNP size increase following nebulization are consistent with the sequential increase in lung luminescence observed in vivo. However, nebulization of LNPs in NaAc buffer alone did not reduce the size increase following nebulization. Example 3: Synthesis and in vitro screening of combinatorial, biodegradable lipid library. [00363] Conventional ionizable lipids for RNA delivery conform to a general model comprising an amine head group linked to tails via a linker (FIG.1A). An ionizable lipid library was rationally desinged in which various tails were linked to amine head groups by biodegradable ester bonds (FIG.1B). A unique feature of this library was the presence of biodegradable tails and a hydroxyl group two carbons away from the carbon attached to the amine head group. This hydroxyl group was afforded by the Aldol chemistry used in the “linker-tail” synthesis as shown in FIG.1C. The “linker-tail” synthesis proceeded by esterification of a commercially available fatty acid with 1,6-hexane diol and gave ester 2, which was then oxidized to the aldehyde 3 using Dess-Martin oxidation. Aldol reaction, facilitated by a (1:1) mixture of Ti(O-n-Bu)4/t-BuOK was used to dimerize the aldehyde to give the respective “linker-tail” as an aldol. To test whether the lipids could be screened without individual purification, 22 lipids both purified and unpurified were prepared, and LNPs were synthesized from these lipids using the T1-5 formulation. The FFL mRNA delivery was tested in A549 cells (an immortalized alveolar epithelial cell line). There was a slight but not statistically significant positive correlation between purified and unpurified lipids with this chemistry (FIG.22, correlation coefficient ^ = 0.14, p=0.66; ^ = 0.47, p=0.15 even after removal of an outlier), suggesting that a screen of unpurified lipids would not be informative. [00364] Utilizing the reactivity of the aldehyde group in the “linker-tail”, thirty different amines (FIG.2) were reacted with appropriate tails to make to make ionizable lipids by reductive amination (FIG.1D). Structures of lipids made using this chemistry are shown in FIGs.3A-3D. It was predicted that unsaturated tails would have optimal activity so lipids with oleic and linoleic acid tails were primarily synthesized (FIG.3B), though lipids with C16 (palmitic acid) tail were also synthesized. Purified lipids were screened in A549 cells, several of which had comparable efficiency to C12-200 (FIG.4A). Of the 4 C 16 -tail lipids, 3/4 had worse activity than headgroup-matched unsaturated tail variants, while the 4 th was not in the top 20 lipids by activity, thus preliminarily validating a focus on unsaturated tails. Example 4: Screening of ionizable lipids for epithelial delivery in air-liquid interface cultures. [00365] [00366] Because nebulization is a low throughput approach and in vitro mRNA delivery assays with classic cell culture techniques can be unreliable, a medium throughput screening approach with good capacity to predict lung epithelial delivery was sought. For such an assay, a model system was desired that recapitulated the primary known barriers to apically delivered lung gene therapy. Air-liquid interface (ALI) cultures derived from primary human bronchial epithelial cells were selected. ALI cultures are grown on porous Transwell inserts such that, upon reaching confluence, media can be removed from the top (apical) side of the insert and the cells can be fed from the bottom, basolateral, side (FIG.12A). This enables recapitulation of the conditions of the native bronchial epithelium, where the apical side of the cells is exposed to the air while the basolateral side is bathed in nutrients. [00367] ALI cultures can be used to examine bronchial epithelial biology and share characteristics of the in vivo bronchial epithelium including differentiation, mucus secretion, periciliary layer formation, and tight junctions. 65–67,74 ALI cultures can be difficult to transfect, 74 likely due to these in vivo-like characteristics, which suggested that these cultures would be a suitable model for screening LNPs for mRNA delivery. Both primary large airway (LA) and small airway (SA) ALI cultures were generated. While large airway ALI cultures are more commonly studied, both large and small airway are important for respiratory diseases including CF, COPD, and asthma. 75–78 Both small and large airway cultures formed tight junctions (FIGs.23A-23B) as measured by transepithelial electrical resistance, 79 and large airway cultures grew more thickly, with dense visible ciliation (FIG. 12B). [00368] To validate ALI cultures as a model for LNP delivery, T1-5 formulated C12-200 LNPs were tested for FFL delivery to ALI cultures up to two weeks after airlift. Transfection efficiency dropped over that period by 2.5-3 orders of magnitude (FIG.12C), consistent with the previous observation that siRNA delivery by traditional in vitro transfection reagents decreases sharply over the first week of ALI culture. 74 Next, 12 top-performing (in the A549 assay) LNPs were screened for mRNA delivery to small airway ALI cultures (FIG.12D), leading to identification of two LNPs in particular with excellent performance, IR-117-17 and IR-19-Py (FIG.12E). [00369] To optimize these top structures and identify structure-activity relationships, 21 and 14 tail- and headgroup variants of IR-117-17 and IR-19-Py were synthesized and screened, respectively, in both small and large airway ALI cultures, along with A549 cells. First, saturated tails of lengths 9-18 were screened for each lipid, and in both cases intermediate tail lengths in the range of C12-C14 tended to be optimal, though none of the saturated tails outperformed unsaturated versions (FIGs.4B-4C). For IR-117-17 in particular, it was reasoned that because linoleic tails (2 unsaturations) outperformed oleic tails (1 unsaturation), adding a third unsaturation may further improve delivery. However, the alpha-linolenic acid (ALA) tailed variant was merely comparable to the linoleic tail. [00370] To further elucidate IR-117-17’s structure-activity relationship, headgroup variants of IR-117-17 with oleic, linoleic, and/or ALA tails were tested, to determine whether shortening the alkyl chains branching off from the tertiary amine would improve performance. Shortening the alkyl chains significantly impaired activity for the linoleic and ALA tails, while activity for the oleic tails was unaffected or improved by tail shortening, though not to the level of the original IR-117-17 (FIGs.24A-24B). Headgroup variants of IR- 19-Py were also tested, and the activity was relatively insensitive to replacement of the pyrazole group with an imidazole, and to demethylation of one of the headgroup nitrogens (FIGs.24C-24D). [00371] Lipids were screened as part of LNPs that contained 50.1% ionizable lipid, 24.6% DOTAP, 16.8% cholesterol, and 8.5% PEG-lipid by mass, and a 10:1 ionizable lipid:mRNA weight ratio. LNPs generated using the 117-17 and 19-Pyrazole ionizable lipids outperformed other screened lipids in ALI cultures (FIG.4A-4C). Subsequently, analogs of 117-17 and 19- Pyrazole were synthesized with varying tail lengths (FIGs.5A-5B), formulated into LNPs and screened in ALI cultures. Some of them performed well in ALI cultures (FIG.4A-4C), though none better than the original 117-17 and 19-Pyrazole. In particular, C12 tail variants were comparably effective to original lipids (original 117-17 has linoleic tail; original 19- Pyrazole has oleic tail). Example 5: In vivo evaluation of lead ionizable lipid LNPs combined with optimized nebulization formulations. [00372] Next, to confirm the efficacy of the identified top lipids in vivo and test the ability of ALI cultures and A549 cells to predict lung delivery, T1-5 formulated IR-117-17 and IR-19- Py (with bPEG20K and NaAc excipients) were nebulized to mice, along with IR-117-17’s C 12 , C 15 , and ALA tail variants. As controls, previously reported lung delivery-optimized hPBAE 53 and NLD1, an LNP that has been reported to have good stability to nebulization and lung mRNA delivery, 54 were also nebulized. As observed in ALI cultures, IR-117-17 (1.1x10 6 p s -1 cm -2 sr -1 ) significantly outperformed C12-200 (6.1x10 5 p s -1 cm -2 sr -1 ) (FIG. 13A). Of note, IR-117-17 also outperformed the polymeric PBAE nanoparticle (5.2x10 5 p s -1 cm -2 sr -1 ) by two-fold and NLD1 (2.8x10 3 p s -1 cm -2 sr -1 ) by 300-fold. Results from the ALI culture experiments also correctly predicted that IR-117-17-C15 would perform poorly relative to IR-117-17-C12 and the original IR-117-17. However, the ALI cultures incorrectly predicted good IR-117-17-ALA activity, as it performed the worst of all tested lipids. Overall, there was not a statistically significant correlation between the ALI culture and in vivo data (FIG.13B). However, the A549 data was substantially worse, predicting nearly everything incorrectly and notably showing C12-200 as the top-performing lipid (FIG.13C). [00373] One possible explanation for the lack of correlation between ALI culture and in vivo results was that the ALI culture screens used hand mixed lipids that were not nebulized. LNPs were therefore generated from C12-200 and the IR-117-17 variants via microfluidic synthesis, in which the LNPs were nebulized using bPEG20K and NaAc excipients, and then A549 cells and ALI cultures were treated with the post-nebulized LNPs. For post-nebulized LNPs, both A549 cells (p=0.0076) and ALI cultures (p=0.0022) showed significant correlations between in vitro and in vivo activity (FIGs.13D-13E), primarily because both predicted IR-117-17 to be effective and IR-117-17-ALA no longer performed well. However, C12-200 continued to be the most effective lipid for A549 cell transfection, while ALI cultures correctly identified IR-117-17 as the top lipid. [00374] Based on these results, IR-117-17, the top-performing lipid, and IR-19-Py, which had statistically comparable delivery to C12-200 and a more chemically distinct headgroup than IR-117-17-C 12 , were further characterized. The three lipids were tested in ALI cultures generated from a person with CF (W1282X/R1162X genotype), finding comparable delivery between the three lipids (FIGs.13F and 23C-23D). To understand if nebulization with bPEG20K and NaAc improved in vivo performance of T1-5 LNPs formulated with IR-117-17 and IR-19-Py as they did for C12-200, the in vivo nebulized delivery of the two biodegradable lipids in either the optimized nebulization formulation or in PBS buffer with no excipient was compared. Nebulization in the optimized formulation improved delivery of LNPs formulated with either biodegradable lipid (FIG.25). These improvements in nebulized delivery are consistent with the observation that nebulization in the presence of bPEG20K and NaAc buffer significantly limited LNP size increase when compared to PBS alone for the biodegradable lipids, similar to the trends in nebulization size and efficacy observed for C12- 200 (FIG.26, FIG.11E). Of note, when IR-117-17 LNPs were nebulized in the presence of bPEG20K and NaAc buffer, the resultant LNPs had an average diameter of only 116nm, the smallest size observed for any LNP following nebulization. Example 6: Pharmacokinetics and pharmacodynamics of top performing LNPs. [00375] The top candidates, 117-17 and 19-Pyrazole, were tested in vivo via nebulization. 117-17 outperformed C12-200 while 19-Pyrazole performed comaparably to C12-200. (FIG. 6A). C12-200 was reported as an aminoalcohol lipoloid in International Application No. PCT/US2009/006018. The lipids provided herein have an additional advantage of being biodegradable, which would likely make them less toxic compared to C12-200. To determine whether the protein expression in the lung could be controlled by nebulized dose, a dose- response study of the three LNPs was performed, whereby mice were nebulized with 0.25, 0.5, or 1mg of mRNA. For all three LNPs, there was an increase in lung luminescence corresponding to increasing dose (FIG.14A). A time-course study of protein-expression in mice following nebulized delivery of the LNPs showed that nebulized delivery of these LNPs led to protein-expression in both the lungs (FIG.6B, 6D, 6E) and nose (FIG.6C, 6E) of mice lasting at least 48h after nebulized dosing. For IR-19-Py, particularly high and extended protein expression was observed in the nose, suggesting that application of this LNP as a nasal vaccine may be of interest. For mRNA protein-replacement therapies to treat pulmonary diseases like cystic fibrosis, repeat dosing of the therapeutic will be required unless genome editing is possible. Therefore, the ability to repeat-dose nebulized LNPs was characterized by administration of 1mg of FFL mRNA every 72h, with measurement of lung luminescence 6h after each nebulization. For all LNPs, no loss in lung luminescence was observed over the course of the three administrations (FIG.6B). Additionally, repeated delivery of the nebulized LNPs was well tolerated as evidenced by the lack of weight loss (FIG.27) and normal liver enzyme levels (FIG.14B) in mice. [00376] The ability to efficiently deliver mRNA to the lung epithelium represents a significant advance in treatment of lung diseases such as cystic fibrosis via RNA-based gene editing or via direct delivery of mRNA encoding therapeutic proteins. Likewise, efficient delivery of mRNA to the nasal epithelium is significant in the development of mucosal vaccines. The use of biodegradable lipids may allow for repeat dosing without toxic bioaccumulation of ionizable lipids. [00377] Unlike the epithelium, the lung endothelium is more accessible by intravenously administered nanomedicines. To identify lipids that can potently facilitate delivery of mRNA to pulmonary endothelial cells, the entire lipid library was formulated into LNPs, and their performance was evaluated in vivo using a pooled firefly luciferase analysis following IV administration. From this analysis, it was observed that 117-7, when formulated with helper lipids (mole percentages of 35% 117-7, 16% DOPE, 46.5% cholesterol, 2.5% C14-PEG2000, 10:1 weight ratio of 117-7 to mRNA) was able to effectively deliver mRNA to the lung at a dose of 0.5 mg/kg of mRNA (FIG.7). [00378] Further optimization of the structure of 117-7 by varying the tail length led to the identification of 117-7-C15 (FIG.8), which was found to be roughly an order of magnitude more potent than 117-7 at the same dose of mRNA (FIG.9). Example 7: Evaluating functional mRNA delivery to lung epithelium with IR-117-17 LNPs in Ai14 mouse model. [00379] To identify which cells in particular were transfected, nebulized delivery of Cre recombinase mRNA to the Ai14 mouse model was tested. Cells in these mice express tdTomato only upon Cre activity (FIG.15A). 70 10mg of Cre mRNA was nebulized to mice over the course of 3 doses, and lung transfection was measured in large and small airways using histology. FIG.15B shows representative images of the large and small airways respectively; transfected (tdTomato+) club and ciliated cells are indicated with arrows. [00380] Next, the images were quantified, indicating averages of 10.3% and 8.8% transfection of large and small airway cells respectively (FIGs.15C & 28A). Club cell transfection was also quantified because club cells collectively are the largest source of CFTR in the lung 80,81 (while individual pulmonary ionocytes highly express CFTR, 80–83 they are rare). They can also act as progenitor cells and are easier to target via nebulization than basal cells 84 so they are excellent candidates for both gene therapy and gene editing for cystic fibrosis. Slightly smaller percentages of club cells (8.4% and 7.6%) were transfected (FIG. 15C), though the difference between club cell transfection and all cell transfection was not significant (p=0.35 for large, p=0.61 for small airway, t-test) respectively. [00381] Additionally, all 21 large airways were quantified, and 140/151 (93%) of small airways had at least 1 transfected cell (FIG.28B). However, microscale heterogeneity was observed in transfection in some images (FIGs.28B-28C), while some individual stretches of airway showed near-complete transfection (FIG.15D). Heterogeneity may be due to differences in transfectability and/or particle deposition. Example 8 [00382] It is disclosed herein that novel excipients and a novel formulation were rationally designed to improve LNP stability during nebulization. The use of the excipients and DOTAP allowed the avoidance of high PEG-lipid content to stabilize LNPs to nebulization as was done previously, 54 and likely contributed to the improved potency of the formulations, as high PEG-lipid content often reduces transfection efficiency. 85 Furthermore, given that the NaAc buffer and bPEG improved delivery for LNPs containing three highly chemically distinct lipids, this buffer-excipient combination is generalizable to other LNPs. [00383] Additionally, in vitro screens based on primary ALI cultures were shown to be an effective means of evaluating mRNA delivery LNPs for the lung. These screens are higher throughput than nebulization and require much less material, while being substantially more accurate than submerged cell culture assays. ALI cultures can be a valuable tool for screening of future delivery vehicles to the lung epithelium or of alternative strategies to improve epithelial mRNA delivery. [00384] Further, the combination of formulation, excipient, our combinatorial lipid library, and ALI culture-based screening yielded optimized biodegradable lipids for nebulized mRNA delivery - IR-117-17 and IR-19-Py. Optimized LNPs using these two biodegradable lipids have state-of-the-art nebulized delivery to the lung and nose, respectively, substantially outperforming previously published work on nebulized LNP delivery. These nebulized LNPs also drive protein expression in multiple epithelial cell types and for multiple days, allow for multiple dosing, and have no apparent toxicity. A further advantage relative to IR-117-17’s closest competitor, PBAEs, is that lipids are monodisperse, while PBAEs generated with step-growth polymerization are polydisperse polymers. 86 . To the knowledge of Applicant, the technology described here is the most potent mRNA delivery formulation reported for nebulized, in vivo mRNA delivery. Example 9: Methods. [00385] Nanoparticle formulation. LNPs were synthesized by mixing an aqueous phase containing the mRNA with an ethanol phase containing the lipids either by pipetting or in a microfluidic chip device. 87 The aqueous phase was prepared in a 10mM citrate buffer with corresponding mRNA (firefly luciferase and Cre recombinase mRNA provided by Translate Bio). The ethanol phase was prepared by solubilizing a mixture of ionizable lipid, helper phospholipid (DOTAP, DOPE, or DSPC [Avanti]), cholesterol (Chol, Sigma-Aldrich), and C14-PEG2000 (Avanti) at pre-determined molar ratios with an ionizable lipid/mRNA weight ratio of 10 to 1. For microfluidically prepared LNPs, the aqueous and ethanol phases were mixed in a microfluidic device at a 3:1 ratio by syringe pumps to a final mRNA concentration of 0.1mg/mL for in vitro studies or 0.2mg/mL for in vivo studies. The resultant formulation was dialyzed against PBS, unless otherwise specified, overnight in a 20K MWCO dialysis cassette (ThermoFisher) at 4°C. For formulations in other buffers, LNPs were first dialyzed against PBS for 4 h followed by overnight dialysis against 0.9% saline, pH 7.0 or 100mM NaAc buffer prepared by diluting 3M, pH 5.2 NaAc with DI H2O. Following dialysis, LNPs were concentrated using Amicon 100K MWCO centrifugation filters (Sigma) at 4°C. For pipette mixed LNPs, the two phases were mixed by repeated pipetting and immediately diluted in PBS to specified concentrations. [00386] For screening of ionizable lipids generated by reductive amination, screening took place holding mass ratios from the T1-5 formulation (with C12-200 as the ionizable lipid) constant. This corresponded to mass ratios of 50.1:24.6:16.8:8.5 Ionizable lipid:DOTAP:Cholesterol:C14-PEG2000. This constant mass ratio formulation was used in all subsequent experiments. [00387] NLD1 LNPs and hPBAE PNPs were prepared as previously described. 53,54 [00388] LNP characterization. mRNA encapsulation efficiencies were measured by a modified Quanti-iT Ribogreen RNA assay (Invitrogen) as previously described. 88 The diameter of the LNPs was measured using dynamic light scattering (Dyna Pro Plate Reader, Wyatt). LNPs were diluted to 0.5ng mRNA/uL in PBS for DLS measurements. LNP diameters are reported as the largest intensity mean peak average, constituting>90% of the nanoparticles present in the sample. [00389] Nebulization of nanoparticles. For characterizing effects of nebulization on LNP size, encapsulation efficiency, and transfection efficiency, 100uL of LNPs at 150ng/uL were loaded into an Aeroneb vibrating mesh nebulizer (Aerogen) and nebulized into 1.5mL microcentrifuge tubes. Where specified, 2% w/v of excipients were added to the LNP formulation following dialysis and immediately prior to nebulization. [00390] Cell culture. A549 lung epithelial cells (ATCC) were grown in DMEM high glucose + sodium pyruvate + GlutaMax (Gibco no.10569-010)+ 10% FBS. [00391] Primary large airway cells (University of North Carolina at Chapel Hill MLI Tissue Procurement and Cell Culture Core) and primary small airway cells (ATCC) were expanded using PneumaCult-ExPlus (StemCell) according to the instructions for the media and plated for ALI cultures at P3 and P4 respectively. [00392] ALI cultures were plated either onto 0.4 ^m pore, 6.5mm diameter PET Transwell inserts for 24-well plates (Corning) or 0.4 ^m pore polycarbonate inserts for 96-well plates (Corning). The 24-well plates were used for histology, the two-week transfection timecourse, and TEER measurements; 96-well plates were used for all other experiments.33,000 cells/well were seeded in the 24 well inserts and 15,000 cells/well were seeded in the 96-well plate inserts. [00393] Per manufacturer instructions, cultures were grown to confluence with both apical and basolateral (ExPlus) media for 2-4 days before airlift. Because polycarbonate inserts are opaque so confluence was not observable, each time cells were thawed and plated on a 96- well insert plate, the same cells were plated on 6.5mm PET inserts.96-well insert plates were airlifted one day after the concurrently plated PET inserts because initial experiments showed that the extra day helped tight junctions form more consistently. Upon airlift, apical media was removed and basolateral media was changed to PneumaCult-ALI (for large airway cells) or ALI-S (for small airway cells) media (StemCell). Qualitative tight junction formation, as measured by a lack of leakage of media overnight into the apical space, was observed for both 24-well and 96-well ALI cultures within a week of airlift. Media was changed 3 times/week and cells were not transfected until at least 20 days of ALI culture. [00394] In vitro transfection experiments. For DOE screening and optimization of the IR- 117-17 and IR-19-Py leads, 10,000 A549 cells/well were plated in white-sided, clear bottom 96-well plates. After 24h of incubation, FFL mRNA encapsulated in either LNPs diluted in PBS or RNAiMAX (ThermoFisher) were added at 50ng/well except for post-nebulized LNP samples which were added at the same volume as the respective pre-nebulized sample. For the initial reductive amination lipid screen, 2,000 A549 cells/well were plated in a white 384- well plate and allowed to grow overnight. The next day, LNPs were generated by pipette mixing (except where otherwise noted) to a final concentration of 100ng/uL mRNA, diluted in PBS to 10ng/uL mRNA, and wells were treated with 20ng mRNA/well. For ALI cultures, LNPs were likewise generated by pipette mixing or microfluidic mixing as noted in the main text, and diluted to 50ng/uL total mRNA with PBS.10 ^L of this 50ng solution was added apically to 96-well inserts, or 20uL to 24-well inserts. [00395] Bioluminescence was measured 24h after transfection using Bright-Glo (Promega) according to the manufacturer’s instructions. Bioluminescence was quantified using the Tecan Infinite M200 Pro plate reader (Tecan). [00396] Animal studies. All procedures were performed under an animal protocol approved by the Massachusetts Institute of Technology Committee on Animal Care (CAC) and the guidelines for animal care in an MIT animal facility. [00397] In vivo nebulized delivery. In vivo nebulized delivery of mRNA to C57BL/6 mice (Jackson Laboratory) was performed either in a whole-body exposure chamber or a nose-only exposure chamber (CH Technologies) where specified. LNPs at 0.3mg/mL of mRNA were loaded into the nebulizer at required volumes with 2% w/v excipients where specified. For the whole-body exposure chamber, the nebulizer was connected to the chamber via a tee and an oxygen flow rate of 15 SCFH was used to direct aerosol into the chamber. For the nose- only exposure chamber, mice were immobilized in restrainers and the restrainers connected to the chamber. A flow rate of 2 SLPM of oxygen was used and pressure within the chamber was maintained at -0.1 din. H2O. Nebulizations were performed until no more aerosol was observed in the chamber. [00398] In vivo bioluminescence.6h after nebulization, unless otherwise noted, mice were injected intraperitoneally with 0.2 ml XenoLight D-luciferin (10 mg/mL in DPBS, PerkinElmer). For whole-body imaging, mice were anesthetized in a ventilated anesthesia chamber with 2.5% isofluorane in oxygen and imaged 10 min after luciferin injection. Otherwise, mice were sacrificed 10 min after luciferin injection and organs were collected for imaging. Luminescence was measured with an in vivo imaging system (IVIS, PerkinElmer) and quantified using the Living Image software (PerkinElmer). [00399] Toxicity study.48h after the third nebulization of FFL mRNA in the repeat dosing study, mice were bled and sera was isolated using microcentrifugation in BD SST microtainers. Serum was analyzed for ALT and AST levels (Custom lipid panel 62149, IDEXX Bioanalytics). [00400] Histology study with Ai14 mice. B6.Cg-Gt(ROSA)26Sor tm14(CAG-tdTomato)Hze /J mice (Jackson Laboratory) were administered three 3mg doses of Cre mRNA via nebulization in the nose-only exposure chamber. Control Ai14 mice were administered PBS. Nebulizations were separated by 48h and mice were sacrificed 5 days after the final dose. Upon CO2 euthanasia, the mouse lungs were first perfused with PBS via the right ventricle. The right lobes of the lung were tied off and removed for flow cytometry. The left lobe was inflated through the trachea with 0.25mL of fresh 4% PFA and then placed in 4% PFA overnight. The following day, the left lobe was submitted for paraffin processing. The lobe was then embedded with the ventral side down and serial sections (5µm each) were obtained until the middle of the lung was reached. For each mouse, two slides were taken for immunofluorescent imaging. One section was taken from the middle of the lung where more large airways are present and one section was taken from a quarter of the way into the lung where many small airways are present. The slides were deparaffinized, permeabilized, blocked, and then stained with rabbit anti-RFP antibody (abcam, ab62341, 1:200) for 1 hr. The slides were then washed and labeled with Dylight 594 goat anti-rabbit antibody (Vector Labs, DI-1594, 1:200), Alexa Fluor 647 anti-acetylated tubulin antibody (Santa Cruz, SC- 23950, 1:200), and Alexa Fluor 488 anti-Uteroglobin/SCGB1A1/CC10 antibody (Santa Cruz, SC-390313, 1:200) for 1 hr. Autofluorescence was blocked with Vector Labs autofluorescence quencher and then slides were mounted with DAPI mounting media. Slides were imaged on a Nikon Spinning-disk confocal microscope. The number of tdTomato positive cells in all airways on these sections were counted manually using FIJI. [00401] Statistics analysis. Design of experiment (DOE) was performed using JMP 13 software (JMP, SAS Institute). Example 10: Synthesis of Lipids. [00402] All solvents and reagents were obtained commercially and used as such unless noted otherwise. 1 H and 13 C NMR spectra were recorded in CDCl3 at room temperature using a Bruker Ultrashield 400 MHz instrument. Spectra were processed with Chemical shifts reported as parts per million (ppm) relative to TMS (0.00) for 1 H. Silica gel chromatography was performed on ISCO CombiFlash Rf+ Lumen Instruments using ISCO RediSep Rf Gold Flash Cartridges (particle size: 20-40 microns). All final compounds were confirmed by mass spectrometry using direct injection method on QTOF-HRMS (Agilent) coupled to an Agilent Infinity 1260 LC system. Only top performing lipids after screening were fully characterized by 1 H and 13 C NMR. Scheme 1: synthesis of tails used in reductive amination library synthesis. [00403] Synthesis of 6-hydroxyhexyl oleate, 3a: Oleic acid (5g, 17.7 mmol), N-(3- dimethylaminopropyl)- N′-ethylcarbodiimide hydrochloride (EDC HCl, 5.1g, 26.6 mmol), hexane-1,6-diol (10.5g, 88.5 mmol), 4-(dimethylamino) pyridine (DMAP, 1.1g, 8.9 mmol) and N, N-diisopropylethylamine (DIPEA, 6.2 ml, 35.4 mmol) were dissolved in dichloromethane (200 ml). The reaction was stirred at room temperature under nitrogen for 18 h, then washed with a saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and the filtrate was evaporated under vacuum. The residue was purified by silica gel chromatography (0–50% ethyl acetate in hexanes) to give 6-hydroxyhexyl oleate, 3a (5.8g, 15.2 mmol, 86%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 5.43 – 5.29 (m, 2H), 4.09 (t, J = 6.7 Hz, 2H), 3.67 (t, J = 6.5 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 2.03 (q, J = 6.5 Hz, 4H), 1.73 – 1.53 (m, 6H), 1.49 – 1.17 (m, 24H), 0.95 – 0.83 (m, 3H). [00404] Synthesis of 6-oxohexyl oleate, 4a: 6-hydroxyhexyl oleate, 3a (5.8g, 15.2 mmol) was dissolved in dichloromethane (300 ml) followed by Dess-Martin Periodinane (9.6g, 22.8 mmol). The reaction was stirred under nitrogen at room temperature for 2 hr. After confirmation of reaction completion by thin layer chromatography, sodium thiosulfate pentahydrate (50% w/v, 200 ml) was added to the reaction and left to stir for additional 15 mins. Organic layer was thereafter separated, washed with brine, dried over Na 2 SO 4 , filtered, and the filtrate was evaporated under vacuum. The residue obtained was purified by silica gel chromatography (0–50% ethyl acetate in hexanes) to give 6-oxohexyl oleate, 4a (3.5g, 9.2 mmol, 61%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 9.79 (s, J = 1.8 Hz, 1H), 5.42 – 5.33 (m, 2H), 4.09 (t, J = 6.6 Hz, 2H), 2.47 (td, J = 7.3, 1.7 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 2.03 (q, J = 6.5 Hz, 4H), 1.67 (dp, J = 15.1, 7.8 Hz, 7H), 1.48 – 1.21 (m, 23H), 0.90 (t, J = 6.8 Hz, 3H). [00405] Synthesis of 5-formyl-6-hydroxyundecane-1,11-diyl dioleate, 5a: Titanium (IV) butoxide (3.1g, 9.2 mmol) and potassium tert-butoxide (1.0g, 9.2 mmol) were dissolved in anhydrous tetrahydrofuran (200ml) and left to stir under nitrogen for 5 mins at room temperature. The mixture was then cooled to 0 0 C. Thereafter, (6-oxohexyl oleate, 11 (3.5g, 9.2 mmol) was added to the reaction and stirring was continued for another 45 mins. The reaction was quenched with 1N HCl (100 ml), and then extracted with ethyl acetate (250 ml). Organic layer was separated, dried over Na2SO4, filtered, and the filtrate was evaporated under vacuum. The residue was purified by silica gel chromatography (0–50% ethyl acetate in hexanes) to give 5-formyl-6-hydroxyundecane-1,11-diyl dioleate, 5a (1.7g, 2.3 mmol, 25%) as a brown oil. 1 H NMR (400 MHz, CDCl3) δ 9.79 (dd, J = 7.1, 2.3 Hz, 1H), 5.45 – 5.32 (m, 4H), 4.09 (td, J = 6.6, 3.3 Hz, 4H), 2.31 (t, J = 7.6 Hz, 4H), 2.05 (dq, J = 12.8, 6.5, 5.7 Hz, 7H), 1.87 (d, J = 5.3 Hz, 2H), 1.74 – 1.46 (m, 15H), 1.46 – 1.07 (m, 42H), 0.90 (t, J = 6.7 Hz, 6H). [00406] Synthesis of 6-hydroxyhexyl (9Z,12Z)-octadeca-9,12-dienoate, 3b: 6-hydroxyhexyl (9Z,12Z)-octadeca-9,12-dienoate, 3b was made using the same procedure for the synthesis of 6-hydroxyhexyl oleate, 3a above. 1 H NMR (500 MHz, CDCl3) δ 5.47 – 5.26 (m, 4H), 4.09 (t, J = 6.7 Hz, 2H), 3.67 (t, J = 6.5 Hz, 2H), 2.80 (t, J = 6.7 Hz, 2H), 2.31 (t, J = 7.6 Hz, 2H), 2.07 (q, J = 7.0 Hz, 4H), 1.74 – 1.53 (m, 7H), 1.49 – 1.18 (m, 18H), 0.91 (t, J = 6.8 Hz, 3H). [00407] Synthesis of 6-oxohexyl (9Z,12Z)-octadeca-9,12-dienoate, 4b: 6-oxohexyl (9Z,12Z)- octadeca-9,12-dienoate, 4b was made using the same procedure for the synthesis of 6- oxohexyl oleate, 4a above. 1 H NMR (400 MHz, CDCl 3 ) δ 9.79 (s, 1H), 5.59 – 5.15 (m, 4H), 4.09 (t, J = 6.6 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H), 2.31 (t, J = 7.6 Hz, 2H), 2.06 (dd, J = 8.1, 5.7 Hz, 4H), 1.68 (dq, J = 14.4, 7.2 Hz, 8H), 1.44 – 1.22 (m, 16H), 0.91 (t, J = 6.7 Hz, 3H). [00408] Synthesis of 5-formyl-6-hydroxyundecane-1,11-diyl (9Z,9'Z,12Z,12'Z)-bis(octadeca- 9,12-dienoate), 5b: 5-formyl-6-hydroxyundecane-1,11-diyl (9Z,9'Z,12Z,12'Z)-bis(octadeca- 9,12-dienoate), 5b was made using the same procedure for the synthesis of 5-formyl-6- hydroxyundecane-1,11-diyl dioleate, 5a. 1 H NMR (400 MHz, CDCl 3 ) δ 9.78 (dd, J = 7.0, 2.3 Hz, 1H), 5.47 – 5.24 (m, 8H), 4.09 (td, J = 6.6, 3.0 Hz, 4H), 3.86 (t, J = 6.1 Hz, 1H), 2.79 (t, J = 6.4 Hz, 4H), 2.31 (t, J = 7.5 Hz, 4H), 2.06 (dd, J = 7.9, 5.9 Hz, 9H), 1.74 – 1.60 (m, 10H), 1.48 – 1.16 (m, 36H), 0.91 (t, J = 6.8 Hz, 6H). [00409] Synthesis of 6-hydroxyhexyl palmitate, 3c: 6-hydroxyhexyl palmitate 3c (octadecanoic acid) was made using the same procedure for the synthesis of 6-hydroxyhexyl oleate, 3a above. 1 H NMR (500 MHz, CDCl3) δ 4.09 (t, J = 6.7 Hz, 2H), 3.67 (q, J = 6.2 Hz, 2H), 2.31 (t, J = 7.6 Hz, 2H), 1.64 (tp, J = 21.2, 6.7 Hz, 7H), 1.48 – 1.36 (m, J = 3.6, 3.0 Hz, 4H), 1.36 – 1.20 (m, 22H), 0.90 (t, J = 6.9 Hz, 3H). [00410] Synthesis of 6-oxohexyl palmitate, 4c: 6-oxohexyl palmitate 4c was made using the same procedure for the synthesis of 6-oxohexyl oleate, 4a above. 1 H NMR (500 MHz, CDCl 3 ) δ 9.79 (s, 1H), 4.09 (t, J = 6.6 Hz, 2H), 2.48 (td, J = 7.3, 1.7 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 1.75 – 1.53 (m, 7H), 1.28 (s, 24H), 0.90 (t, J = 6.9 Hz, 3H). [00411] Synthesis of 5-formyl-6-hydroxyundecane-1,11-diyl dipalmitate, 5c: 5-formyl-6- hydroxyundecane-1,11-diyl dipalmitate, 5c was made using the same procedure for the synthesis of 5-formyl-6-hydroxyundecane-1,11-diyl dioleate, 5a. 1 H NMR (500 MHz, CDCl3) δ 9.79 (s, 1H), 4.09 (qd, J = 6.7, 5.8, 2.4 Hz, 4H), 3.91 – 3.78 (m, 1H), 2.31 (t, J = 7.6 Hz, 5H), 2.07 (d, J = 5.6 Hz, 2H), 1.91 – 1.75 (m, 3H), 1.75 – 1.49 (m, 16H), 1.46 – 1.21 (m, 43H), 0.90 (t, J = 6.9 Hz, 6H). [00412] Synthesis of 5-(((3-(1H-pyrazol-1-yl)propyl)(methyl)amino)methyl)-6- hydroxyundecane-1,11-diyl dioleate, IR-19-pyrazole: N-methyl-3-(1H-pyrazol-1-yl)propan- 1-amine (0.18g, 1.30 mmol) was added to a solution of 5-formyl-6-hydroxyundecane-1,11- diyl dioleate, 5a (0.5g, 0.66 mmol) in dichloromethane (100 ml) and left to stir under nitrogen at room temperature for 1 hr. Sodium triacetoxyborohydride (0.42g, 1.97 mmol) was then added and the reaction was left to stir at room temperature overnight. Solvent was evaporated off, and the residue was purified by silica gel chromatography (10% methanol in dichloromethane with 0.1% NH4OH) to give IR-19-Pyrazole as a colorless oil (0.37g, 0.42 mmol, 63%). QTOF MS (ESI): m/z calcd for C 55 H 102 N 3 O 5 + (M+H), 884.78140; found,884.7847. 1 H NMR (400 MHz, CDCl 3 ) δ 7.52 (d, J = 1.8 Hz, 1H), 7.45 (dd, J = 5.6, 2.3 Hz, 1H), 6.24 (t, J = 2.0 Hz, 1H), 5.42 – 5.31 (m, 4H), 4.24 – 4.12 (m, 2H), 4.07 (q, J = 7.1 Hz, 4H), 3.52 (t, J = 8.3 Hz, 1H), 2.76 – 2.38 (m, 3H), 2.37 – 2.18 (m, 8H), 2.17 – 1.92 (m, 11H), 1.62 (tdd, J = 14.3, 12.1, 10.1, 5.0 Hz, 10H), 1.48 – 1.20 (m, 46H), 1.14 – 1.00 (m, 1H), 0.94 – 0.83 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 173.98, 173.91, 173.89, 139.42, 130.02, 129.99, 129.76, 129.71, 105.22, 64.39, 63.97, 63.93, 63.59, 60.39, 59.87, 54.89, 49.52, 49.46, 41.92, 41.86, 39.41, 39.22, 35.24, 34.37, 34.33, 31.90, 29.76, 29.70, 29.52, 29.32, 29.30, 29.19, 29.15, 29.12, 29.04, 28.86, 28.81, 27.22, 27.17, 26.23, 26.20, 24.99, 22.68, 14.12. [00413] Synthesis of 5-(((3-(dibutylamino) propyl) amino) methyl)-6-hydroxyundecane-1,11- diyl (9Z,9'Z,12Z,12'Z)-bis(octadeca-9,12-dienoate) IR-117-17: N 1 , N 1 -dibutylpropane-1,3- diamine (0.1g, 0.0.54 mmol) was added to a solution of 5-formyl-6-hydroxyundecane-1,11- diyl (9Z,9'Z,12Z,12'Z)-bis(octadeca-9,12-dienoate), 5b (0.21g, 0.28 mmol) in dichloromethane (50 ml) and left to stir under nitrogen at room temperature for 1 hr. Sodium triacetoxyborohydride (0.18g, 0.84 mmol) was then added and the reaction was left to stir at room temperature overnight. Solvent was evaporated off, and the residue was purified by silica gel chromatography (10% methanol in dichloromethane with 0.1% NH 4 OH) to give 5- (((3-(dibutylamino) propyl) amino) methyl)-6-hydroxyundecane-1,11-diyl (9Z,9'Z,12Z,12'Z)- bis(octadeca-9,12-dienoate), IR-117-17 as a light brown oil (0.16g, 0.17 mmol, 61%). QTOF MS (ESI): m/z calcd for C 59 H 111 N 2 O 5 + (M+H), 927.84875; found, 927.8491. 1 H NMR (500 MHz, CDCl 3 ) δ 5.45 – 5.29 (m, 8H), 4.08 (t, J = 6.7 Hz, 4H), 3.75 (dt, J = 9.5, 2.9 Hz, 1H), 3.56 (td, J = 7.6, 2.8 Hz, 1H), 2.96 – 2.86 (m, 1H), 2.79 (t, J = 6.7 Hz, 4H), 2.76 – 2.59 (m, 3H), 2.55 – 2.36 (m, 6H), 2.31 (td, J = 7.6, 2.2 Hz, 4H), 2.07 (q, J = 7.0 Hz, 8H), 1.80 – 1.58 (m, 12H), 1.51 – 1.15 (m, 46H), 0.93 (dq, J = 11.3, 8.0, 7.0 Hz, 12H). 13 C NMR (126 MHz, CDCl3) δ 173.97, 173.91, 130.23, 130.22, 130.07, 130.03, 128.07, 128.04, 127.92, 127.90, 75.95, 64.41, 64.39, 64.05, 64.03, 53.76, 53.73, 52.84, 52.78, 49.54, 49.30, 42.00, 41.80, 36.11, 34.38, 34.34, 32.90, 31.53, 31.51, 31.50, 29.65, 29.62, 29.35, 29.21, 29.20, 29.16, 29.13, 29.08, 29.04, 28.97, 28.81, 28.79, 27.24, 27.21, 26.81, 26.36, 26.22, 26.20, 25.67, 25.66, 25.64, 25.34, 25.00, 24.12, 23.54, 22.58, 20.72, 14.11, 14.08, 14.06. References: 1. Kowalski, P. S., Rudra, A., Miao, L. & Anderson, D. G. Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery. Mol. Ther.27, 710–728 (2019). 2. Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater.2, 1–17 (2017). 3. Han, X. et al. An ionizable lipid toolbox for RNA delivery. Nat. Commun.12, 7233 (2021). 4. Qiu, M. et al. Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single- guide RNA achieves liver-specific in vivo genome editing of Angptl3. Proc. Natl. Acad. Sci. 118, (2021). 5. Swingle, K. L., Hamilton, A. G. & Mitchell, M. J. Lipid Nanoparticle-Mediated Delivery of mRNA Therapeutics and Vaccines. Trends Mol. Med.27, 616–617 (2021). 6. Miao, L. et al. Delivery of mRNA vaccines with heterocyclic lipids increases anti- tumor efficacy by STING-mediated immune cell activation. Nat. Biotechnol.37, 1174–1185 (2019). 7. Zhang, X. et al. Functionalized lipid-like nanoparticles for in vivo mRNA delivery and base editing. Sci. Adv.6, eabc2315. 8. Billingsley, M. M. et al. Ionizable Lipid Nanoparticle-Mediated mRNA Delivery for Human CAR T Cell Engineering. Nano Lett.20, 1578–1589 (2020). 9. Riley, R. S. et al. Ionizable lipid nanoparticles for in utero mRNA delivery. Sci. Adv. 7, eaba1028. 10. Sabnis, S. et al. A Novel Amino Lipid Series for mRNA Delivery: Improved Endosomal Escape and Sustained Pharmacology and Safety in Non-human Primates. Mol. Ther.26, 1509–1519 (2018). 11. Fenton, O. S. et al. Synthesis and Biological Evaluation of Ionizable Lipid Materials for the In Vivo Delivery of Messenger RNA to B Lymphocytes. Adv. Mater.29, 1606944 (2017). 12. Liu, J. et al. Fast and Efficient CRISPR/Cas9 Genome Editing In Vivo Enabled by Bioreducible Lipid and Messenger RNA Nanoparticles. Adv. Mater.31, 1902575 (2019). 13. Polack, F. P. et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N. Engl. J. Med.383, 2603–2615 (2020). 14. Baden, L. R. et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N. Engl. J. Med.384, 403–416 (2021). 15. Gillmore, J. D. et al. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. N. Engl. J. Med.385, 493–502 (2021). 16. Cornebise, M. et al. Discovery of a Novel Amino Lipid That Improves Lipid Nanoparticle Performance through Specific Interactions with mRNA. Adv. Funct. Mater. n/a, 2106727. 17. Barbier, A. J., Jiang, A. Y., Zhang, P., Wooster, R. & Anderson, D. G. The clinical progress of mRNA vaccines and immunotherapies. Nat. Biotechnol.40, 840–854 (2022). 18. Chakraborty, C., Sharma, A. R., Bhattacharya, M. & Lee, S.-S. From COVID-19 to Cancer mRNA Vaccines: Moving From Bench to Clinic in the Vaccine Landscape. Front. Immunol.12, 2648 (2021). 19. Cafri, G. et al. mRNA vaccine–induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J. Clin. Invest.130, 5976–5988 (2020). 20. Oberli, M. A. et al. Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy. Nano Lett.17, 1326–1335 (2017). 21. Espeseth, A. S. et al. Modified mRNA/lipid nanoparticle-based vaccines expressing respiratory syncytial virus F protein variants are immunogenic and protective in rodent models of RSV infection. Npj Vaccines 5, 1–14 (2020). 22. Aliprantis, A. O. et al. A phase 1, randomized, placebo-controlled study to evaluate the safety and immunogenicity of an mRNA-based RSV prefusion F protein vaccine in healthy younger and older adults. Hum. Vaccines Immunother.17, 1248–1261 (2021). 23. Bahl, K. et al. Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses. Mol. Ther.25, 1316–1327 (2017). 24. Feldman, R. A. et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 37, 3326–3334 (2019). 25. John, S. et al. Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity. Vaccine 36, 1689–1699 (2018). 26. Medina-Magües, L. G. et al. mRNA Vaccine Protects against Zika Virus. Vaccines 9, 1464 (2021). 27. Mu, Z., Haynes, B. F. & Cain, D. W. HIV mRNA Vaccines—Progress and Future Paths. Vaccines 9, 134 (2021). 28. Zabaleta, N., Torella, L., Weber, N. D. & Gonzalez-Aseguinolaza, G. mRNA and gene editing: Late breaking therapies in liver diseases. Hepatology n/a,. 29. Robinson, E. et al. Lipid Nanoparticle-Delivered Chemically Modified mRNA Restores Chloride Secretion in Cystic Fibrosis. Mol. Ther.26, 2034–2046 (2018). 30. Da Silva Sanchez, A., Paunovska, K., Cristian, A. & Dahlman, J. E. Treating Cystic Fibrosis with mRNA and CRISPR. Hum. Gene Ther.31, 940–955 (2020). 31. Lai, M. et al. Gene editing of DNAH11 restores normal cilia motility in primary ciliary dyskinesia. J. Med. Genet.53, 242–249 (2016). 32. Paff, T., Omran, H., Nielsen, K. G. & Haarman, E. G. Current and Future Treatments in Primary Ciliary Dyskinesia. Int. J. Mol. Sci.22, 9834 (2021). 33. Guan, S., Darmstädter, M., Xu, C. & Rosenecker, J. In Vitro Investigations on Optimizing and Nebulization of IVT-mRNA Formulations for Potential Pulmonary-Based Alpha-1-Antitrypsin Deficiency Treatment. Pharmaceutics 13, 1281 (2021). 34. Zeyer, F. et al. mRNA-Mediated Gene Supplementation of Toll-Like Receptors as Treatment Strategy for Asthma In Vivo. PLOS ONE 11, e0154001 (2016). 35. Mays, L. E. et al. Modified Foxp3 mRNA protects against asthma through an IL-10– dependent mechanism. J. Clin. Invest.123, 1216–1228 (2013). 36. Rakhra, K. et al. Exploiting albumin as a mucosal vaccine chaperone for robust generation of lung-resident memory T cells. Sci. Immunol.6, eabd8003 (2021). 37. Bivas-Benita, M. et al. Pulmonary delivery of chitosan-DNA nanoparticles enhances the immunogenicity of a DNA vaccine encoding HLA-A*0201-restricted T-cell epitopes of Mycobacterium tuberculosis. Vaccine 22, 1609–1615 (2004). 38. Rajapaksa, A. E. et al. Effective pulmonary delivery of an aerosolized plasmid DNA vaccine via surface acoustic wave nebulization. Respir. Res.15, 60 (2014). 39. Wu, M. et al. Intranasal Vaccination with Mannosylated Chitosan Formulated DNA Vaccine Enables Robust IgA and Cellular Response Induction in the Lungs of Mice and Improves Protection against Pulmonary Mycobacterial Challenge. Front. Cell. Infect. Microbiol.7, 445 (2017). 40. King, R. G. et al. Single-Dose Intranasal Administration of AdCOVID Elicits Systemic and Mucosal Immunity against SARS-CoV-2 and Fully Protects Mice from Lethal Challenge. Vaccines 9, 881 (2021). 41. An, X. et al. Single-dose intranasal vaccination elicits systemic and mucosal immunity against SARS-CoV-2. iScience 24, 103037 (2021). 42. Kim, Y. C. et al. Strategy to Enhance Dendritic Cell-Mediated DNA Vaccination in the Lung. Adv. Ther.3, 2000013 (2020). 43. Lu, D. & Hickey, A. J. Pulmonary vaccine delivery. Expert Rev. Vaccines 6, 213–226 (2007). 44. Sou, T. et al. New developments in dry powder pulmonary vaccine delivery. Trends Biotechnol.29, 191–198 (2011). 45. Huang, J. et al. A novel dry powder influenza vaccine and intranasal delivery technology: induction of systemic and mucosal immune responses in rats. Vaccine 23, 794– 801 (2004). 46. Minne, A. et al. The delivery site of a monovalent influenza vaccine within the respiratory tract impacts on the immune response. Immunology 122, 316–325 (2007). 47. Wang, Z. et al. Exosomes decorated with a recombinant SARS-CoV-2 receptor- binding domain as an inhalable COVID-19 vaccine. Nat. Biomed. Eng.1–15 (2022) doi:10.1038/s41551-022-00902-5. 48. Cheng, Q. et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing. Nat. Nanotechnol.15, 313–320 (2020). 49. Kaczmarek, J. C. et al. Optimization of a Degradable Polymer–Lipid Nanoparticle for Potent Systemic Delivery of mRNA to the Lung Endothelium and Immune Cells. Nano Lett. 18, 6449–6454 (2018). 50. Kaczmarek, J. C. et al. Polymer–Lipid Nanoparticles for Systemic Delivery of mRNA to the Lungs. Angew. Chem. Int. Ed.55, 13808–13812 (2016). 51. Kaczmarek, J. C. et al. Systemic Delivery of mRNA and DNA to the Lung using Polymer-Lipid Nanoparticles. Biomaterials 120966 (2021) doi:10.1016/j.biomaterials.2021.120966. 52. Kim, N., Duncan, G. A., Hanes, J. & Suk, J. S. Barriers to inhaled gene therapy of obstructive lung diseases: A review. J. Controlled Release 240, 465–488 (2016). 53. Patel, A. K. et al. Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium. Adv. Mater.31, 1805116 (2019). 54. Lokugamage, M. P. et al. Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs. Nat. Biomed. Eng.5, 1059–1068 (2021). 55. Wilson, C. Future therapies for cystic fibrosis. Lancet Respir. Med.0, (2022). 56. Witten, J., Samad, T. & Ribbeck, K. Selective permeability of mucus barriers. Curr. Opin. Biotechnol.52, 124–133 (2018). 57. Witten, J. & Ribbeck, K. The particle in the spider’s web: transport through biological hydrogels. Nanoscale 9, 8080–8095 (2017). 58. Cone, R. A. Barrier properties of mucus. Adv. Drug Deliv. Rev.61, 75–85 (2009). 59. Lieleg, O. & Ribbeck, K. Biological hydrogels as selective diffusion barriers. Trends Cell Biol.21, 543–551 (2011). 60. Coyne, C. B., Kelly, M. M., Boucher, R. C. & Johnson, L. G. Enhanced Epithelial Gene Transfer by Modulation of Tight Junctions with Sodium Caprate. Am. J. Respir. Cell Mol. Biol.23, 602–609 (2000). 61. Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater.6, 1078–1094 (2021). 62. Andries, O. et al. Comparison of the Gene Transfer Efficiency of mRNA/GL67 and pDNA/GL67 Complexes in Respiratory Cells. Mol. Pharm.9, 2136–2145 (2012). 63. Paunovska, K. et al. A Direct Comparison of in Vitro and in Vivo Nucleic Acid Delivery Mediated by Hundreds of Nanoparticles Reveals a Weak Correlation. Nano Lett.18, 2148–2157 (2018). 64. Whitehead, K. A. et al. In Vitro–In Vivo Translation of Lipid Nanoparticles for Hepatocellular siRNA Delivery. ACS Nano 6, 6922–6929 (2012). 65. Hill, D. B. & Button, B. Establishment of Respiratory Air–Liquid Interface Cultures and Their Use in Studying Mucin Production, Secretion, and Function. in Mucins: Methods and Protocols (eds. McGuckin, M. A. & Thornton, D. J.) 245–258 (Humana Press, 2012). doi:10.1007/978-1-61779-513-8_15. 66. Ramachandran, S. et al. Efficient delivery of RNA interference oligonucleotides to polarized airway epithelia in vitro. Am. J. Physiol.-Lung Cell. Mol. Physiol.305, L23–L32 (2013). 67. Pezzulo, A. A. et al. The air-liquid interface and use of primary cell cultures are important to recapitulate the transcriptional profile of in vivo airway epithelia. Am. J. Physiol.-Lung Cell. Mol. Physiol.300, L25–L31 (2011). 68. Kauffman, K. J. et al. Optimization of Lipid Nanoparticle Formulations for mRNA Delivery in Vivo with Fractional Factorial and Definitive Screening Designs. Nano Lett.15, 7300–7306 (2015). 69. Billingsley, M. M. et al. Orthogonal Design of Experiments for Optimization of Lipid Nanoparticles for mRNA Engineering of CAR T Cells. Nano Lett.22, 533–542 (2022). 70. Kauffman, K. J. et al. Rapid, Single-Cell Analysis and Discovery of Vectored mRNA Transfection In Vivo with a loxP-Flanked tdTomato Reporter Mouse. Mol. Ther. - Nucleic Acids 10, 55–63 (2018). 71. Numata, M. et al. Phosphatidylglycerol provides short-term prophylaxis against respiratory syncytial virus infection. J. Lipid Res.54, 2133–2143 (2013). 72. Ball, R. L., Bajaj, P. & Whitehead, K. A. Achieving long-term stability of lipid nanoparticles: examining the effect of pH, temperature, and lyophilization. Int. J. Nanomedicine 12, 305–315 (2017). 73. Eastman, S. J. et al. Optimization of formulations and conditions for the aerosol delivery of functional cationic lipid:DNA complexes. Hum. Gene Ther.8, 313–322 (1997). 74. Krishnamurthy, S. et al. Manipulation of Cell Physiology Enables Gene Silencing in Well-differentiated Airway Epithelia. Mol. Ther. - Nucleic Acids 1, e41 (2012). 75. Burgel, P.-R., Montani, D., Danel, C., Dusser, D. J. & Nadel, J. A. A morphometric study of mucins and small airway plugging in cystic fibrosis. Thorax 62, 153–161 (2007). 76. Ratjen, F. Cystic Fibrosis: The Role of the Small Airways. J. Aerosol Med. Pulm. Drug Deliv.25, 261–264 (2012). 77. van den Berge, M., ten Hacken, N. H. T., Cohen, J., Douma, W. R. & Postma, D. S. Small Airway Disease in Asthma and COPD: Clinical Implications. Chest 139, 412–423 (2011). 78. Tiddens, H. A. W. M., Donaldson, S. H., Rosenfeld, M. & Paré, P. D. Cystic fibrosis lung disease starts in the small airways: Can we treat it more effectively? Pediatr. Pulmonol. 45, 107–117 (2010). 79. Tatsuta, M. et al. Effects of cigarette smoke on barrier function and tight junction proteins in the bronchial epithelium: protective role of cathelicidin LL-37. Respir. Res.20, 251 (2019). 80. Okuda, K. et al. Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia. Am. J. Respir. Crit. Care Med.203, 1275–1289 (2021). 81. Carraro, G. et al. Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition. Nat. Med.27, 806–814 (2021). 82. Montoro, D. T. et al. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature 560, 319 (2018). 83. Plasschaert, L. W. et al. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature 560, 377 (2018). 84. Hodges, C. A. & Conlon, R. A. Delivering on the promise of gene editing for cystic fibrosis. Genes Dis.6, 97–108 (2019). 85. Ryals, R. C. et al. The effects of PEGylation on LNP based mRNA delivery to the eye. PLOS ONE 15, e0241006 (2020). 86. Eltoukhy, A. A. et al. Effect of molecular weight of amine end-modified poly(β- amino ester)s on gene delivery efficiency and toxicity. Biomaterials 33, 3594–3603 (2012). 87. Chen, D. et al. Rapid Discovery of Potent siRNA-Containing Lipid Nanoparticles Enabled by Controlled Microfluidic Formulation. J. Am. Chem. Soc.134, 6948–6951 (2012). 88. Heyes, J., Palmer, L., Bremner, K. & MacLachlan, I. Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids. J. Control. Release Off. J. Control. Release Soc.107, 276–287 (2005). 89. Maier, M. A.; Jayaraman, M.; Matsuda, S.; Liu, J.; Barros, S.; Querbes, W.; Tam, Y. K.; Ansell, S. M.; Kumar, V.; Qin, J.; et al. Biodegradable Lipids Enabling Rapidly Eliminated Lipid Nanoparticles for Systemic Delivery of RNAi Therapeutics. Mol. Ther. 2013, 21 (8), 1570–1578. https://doi.org/https://doi.org/10.1038/mt.2013.124. 90 Reddy Guduru, S. K.; Chamakuri, S.; Raji, I. O.; MacKenzie, K. R.; Santini, C.; Young, D. W. Synthesis of Enantiomerically Pure 3-Substituted Piperazine-2-Acetic Acid Esters as Intermediates for Library Production. J. Org. Chem.2018, 83 (19). https://doi.org/10.1021/acs.joc.8b01708. 91 Han, Z.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. A Highly Effective Aldol Reaction Mediated by Ti(O-n-Bu)4/t-BuOK Combined Reagent. Tetrahedron Lett.2000, 41 (22), 4415–4418. https://doi.org/https://doi.org/10.1016/S0040-4039(00)00642- 0. 92 Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures1. J. Org. Chem.1996, 61 (11), 3849–3862. https://doi.org/10.1021/jo960057x. 93. Ghanem, R.; Laurent, V.; Roquefort, P.; Haute, T.; Ramel, S.; Le Gall, T.; Aubry, T.; Montier, T. Optimizations of In Vitro Mucus and Cell Culture Models to Better Predict In Vivo Gene Transfer in Pathological Lung Respiratory Airways: Cystic Fibrosis as an Example. Pharmaceutics .2021. https://doi.org/10.3390/pharmaceutics13010047. 94. Yin, H.; Song, C.-Q.; Suresh, S.; Wu, Q.; Walsh, S.; Rhym, L. H.; Mintzer, E.; Bolukbasi, M. F.; Zhu, L. J.; Kauffman, K.; et al. Structure-Guided Chemical Modification of Guide RNA Enables Potent Non-Viral in Vivo Genome Editing. Nat. Biotechnol.2017, 35 (12), 1179–1187. https://doi.org/10.1038/nbt.4005. EQUIVALENTS AND SCOPE [00414] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. [00415] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [00416] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art. [00417] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.
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