Lipid nanoparticle technology for therapeutic gene regulation in the liver

Williams, 2014, Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis, Lancet Lond. Engl., 384, 1953, 10.1016/S0140-6736(14)61838-9 Asrani, 2019, Burden of liver diseases in the world, J. Hepatol., 70, 151, 10.1016/j.jhep.2018.09.014 Crooke, 2018, RNA-targeted therapeutics, Cell Metab., 27, 714, 10.1016/j.cmet.2018.03.004 Springer, 2018, GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics, Nucleic Acid Ther., 28, 109, 10.1089/nat.2018.0736 Kulkarni, 2019, Lipid nanoparticle technology for clinical translation of siRNA therapeutics, Acc. Chem. Res., 52, 2435, 10.1021/acs.accounts.9b00368 Dunbar, 2018, Gene therapy comes of age, Science, 359, 10.1126/science.aan4672 Wang, 2019, Adeno-associated virus vector as a platform for gene therapy delivery, Nat. Rev. Drug Discov., 18, 358, 10.1038/s41573-019-0012-9 Pardi, 2018, mRNA vaccines-a new era in vaccinology, Nat. Rev. Drug Discov., 17, 261, 10.1038/nrd.2017.243 Sahin, 2018, Personalized vaccines for cancer immunotherapy, Science., 359, 1355, 10.1126/science.aar7112 Xu, 2019, Rational designs of in vivo CRISPR-Cas delivery systems, Adv. Drug Deliv. Rev., 10.1016/j.addr.2019.11.005 Wilbie, 2019, Delivery aspects of CRISPR/Cas for in vivo genome editing, Acc. Chem. Res., 52, 1555, 10.1021/acs.accounts.9b00106 Dowdy, 2017, Overcoming cellular barriers for RNA therapeutics, Nat. Biotechnol., 35, 222, 10.1038/nbt.3802 Barros, 2012, Safety profile of RNAi nanomedicines, Adv. Drug Deliv. Rev., 64, 1730, 10.1016/j.addr.2012.06.007 Wittrup, 2015, Knocking down disease: a progress report on siRNA therapeutics, Nat. Rev. Genet., 16, 543, 10.1038/nrg3978 Wang, 2015, Delivery of oligonucleotides with lipid nanoparticles, Adv. Drug Deliv. Rev., 87, 68, 10.1016/j.addr.2015.02.007 Allen, 2013, Liposomal drug delivery systems: from concept to clinical applications, Adv. Drug Deliv. Rev., 65, 36, 10.1016/j.addr.2012.09.037 Cullis, 2017, Lipid nanoparticle systems for enabling gene therapies, Mol. Ther., 25, 1467, 10.1016/j.ymthe.2017.03.013 Kulkarni, 2018, Lipid nanoparticles enabling gene therapies: from concepts to clinical utility, Nucleic Acid Ther., 28, 146, 10.1089/nat.2018.0721 Fire, 1998, Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans, Nature., 391, 806, 10.1038/35888 Elbashir, 2001, Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells, Nature., 411, 494, 10.1038/35078107 Dong, 2019, Strategies, design, and chemistry in siRNA delivery systems, Adv. Drug Deliv. Rev., 10.1016/j.addr.2019.05.004 Ku, 2016, Chemical and structural modifications of RNAi therapeutics, Adv. Drug Deliv. Rev., 104, 16, 10.1016/j.addr.2015.10.015 Mui, 2013, Influence of polyethylene glycol lipid desorption rates on pharmacokinetics and pharmacodynamics of siRNA lipid nanoparticles, Mol. Ther. Nucleic Acids., 2, 10.1038/mtna.2013.66 Kumar, 2014, Shielding of lipid nanoparticles for siRNA delivery: impact on physicochemical properties, cytokine induction, and efficacy, Mol. Ther. Nucleic Acids., 3, 10.1038/mtna.2014.61 Judge, 2006, Hypersensitivity and loss of disease site targeting caused by antibody responses to PEGylated liposomes, Mol. Ther., 13, 328, 10.1016/j.ymthe.2005.09.014 Heyes, 2006, Synthesis and characterization of novel poly(ethylene glycol)-lipid conjugates suitable for use in drug delivery, J. Control. Release., 112, 280, 10.1016/j.jconrel.2006.02.012 Kulkarni, 2019, On the role of helper lipids in lipid nanoparticle formulations of siRNA, Nanoscale., 11, 21733, 10.1039/C9NR09347H Kulkarni, 2017, Design of lipid nanoparticles for in vitro and in vivo delivery of plasmid DNA, Nanomed. Nanotechnol. Biol. Med., 13, 1377, 10.1016/j.nano.2016.12.014 Akinc, 2008, A combinatorial library of lipid-like materials for delivery of RNAi therapeutics, Nat. Biotechnol., 26, 561, 10.1038/nbt1402 Semple, 2010, Rational design of cationic lipids for siRNA delivery, Nat. Biotechnol., 28, 172, 10.1038/nbt.1602 Jayaraman, 2012, Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo, Angew. Chem. Int. Ed Engl., 51, 8529, 10.1002/anie.201203263 Adams, 2018, Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis, N. Engl. J. Med., 379, 11, 10.1056/NEJMoa1716153 Akinc, 2019, The Onpattro® story and the clinical translation of nanomedicines containing nucleic acid-based drugs, Nat. Nanotechnol., 14, 1084, 10.1038/s41565-019-0591-y Adams, 2019, Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease, Nat Rev Neurol., 15, 10.1038/s41582-019-0210-4 Maeki, 2018, Advances in microfluidics for lipid nanoparticles and extracellular vesicles and applications in drug delivery systems, Adv. Drug Deliv. Rev., 128, 84, 10.1016/j.addr.2018.03.008 Evers, 2018, State-of-the-Art design and rapid-mixing production techniques of lipid nanoparticles for nucleic acid delivery, Small Methods., 2, 1700375, 10.1002/smtd.201700375 Trefts, 2017, The liver, Curr. Biol., 27, R1147, 10.1016/j.cub.2017.09.019 Wang, 2014, The global burden of liver disease: the major impact of China, Hepatol. Baltim. Md., 60, 2099, 10.1002/hep.27406 Gissen, 2015, Structural and functional hepatocyte polarity and liver disease, J. Hepatol., 63, 1023, 10.1016/j.jhep.2015.06.015 Zhou, 2016, Hepatocytes: a key cell type for innate immunity, Cell. Mol. Immunol., 13, 301, 10.1038/cmi.2015.97 Zhang, 2016, Nanoparticle–liver interactions: cellular uptake and hepatobiliary elimination, J. Control. Release., 240, 332, 10.1016/j.jconrel.2016.01.020 Poon, 2019, Elimination pathways of nanoparticles, ACS Nano., 13, 5785, 10.1021/acsnano.9b01383 Sago, 2018, Modifying a commonly expressed endocytic receptor retargets nanoparticles in vivo, Nano Lett., 18, 7590, 10.1021/acs.nanolett.8b03149 Dolina, 2013, Lipidoid nanoparticles containing PD-L1 siRNA delivered in vivo enter kupffer Cells and enhance NK and CD8(+) T cell-mediated hepatic antiviral immunity, Mol. Ther. Nucleic Acids., 2, 10.1038/mtna.2012.63 S.A. MacParland, J.C. Liu, X.-Z. Ma, B.T. Innes, A.M. Bartczak, B.K. Gage, J. Manuel, N. Khuu, J. Echeverri, I. Linares, R. Gupta, M.L. Cheng, L.Y. Liu, D. Camat, S.W. Chung, R.K. Seliga, Z. Shao, E. Lee, S. Ogawa, M. Ogawa, M.D. Wilson, J.E. Fish, M. Selzner, A. Ghanekar, D. Grant, P. Greig, G. Sapisochin, N. Selzner, N. Winegarden, O. Adeyi, G. Keller, G.D. Bader, I.D. McGilvray, Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations, Nat. Commun. 9 (2018) 4383. https://doi.org/10.1038/s41467-018-06318-7. Aizarani, 2019, A human liver cell atlas reveals heterogeneity and epithelial progenitors, Nature, 572, 199, 10.1038/s41586-019-1373-2 Bertrand, 2012, The journey of a drug-carrier in the body: An anatomo-physiological perspective, J. Controlled Release., 161, 152, 10.1016/j.jconrel.2011.09.098 Mosby, 2020 Shi, 2011, Biodistribution of small interfering RNA at the organ and cellular levels after lipid nanoparticle-mediated delivery, J. Histochem. Cytochem. Off. J. Histochem. Soc., 59, 727, 10.1369/0022155411410885 Sago, 2019, Cell subtypes within the liver microenvironment differentially interact with lipid nanoparticles, Cell. Mol. Bioeng., 12, 389, 10.1007/s12195-019-00573-4 Hajj, 2020, A potent branched-tail lipid nanoparticle enables multiplexed mrna delivery and gene editing in vivo, Nano Lett., 10.1021/acs.nanolett.0c00596 Bilzer, 2006, Role of Kupffer cells in host defense and liver disease, Liver Int. Off. J. Int. Assoc. Study Liver., 26, 1175, 10.1111/j.1478-3231.2006.01342.x Vollmar, 2009, The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair, Physiol. Rev., 89, 1269, 10.1152/physrev.00027.2008 Wisse, 2008, The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer, Gene Ther., 15, 1193, 10.1038/gt.2008.60 Electron Miscroscopy Toth, 1992, Liver endocytosis and Kupffer cells, Hepatol. Baltim. Md., 16, 255, 10.1002/hep.1840160137 PrabhuDas, 2017, A consensus definitive classification of scavenger receptors and their roles in health and disease, J. Immunol., 198, 3775, 10.4049/jimmunol.1700373 Peiser, 2001, The function of scavenger receptorsexpressed by macrophages and their rolein the regulation of inflammation, Microbes Infect., 3, 149, 10.1016/S1286-4579(00)01362-9 Dobrovolskaia, 2008, Preclinical studies to understand nanoparticle interaction with the immune system and its potential effects on nanoparticle biodistribution, Mol. Pharm., 5, 487, 10.1021/mp800032f Aggarwal, 2009, Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy, Adv. Drug Deliv. Rev., 61, 428, 10.1016/j.addr.2009.03.009 Chen, 2019, The role of surface chemistry in serum protein corona-mediated cellular delivery and gene silencing with lipid nanoparticles, Nanoscale., 11, 8760, 10.1039/C8NR09855G Poisson, 2017, Liver sinusoidal endothelial cells: Physiology and role in liver diseases, J. Hepatol., 66, 212, 10.1016/j.jhep.2016.07.009 Wisse, 1970, An electron microscopic study of the fenestrated endothelial lining of rat liver sinusoids, J. Ultrastruct. Res., 31, 125, 10.1016/S0022-5320(70)90150-4 Braet, 2002, Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review, Comp. Hepatol., 1, 1, 10.1186/1476-5926-1-1 Wisse, 1985, The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of disse, Hepatology., 5, 683, 10.1002/hep.1840050427 Braet, 2003, Thirty-five years of liver sinusoidal cells: Eddie wisse in retirement, Hepatology., 38, 1056, 10.1002/hep.1840380434 Braet, 2009, Three-dimensional organization of fenestrae labyrinths in liver sinusoidal endothelial cells, Liver Int. Off. J. Int. Assoc. Study Liver., 29, 603, 10.1111/j.1478-3231.2008.01836.x Campbell, 2018, Directing Nanoparticle biodistribution through evasion and exploitation of stab2-dependent nanoparticle uptake, ACS Nano., 12, 2138, 10.1021/acsnano.7b06995 Charels, 1986, Influence of acute alcohol administration on endothelial fenestrae of rat livers: an in vivo and in vitro scanning electron microscopic study, Cells Hepatic Sinusoid., 1, 497 Snoeys, 2007, Species differences in transgene DNA uptake in hepatocytes after adenoviral transfer correlate with the size of endothelial fenestrae, Gene Ther., 14, 604, 10.1038/sj.gt.3302899 Blomhoff, 1991, Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis, FASEB J., 5, 271, 10.1096/fasebj.5.3.2001786 Koyama, 2017, Liver inflammation and fibrosis, J. Clin. Invest., 127, 55, 10.1172/JCI88881 Tsuchida, 2017, Mechanisms of hepatic stellate cell activation, Nat. Rev. Gastroenterol. Hepatol., 14, 397, 10.1038/nrgastro.2017.38 Hernandez-Gea, 2011, Pathogenesis of liver fibrosis, Annu. Rev. Pathol. Mech. Dis., 6, 425, 10.1146/annurev-pathol-011110-130246 Iredale, 2007, Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ, J. Clin. Invest., 117, 539, 10.1172/JCI30542 Akinc, 2010, Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms, Mol. Ther. J. Am. Soc. Gene Ther., 18, 1357, 10.1038/mt.2010.85 Witzigmann, 2020 Orphanet Kay, 2011, State-of-the-art gene-based therapies: the road ahead, Nat. Rev. Genet., 12, 316, 10.1038/nrg2971 High, 2011, Gene therapy for haemophilia: a long and winding road, J. Thromb. Haemost., 9, 2, 10.1111/j.1538-7836.2011.04369.x Fagiuoli, 2013, Monogenic diseases that can be cured by liver transplantation, J. Hepatol., 59, 595, 10.1016/j.jhep.2013.04.004 Bergmann, 2014, Late-onset ornithine transcarbamylase deficiency: treatment and outcome of hyperammonemic crisis, Pediatrics., 133, E1072, 10.1542/peds.2013-1324 Raal, 2012, Homozygous familial hypercholesterolemia: Current perspectives on diagnosis and treatment, Atherosclerosis., 223, 262, 10.1016/j.atherosclerosis.2012.02.019 Seidah, 2014, PCSK9: A key modulator of cardiovascular health, Circ. Res., 114, 1022, 10.1161/CIRCRESAHA.114.301621 Hawkins, 2015, Evolving landscape in the management of transthyretin amyloidosis, Ann. Med., 47, 625, 10.3109/07853890.2015.1068949 Suhr, 2015, Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study, Orphanet J. Rare Dis., 10, 109, 10.1186/s13023-015-0326-6 Bereczky, 2010, Protein C and protein S deficiencies: similarities and differences between two brothers playing in the same game, Clin. Chem. Lab. Med., 48, S53, 10.1515/CCLM.2010.369 Qi, 2013, Prevalence of inherited antithrombin, protein C, and protein S deficiencies in portal vein system thrombosis and Budd-Chiari syndrome: a systematic review and meta-analysis of observational studies, J. Gastroenterol. Hepatol., 28, 432, 10.1111/jgh.12085 Hoppe, 2012, An update on primary hyperoxaluria, Nat. Rev. Nephrol., 8, 467, 10.1038/nrneph.2012.113 Bosma, 2003, Inherited disorders of bilirubin metabolism, J. Hepatol., 38, 107, 10.1016/S0168-8278(02)00359-8 van Dijk, 2015, Gene replacement therapy for genetic hepatocellular jaundice, Clin. Rev. Allergy Immunol., 48, 243, 10.1007/s12016-014-8454-7 Flotte, 2011, Gene therapy for alpha-1 antitrypsin deficiency, Hum. Mol. Genet., 20, R87, 10.1093/hmg/ddr156 Stoller, 2012, A review of alpha(1)-antitrypsin deficiency, Am. J. Respir. Crit. Care Med., 185, 246, 10.1164/rccm.201108-1428CI Rosencrantz, 2011, Wilson disease: pathogenesis and clinical considerations in diagnosis and treatment, Semin. Liver Dis., 31, 245, 10.1055/s-0031-1286056 Purchase, 2013, The treatment of Wilson’s disease, a rare genetic disorder of copper metabolism, Sci. Prog., 96, 19, 10.3184/003685013X13587771579987 Nobili, 2010, Tyrosinemia type 1: metastatic hepatoblastoma with a favorable outcome, Pediatrics., 126, E235, 10.1542/peds.2009-1639 Kitagawa, 2012, Hepatorenal tyrosinemia, Proc. Jpn. Acad. Ser. B-Phys. Biol. Sci., 88, 192, 10.2183/pjab.88.192 Pietrangelo, 2010, Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment, Gastroenterology., 139, 393, 10.1053/j.gastro.2010.06.013 Babitt, 2011, The molecular pathogenesis of hereditary hemochromatosis, Semin. Liver Dis., 31, 280, 10.1055/s-0031-1286059 Ozen, 2007, Glycogen storage diseases: new perspectives, World J. Gastroenterol., 13, 2541, 10.3748/wjg.v13.i18.2541 Byrne, 2011, Pompe disease gene therapy, Hum. Mol. Genet., 20, R61, 10.1093/hmg/ddr174 El-Serag, 2007, Hepatocellular carcinoma: epidemiology and molecular carcinogenesis, Gastroenterology., 132, 2557, 10.1053/j.gastro.2007.04.061 El-Serag, 2011, Hepatocellular carcinoma, N. Engl. J. Med., 365, 1118, 10.1056/NEJMra1001683 Forner, 2012, Hepatocellular carcinoma, Lancet Lond. Engl., 379, 1245, 10.1016/S0140-6736(11)61347-0 Bouchard, 2011, Hepatitis B and C virus hepatocarcinogenesis: lessons learned and future challenges, Cancer Lett., 305, 123, 10.1016/j.canlet.2010.11.014 Chisari, 2010, Pathogenesis of hepatitis B virus infection, Pathol. Biol. (Paris)., 58, 258, 10.1016/j.patbio.2009.11.001 Liaw, 2009, Hepatitis B virus infection, Lancet Lond. Engl., 373, 582, 10.1016/S0140-6736(09)60207-5 Trépo, 2014, Hepatitis B virus infection, Lancet Lond. Engl., 384, 2053, 10.1016/S0140-6736(14)60220-8 Lavanchy, 2011, Evolving epidemiology of hepatitis C virus, Clin. Microbiol. Infect., 17, 107, 10.1111/j.1469-0691.2010.03432.x Gebhardt, 2014, Liver zonation: Novel aspects of its regulation and its impact on homeostasis, World J. Gastroenterol. WJG., 20, 8491, 10.3748/wjg.v20.i26.8491 Kietzmann, 2017, Metabolic zonation of the liver: the oxygen gradient revisited, Redox Biol., 11, 622, 10.1016/j.redox.2017.01.012 Jungermann, 1989, Functional specialization of different hepatocyte populations, Physiol. Rev., 69, 708, 10.1152/physrev.1989.69.3.708 Gebhardt, 1992, Metabolic zonation of the liver: regulation and implications for liver function, Pharmacol. Ther., 53, 275, 10.1016/0163-7258(92)90055-5 Bell, 2011, Inverse zonation of hepatocyte transduction with AAV vectors between mice and non-human primates, Mol. Genet. Metab., 104, 395, 10.1016/j.ymgme.2011.06.002 Baruteau, 2017, Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects, J. Inherit. Metab. Dis., 40, 497, 10.1007/s10545-017-0053-3 MacParland, 2017, Phenotype determines nanoparticle uptake by human macrophages from liver and blood, ACS Nano., 11, 2428, 10.1021/acsnano.6b06245 Guillot, 2019, Liver macrophages: old dogmas and new insights, Hepatol. Commun., 3, 730, 10.1002/hep4.1356 Sleyster, 1982, Relation between localization and function of rat liver Kupffer cells, Lab. Investig. J. Tech. Methods Pathol., 47, 484 Bartneck, 2014, Therapeutic targeting of liver inflammation and fibrosis by nanomedicine, Hepatobiliary Surg. Nutr., 3, 364 Shi, 2013, Expression of asialoglycoprotein receptor 1 in human hepatocellular carcinoma, J. Histochem. Cytochem. Off. J. Histochem. Soc., 61, 901, 10.1369/0022155413503662 Witzigmann, 2016, Variable asialoglycoprotein receptor 1 expression in liver disease: Implications for therapeutic intervention, Hepatol. Res., 46, 686, 10.1111/hepr.12599 Niemietz, 2020, APOE polymorphism in ATTR amyloidosis patients treated with lipid nanoparticle siRNA, Amyloid., 27, 45, 10.1080/13506129.2019.1681392 van der Meel, 2019, Smart cancer nanomedicine, Nat. Nanotechnol., 14, 1007, 10.1038/s41565-019-0567-y Fraley, 1979, Entrapment of a bacterial plasmid in phospholipid vesicles: potential for gene transfer, Proc. Natl. Acad. Sci. U. S. A., 76, 3348, 10.1073/pnas.76.7.3348 Fraley, 1980, Introduction of liposome-encapsulated SV40 DNA into cells, J. Biol. Chem., 255, 10431, 10.1016/S0021-9258(19)70482-7 Guo, 2019, Transfection reagent Lipofectamine triggers type I interferon signaling activation in macrophages, Immunol. Cell Biol., 97, 92, 10.1111/imcb.12194 Gruner, 1985, Lipid polymorphism:the molecular basis of nonbilayer phases, Annu. Rev. Biophys. Biophys. Chem., 14, 211, 10.1146/annurev.bb.14.060185.001235 Heyes, 2005, Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids, J. Control. Release Off. J. Control. Release Soc., 107, 276, 10.1016/j.jconrel.2005.06.014 Lin, 2013, Influence of cationic lipid composition on uptake and intracellular processing of lipid nanoparticle formulations of siRNA, Nanomedicine Nanotechnol. Biol. Med., 9, 233, 10.1016/j.nano.2012.05.019 Maier, 2013, Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics, Mol. Ther., 21, 1570, 10.1038/mt.2013.124 Shirazi, 2011, Synthesis and characterization of degradable multivalent cationic lipids with disulfide-bond spacers for gene delivery, Biochim. Biophys. Acta., 1808, 2156, 10.1016/j.bbamem.2011.04.020 Akita, 2015, Molecular tuning of a vitamin E-scaffold pH-sensitive and reductive cleavable lipid-like material for accelerated in vivo hepatic siRNA delivery, ACS Biomater. Sci. Eng., 1, 834, 10.1021/acsbiomaterials.5b00203 Zimmermann, 2006, RNAi-mediated gene silencing in non-human primates, Nature., 441, 111, 10.1038/nature04688 Dong, 2014, Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates, Proc. Natl. Acad. Sci. U. S. A, 111, 3955, 10.1073/pnas.1322937111 Li, 2015, An orthogonal array optimization of lipid-like nanoparticles for mRNA delivery in vivo, Nano Lett., 15, 8099, 10.1021/acs.nanolett.5b03528 Akita, 2015, A neutral lipid envelope-type nanoparticle composed of a pH-activated and vitamin E-scaffold lipid-like material as a platform for a gene carrier targeting renal cell carcinoma, J. Control. Release Off. J. Control. Release Soc., 200, 97, 10.1016/j.jconrel.2014.12.029 Conway, 2019, Non-viral delivery of zinc finger nuclease mRNA enables highly efficient in vivo genome editing of multiple therapeutic gene targets, Mol. Ther. J. Am. Soc. Gene Ther., 27, 866, 10.1016/j.ymthe.2019.03.003 Sabnis, 2018, A novel amino lipid series for mrna delivery: improved endosomal escape and sustained pharmacology and safety in non-human primates, Mol. Ther. J. Am. Soc. Gene Ther., 26, 1509, 10.1016/j.ymthe.2018.03.010 Cheng, 2016, The role of helper lipids in lipid nanoparticles (LNPs) designed for oligonucleotide delivery, Adv. Drug Deliv. Rev., 99, 129, 10.1016/j.addr.2016.01.022 Rodrigueza, 1995, Transbilayer movement and net flux of cholesterol and cholesterol sulfate between liposomal membranes, Biochemistry., 34, 6208, 10.1021/bi00018a025 Sato, 2020, Hydrophobic scaffolds of pH-sensitive cationic lipids contribute to miscibility with phospholipids and improve the efficiency of delivering short interfering RNA by small-sized lipid nanoparticles, Acta Biomater., 102, 341, 10.1016/j.actbio.2019.11.022 Kauffman, 2015, Optimization of lipid nanoparticle formulations for mRNA delivery in vivo with fractional factorial and definitive screening designs, Nano Lett., 15, 7300, 10.1021/acs.nanolett.5b02497 Paunovska, 2019, Nanoparticles containing oxidized cholesterol deliver mRNA to the liver microenvironment at clinically relevant doses, Adv. Mater. Deerfield Beach Fla., 31 De Rijke, 1994, Binding characteristics of scavenger receptors on liver endothelial and Kupffer cells for modified low-density lipoproteins, Biochem. J., 304, 69, 10.1042/bj3040069 Gillotte-Taylor, 2001, Scavenger receptor class B type I as a receptor for oxidized low density lipoprotein, J. Lipid Res., 42, 1474, 10.1016/S0022-2275(20)30281-9 Belliveau, 2012, Microfluidic synthesis of highly potent limit-size lipid nanoparticles for in vivo delivery of siRNA, Mol. Ther. Nucleic Acids., 1, 10.1038/mtna.2012.28 Chen, 2014, Development of lipid nanoparticle formulations of siRNA for hepatocyte gene silencing following subcutaneous administration, J Control Release., 196, 106, 10.1016/j.jconrel.2014.09.025 Dahlman, 2017, Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics, Proc. Natl. Acad. Sci. U. S. A., 114, 2060, 10.1073/pnas.1620874114 Sieber, 2019, Zebrafish as a predictive screening model to assess macrophage clearance of liposomes in vivo, Nanomed. Nanotechnol. Biol. Med., 17, 82, 10.1016/j.nano.2018.11.017 Holland, 1996, Poly(ethylene glycol)--lipid conjugates regulate the calcium-induced fusion of liposomes composed of phosphatidylethanolamine and phosphatidylserine, Biochemistry., 35, 2618, 10.1021/bi952000v Harvie, 2000, Use of poly(ethylene glycol)–lipid conjugates to regulate the surface attributes and transfection activity of lipid–DNA particles, J. Pharm. Sci., 89, 652, 10.1002/(SICI)1520-6017(200005)89:5<652::AID-JPS11>3.0.CO;2-H Hafez, 2001, On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids, Gene Ther., 8, 1188, 10.1038/sj.gt.3301506 Chen, 2016, Influence of particle size on the in vivo potency of lipid nanoparticle formulations of siRNA, J. Control. Release Off. J. Control. Release Soc., 235, 236, 10.1016/j.jconrel.2016.05.059 Jeffs, 2005, A scalable, extrusion-free method for efficient liposomal encapsulation of plasmid DNA, Pharm. Res., 22, 362, 10.1007/s11095-004-1873-z Batzri, 1973, Single bilayer liposomes prepared without sonication, Biochim. Biophys. Acta., 298, 1015, 10.1016/0005-2736(73)90408-2 Hirota, 1999, Simple mixing device to reproducibly prepare cationic lipid-DNA complexes (lipoplexes), BioTechniques., 27, 286, 10.2144/99272bm16 Kulkarni, 2018, On the formation and morphology of lipid nanoparticles containing ionizable cationic lipids and siRNA, ACS Nano., 12, 4787, 10.1021/acsnano.8b01516 Kulkarni, 2017, Rapid synthesis of lipid nanoparticles containing hydrophobic inorganic nanoparticles, Nanoscale., 9, 13600, 10.1039/C7NR03272B Sato, 2016, Relationship between the physicochemical properties of lipid nanoparticles and the quality of siRNA delivery to liver cells, Mol. Ther., 24, 788, 10.1038/mt.2015.222 Shobaki, 2018, Mixing lipids to manipulate the ionization status of lipid nanoparticles for specific tissue targeting, Int. J. Nanomedicine., 13, 8395, 10.2147/IJN.S188016 Yu, 2004, Endothelial lipase is synthesized by hepatic and aorta endothelial cells and its expression is altered in apoE-deficient mice, J. Lipid Res., 45, 1614, 10.1194/jlr.M400069-JLR200 Monopoli, 2012, Biomolecular coronas provide the biological identity of nanosized materials, Nat. Nanotechnol., 7, 779, 10.1038/nnano.2012.207 Francia, 2019, Corona composition can affect the mechanisms cells use to internalize nanoparticles, ACS Nano., 13, 11107, 10.1021/acsnano.9b03824 Albanese, 2014, Secreted biomolecules alter the biological identity and cellular interactions of nanoparticles, ACS Nano., 8, 5515, 10.1021/nn4061012 Miao, 2020, Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver, Nat. Commun., 11, 2424, 10.1038/s41467-020-16248-y Kawabata, 1995, The fate of plasmid DNA after intravenous injection in mice: involvement of scavenger receptors in its hepatic uptake, Pharm. Res., 12, 825, 10.1023/A:1016248701505 Maurer, 2001, Spontaneous entrapment of polynucleotides upon electrostatic interaction with ethanol-destabilized cationic liposomes, Biophys. J., 80, 2310, 10.1016/S0006-3495(01)76202-9 Main Buck, 2019, Lipid-based DNA therapeutics: hallmarks of non-viral gene delivery, ACS Nano., 13, 3754, 10.1021/acsnano.8b07858 Wheeler, 1999, Stabilized plasmid-lipid particles: construction and characterization, Gene Ther., 6, 271, 10.1038/sj.gt.3300821 Tam, 2000, Stabilized plasmid-lipid particles for systemic gene therapy, Gene Ther., 7, 1867, 10.1038/sj.gt.3301308 Aronsohn, 1998, Nuclear localization signal peptides enhance cationic liposome-mediated gene therapy, J. Drug Target., 5, 163, 10.3109/10611869808995871 Khalil, 2018, Synergism between a cell penetrating peptide and a pH-sensitive cationic lipid in efficient gene delivery based on double-coated nanoparticles, J. Control. Release Off. J. Control. Release Soc., 275, 107, 10.1016/j.jconrel.2018.02.016 Akita, 2011, Improving in vivo hepatic transfection activity by controlling intracellular trafficking: the function of GALA and maltotriose, Mol. Pharm., 8, 1436, 10.1021/mp200189s Yaari, 2016, Theranostic barcoded nanoparticles for personalized cancer medicine, Nat. Commun., 7, 10.1038/ncomms13325 Wang, 2015, Delivery of oligonucleotides with lipid nanoparticles, Adv, Drug Deliv Rev., 87, 68, 10.1016/j.addr.2015.02.007 Goodwin, 2017, Liver specific gene immunotherapies resolve immune suppressive ectopic lymphoid structures of liver metastases and prolong survival, Biomaterials., 141, 260, 10.1016/j.biomaterials.2017.07.007 Hu, 2019, Relaxin gene delivery mitigates liver metastasis and synergizes with check point therapy, Nat. Commun., 10, 2993, 10.1038/s41467-019-10893-8 O. of the Commissioner Foster, 2018, Advanced siRNA designs further improve in vivo performance of GalNAc-siRNA conjugates, Mol. Ther., 26, 708, 10.1016/j.ymthe.2017.12.021 Thi, 2015, Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates, Nature., 521, 362, 10.1038/nature14442 Sato, 2017, Highly specific delivery of siRNA to hepatocytes circumvents endothelial cell-mediated lipid nanoparticle-associated toxicity leading to the safe and efficacious decrease in the hepatitis B virus, J. Control. Release Off. J. Control. Release Soc., 266, 216, 10.1016/j.jconrel.2017.09.044 Ye, 2019, Hepatitis B virus therapeutic agent ARB-1740 Has inhibitory effect on hepatitis delta virus in a new dually-infected humanized mouse model, ACS Infect. Dis., 5, 738, 10.1021/acsinfecdis.8b00192 Moon, 2016, Inhibition of hepatitis C virus in mouse models by lipidoid nanoparticle-mediated systemic delivery of siRNA against PRK2, Nanomed. Nanotechnol. Biol. Med., 12, 1489, 10.1016/j.nano.2016.02.015 Semple, 2011, Abstract 2829: preclinical characterization of TKM-080301, a lipid nanoparticle formulation of a small interfering RNA directed against polo-like kinase 1, Cancer Res., 71, 2829, 10.1158/1538-7445.AM2011-2829 Doan, 2014, Simultaneous silencing of VEGF and KSP by siRNA cocktail inhibits proliferation and induces apoptosis of hepatocellular carcinoma Hep3B cells, Biol. Res., 47, 70, 10.1186/0717-6287-47-70 Zhou, 2016, Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model, Proc. Natl. Acad. Sci., 113, 520, 10.1073/pnas.1520756113 Frank-Kamenetsky, 2008, Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates, Proc. Natl. Acad. Sci. U. S. A, 105, 11915, 10.1073/pnas.0805434105 Jørgensen, 2014, Loss-of-function mutations in APOC3 and risk of ischemic vascular disease, N. Engl. J. Med., 371, 32, 10.1056/NEJMoa1308027 Tikka, 2014, Silencing of ANGPTL 3 (angiopoietin-like protein 3) in human hepatocytes results in decreased expression of gluconeogenic genes and reduced triacylglycerol-rich VLDL secretion upon insulin stimulation, Biosci. Rep., 34, 10.1042/BSR20140115 Hou, 2007, Transthyretin and familial amyloidotic polyneuropathy. Recent progress in understanding the molecular mechanism of neurodegeneration, FEBS J., 274, 1637, 10.1111/j.1742-4658.2007.05712.x Butler, 2016, Preclinical evaluation of RNAi as a treatment for transthyretin-mediated amyloidosis, Amyloid Int. J. Exp. Clin. Investig. Off. J. Int. Soc. Amyloidosis., 23, 109, 10.3109/13506129.2016.1160882 Pardi, 2019, Characterization of HIV-1 nucleoside-modified mRNA vaccines in rabbits and rhesus macaques, Mol. Ther. Nucleic Acids., 15, 36, 10.1016/j.omtn.2019.03.003 Pardi, 2018, mRNA vaccines-a new era in vaccinology, Nat Rev Drug Discov., 17, 261, 10.1038/nrd.2017.243 Pardi, 2017, Nucleoside modified mRNA vaccines for infectious diseases, Methods Mol. Biol. Clifton NJ., 1499, 109, 10.1007/978-1-4939-6481-9_6 Pardi, 2018, Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies, Nat. Commun., 9, 3361, 10.1038/s41467-018-05482-0 Pardi, 2018, Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses, J. Exp. Med., 215, 1571, 10.1084/jem.20171450 Pardi, 2017, Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination, Nature, 543, 248, 10.1038/nature21428 Hassett, 2019, Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines, Mol. Ther. Nucleic Acids., 15, 1, 10.1016/j.omtn.2019.01.013 Reichmuth, 2016, mRNA vaccine delivery using lipid nanoparticles, Ther. Deliv., 7, 319, 10.4155/tde-2016-0006 Pardi, 2017, Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge, Nat Commun., 8, 14630, 10.1038/ncomms14630 Thran, 2017, mRNA mediates passive vaccination against infectious agents, toxins, and tumors, EMBO Mol. Med., 9, 1434, 10.15252/emmm.201707678 Thess, 2015, Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals, Mol. Ther. J. Am. Soc. Gene Ther., 23, 1456, 10.1038/mt.2015.103 DeRosa, 2016, Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system, Gene Ther., 23, 699, 10.1038/gt.2016.46 Yin, 2014, Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype, Nat. Biotechnol., 32, 551, 10.1038/nbt.2884 Finn, 2018, A single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing, Cell Rep., 22, 2227, 10.1016/j.celrep.2018.02.014 Cheng, 2020, Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing, Nat. Nanotechnol., 15, 313, 10.1038/s41565-020-0669-6 van der Meel, 2020, Nanotechnology for organ-tunable gene editing, Nat. Nanotechnol., 15, 253, 10.1038/s41565-020-0666-9 Rosigkeit, 2018, Monitoring translation activity of mRNA-loaded nanoparticles in mice, Mol. Pharm., 15, 3909, 10.1021/acs.molpharmaceut.8b00370 Liu, 2019, Fast and efficient CRISPR/Cas9 genome editing in vivo enabled by bioreducible lipid and messenger RNA nanoparticles, Adv. Mater., 31, 1902575, 10.1002/adma.201902575 Kowalski, 2019, Delivering the messenger: advances in technologies for therapeutic mRNA delivery, Mol. Ther., 27, 710, 10.1016/j.ymthe.2019.02.012 Trial to Evaluate Safety and Tolerability of ALN-TTR01 in Transthyretin (TTR) Coelho, 2013, Safety and efficacy of RNAi therapy for transthyretin amyloidosis, N. Engl. J. Med., 369, 819, 10.1056/NEJMoa1208760 Dyck, 2019, Development of measures of polyneuropathy impairment in hATTR amyloidosis: from NIS to mNIS + 7, J. Neurol. Sci., 405, 116424, 10.1016/j.jns.2019.116424 T.B. Inc An, 2019, Long-term efficacy and safety of mRNA therapy in two murine models of methylmalonic acidemia, EBioMedicine., 45, 519, 10.1016/j.ebiom.2019.07.003 Haussecker, 2014, Current issues of RNAi therapeutics delivery and development, J. Controlled Release., 195, 49, 10.1016/j.jconrel.2014.07.056 Szebeni, 2018, Mechanism of nanoparticle-induced hypersensitivity in pigs: complement or not complement?, Drug Discov. Today., 23, 487, 10.1016/j.drudis.2018.01.025 Szebeni, 2011, Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention, Adv. Drug Deliv. Rev., 63, 1020, 10.1016/j.addr.2011.06.017 Szebeni, 2012, Liposome-induced complement activation and related cardiopulmonary distress in pigs: factors promoting reactogenicity of Doxil and AmBisome, Nanomed. Nanotechnol. Biol. Med., 8, 176, 10.1016/j.nano.2011.06.003 Adams, 2017, Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy, BMC Neurol., 17, 181, 10.1186/s12883-017-0948-5 Adams, 2018, Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis, N Engl J Med., 379, 11, 10.1056/NEJMoa1716153 Tabernero, 2013, First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement, Cancer Discov., 3, 406, 10.1158/2159-8290.CD-12-0429 Eley, 2017, Pharmacokinetics and exploratory exposure-response of siRNAs administered monthly as ARB-001467 (ARB-1467) in a Phase 2a study in HBeAg positive and negative virally suppressed subjects with chronic hepatitis B, Hepatology, 66 Demeure, 2016, A phase I/II study of TKM-080301, a PLK1-targeted RNAi in patients with adrenocortical cancer (ACC), J. Clin. Oncol., 34, 2547, 10.1200/JCO.2016.34.15_suppl.2547 Schultheis, 2014, First-in-human phase I study of the liposomal RNA interference therapeutic Atu027 in patients with advanced solid tumors, J. Clin. Oncol., 32, 4141, 10.1200/JCO.2013.55.0376 Soule, 2018, Safety, tolerability, and pharmacokinetics of BMS-986263/ND-L02-s0201, a novel targeted lipid nanoparticle delivering HSP47 siRNA, in healthy participants: A randomised, placebo-controlled, double-blind, phase 1 study, J. Hepatol., 68, S112, 10.1016/S0168-8278(18)30442-2 Wagner, 2017, Preclinical mammalian safety studies of EPHARNA (DOPC Nanoliposomal EphA2-Targeted siRNA), Mol. Cancer Ther., 16, 1114, 10.1158/1535-7163.MCT-16-0541 Jabulowsky, 2018, Abstract CT156: A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles encoding shared tumor antigens for immunotherapy of malignant melanoma, Cancer Res., 78, 10.1158/1538-7445.AM2018-CT156 Pirollo, 2016, Safety and efficacy in advanced solid tumors of a targeted nanocomplex carrying the p53 gene used in combination with docetaxel: A phase 1b study, Mol. Ther., 24, 1697, 10.1038/mt.2016.135 Sarker, 2019, 455PDFirst-in-human, first-in-class phase I study of MTL-CEBPA, a RNA oligonucleotide targeting the myeloid cell master regulator C/EBP-α, in patients with advanced hepatocellular cancer (HCC), Ann. Oncol., 30, 10.1093/annonc/mdz244.017 Intellia Therapeutics Announces Second Quarter 2019 Financial Results and Company Update, Intellia Ther Fitzgerald, 2014, Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial, Lancet Lond. Engl., 383, 60, 10.1016/S0140-6736(13)61914-5 Benson, 2018, Inotersen treatment for patients with hereditary transthyretin amyloidosis, N. Engl. J. Med., 379, 22, 10.1056/NEJMoa1716793 Sardh, 2019, Phase 1 trial of an RNA interference therapy for acute intermittent porphyria, N. Engl. J. Med., 380, 549, 10.1056/NEJMoa1807838 Balwani, 2019, GS-14-ENVISION, a phase 3 study to evaluate efficacy and safety of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1, in acute hepatic porphyria patients, J. Hepatol., 70, e81, 10.1016/S0618-8278(19)30142-2 van’t Hoff, 2019, Sun-325 safety and efficacy of lumasiran, an investigational rna interference (RNAi) therapeutic, in adult and pediatric patients with primary hyperoxaluria type 1, Kidney Int. Rep., 4, S295, 10.1016/j.ekir.2019.05.734 Yaacov, 2019, Mp12-14safety and efficacy study of lumasiran, an investigational rna interference (rnai) therapeutic, in adult and pediatric patients with primary hyperoxaluria type 1 (ph1), J. Urol., 201 Iacobucci, 2020, Inclisiran: UK to roll out new cholesterol lowering drug from next year, BMJ, 368 Ray, 2017, Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol, N. Engl. J. Med., 376, 1430, 10.1056/NEJMoa1615758 Wright, 2020, Effects of renal impairment on the pharmacokinetics, efficacy, and safety of inclisiran: An analysis of the ORION-7 and ORION-1 studies, Mayo Clin. Proc., 95, 77, 10.1016/j.mayocp.2019.08.021 Adams, 2019, Phase 1 study of ALN-TTRsc02, a subcutaneously administered investigational RNAi therapeutic for the treatment of transthyretin-mediated amyloidosis, Rev. Neurol. (Paris), 175, 10.1016/j.neurol.2019.01.339 Basha, 2016, Lipid nanoparticle delivery of siRNA to osteocytes leads to effective silencing of SOST and inhibition of sclerostin in vivo, Mol. Ther. Nucleic Acids., 5, 10.1038/mtna.2016.68 Lee, 2016, A glu-urea-lys ligand-conjugated lipid nanoparticle/siRNA system inhibits androgen receptor expression in vivo, Mol. Ther. Nucleic Acids., 5, 10.1038/mtna.2016.43 Yamamoto, 2015, siRNA lipid nanoparticle potently silences clusterin and delays progression when combined with androgen receptor cotargeting in enzalutamide-resistant prostate cancer, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res., 21, 4845, 10.1158/1078-0432.CCR-15-0866 Ramishetti, 2015, Systemic gene silencing in primary T lymphocytes using targeted lipid nanoparticles, ACS Nano., 9, 6706, 10.1021/acsnano.5b02796 Weinstein, 2016, Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies, Proc. Natl. Acad. Sci. U. S. A., 113, E16, 10.1073/pnas.1519273113 Kedmi, 2018, A modular platform for targeted RNAi therapeutics, Nat. Nanotechnol., 13, 214, 10.1038/s41565-017-0043-5 Veiga, 2019, Leukocyte-specific siRNA delivery revealing IRF8 as a potential anti-inflammatory target, J. Control. Release Off. J. Control. Release Soc., 313, 33, 10.1016/j.jconrel.2019.10.001 Novobrantseva, 2012, Systemic RNAi-mediated gene silencing in nonhuman primate and rodent myeloid cells, Mol. Ther. Nucleic Acids., 1, 10.1038/mtna.2011.3 Veiga, 2020, Targeted lipid nanoparticles for RNA therapeutics and immunomodulation in leukocytes, Adv. Drug Deliv. Rev., 10.1016/j.addr.2020.04.002 Ramaswamy, 2017, Systemic delivery of factor IX messenger RNA for protein replacement therapy, Proc. Natl. Acad. Sci. U. S. A., 114, E1941, 10.1073/pnas.1619653114 Kose, 2019, A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against chikungunya infection, Sci. Immunol., 4, 10.1126/sciimmunol.aaw6647 Veiga, 2018, Cell specific delivery of modified mRNA expressing therapeutic proteins to leukocytes, Nat. Commun., 9, 4493, 10.1038/s41467-018-06936-1 Fenton, 2017, Synthesis and biological evaluation of ionizable lipid materials for the in vivo delivery of messenger RNA to B lymphocytes, Adv. Mater. Deerfield Beach Fla., 29 Oberli, 2017, Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy, Nano Lett., 17, 1326, 10.1021/acs.nanolett.6b03329 Kranz, 2016, Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy, Nature., 534, 396, 10.1038/nature18300 Billingsley, 2020, Ionizable lipid nanoparticle mediated mrna delivery for human CAR T cell engineering, Nano Lett., 10.1021/acs.nanolett.9b04246 Pardi, 2019, Characterization of HIV-1 nucleoside-modified mRNA vaccines in rabbits and rhesus macaques, Mol. Ther. Nucleic Acids., 15, 36, 10.1016/j.omtn.2019.03.003 Pardi, 2018, Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies, Nat. Commun., 9, 3361, 10.1038/s41467-018-05482-0 Pardi, 2018, Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses, J. Exp. Med., 215, 1571, 10.1084/jem.20171450 N. Pardi, M.J. Hogan, R.S. Pelc, H. Muramatsu, H. Andersen, C.R. DeMaso, K.A. Dowd, L.L. Sutherland, R.M. Scearce, R. Parks, W. Wagner, A. Granados, J. Greenhouse, M. Walker, E. Willis, J.-S. Yu, C.E. McGee, G.D. Sempowski, B.L. Mui, Y.K. Tam, Y.-J. Huang, D. Vanlandingham, V.M. Holmes, H. Balachandran, S. Sahu, M. Lifton, S. Higgs, S.E. Hensley, T.D. Madden, M.J. Hope, K. Karikó, S. Santra, B.S. Graham, M.G. Lewis, T.C. Pierson, B.F. Haynes, D. Weissman, Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination, Nature. 543 (2017) 248–251. doi:10.1038/nature21428. Pardi, 2015, Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes, J. Control. Release Off. J. Control. Release Soc., 217, 345, 10.1016/j.jconrel.2015.08.007 Feldman, 2019, 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, 10.1016/j.vaccine.2019.04.074 McKay, 2020, Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine induces equivalent preclinical antibody titers and viral neutralization to recovered COVID-19 patients, BioRxiv BioNTech and Pfizer announce completion of dosing for first cohort of Phase 1/2 trial of COVID-19 vaccine candidates in Germany CureVac´s Optimized mRNA Platform Provides Positive Pre-Clinical Results at Low Dose for Coronavirus Vaccine Candidate | English, CureVac. (2020). https%3A%2F%2Fwww.curevac.com%2Fnews%2Fcurevac-s-optimized-mrna-platform-provides-positive-pre-clinical-results-at-low-dose-for-coronavirus-vaccine-candidate (accessed June 4, 2020). Lutz, 2017, Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines, Npj Vaccines., 2, 1, 10.1038/s41541-017-0032-6 Nguyen, 2012, Lipid-derived nanoparticles for immunostimulatory RNA adjuvant delivery, Proc. Natl. Acad. Sci., 109, E797, 10.1073/pnas.1121423109 Chen, 2018, Dexamethasone prodrugs as potent suppressors of the immunostimulatory effects of lipid nanoparticle formulations of nucleic acids, J. Control. Release Off. J. Control. Release Soc., 286, 46, 10.1016/j.jconrel.2018.07.026 2020, bioRxiv Sahay, 2013, Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling, Nat. Biotechnol., 31, 653, 10.1038/nbt.2614 Patel, 2019, Brief update on endocytosis of nanomedicines, Adv. Drug Deliv. Rev., 144, 90, 10.1016/j.addr.2019.08.004 Patel, 2017, Boosting intracellular delivery of lipid nanoparticle-encapsulated mRNA, Nano Lett., 17, 5711, 10.1021/acs.nanolett.7b02664 Sayers, 2019, Endocytic profiling of cancer cell models reveals critical factors influencing LNP-mediated mRNA delivery and protein expression, Mol. Ther., 27, 1950, 10.1016/j.ymthe.2019.07.018 Böhmert, 2020, Isolation methods for particle protein corona complexes from protein-rich matrices, Nanoscale Adv., 2, 563, 10.1039/C9NA00537D Zhang, 2020, An analysis of the binding function and structural organization of the protein corona, J. Am. Chem. Soc., 142, 8827, 10.1021/jacs.0c01853