Hopkins, A. L. & Groom, C. R. The druggable genome. Nat. Rev. Drug. Discov. 1, 727–730 (2002).
Google Scholar
Roberts, T. C., Langer, R. & Wood, M. J. A. Advances in oligonucleotide drug delivery. Nat. Rev. Drug Discov. 19, 673–694 (2020).
Google Scholar
High, K. A. & Roncarolo, M. G. Gene therapy. N. Engl. J. Med. 381, 455–464 (2019).
Google Scholar
Pasi, K. J. et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N. Engl. J. Med. 382, 29–40 (2020).
Google Scholar
Mendell, J. R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377, 1713–1722 (2017).
Google Scholar
Frangoul, H. et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N. Engl. J. Med. 384, 252–260 (2021).
Google Scholar
Esrick, E. B. et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N. Engl. J. Med. 384, 205–215 (2021).
Google Scholar
Kohn, D. B. et al. Autologous ex vivo lentiviral gene therapy for adenosine deaminase deficiency. N. Engl. J. Med. 384, 2002–2013 (2021).
Google Scholar
Russell, S. et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 390, 849–860 (2017).
Google Scholar
Aronson, S. J. et al. Prevalence and relevance of pre-existing anti-adeno-associated virus immunity in the context of gene therapy for Crigler–Najjar syndrome. Hum. Gene Ther. 30, 1297–1305 (2019).
Google Scholar
Bryson, T. E., Anglin, C. M., Bridges, P. H. & Cottle, R. N. Nuclease-mediated gene therapies for inherited metabolic diseases of the liver. Yale J. Biol. Med. 90, 553–566 (2017).
Google Scholar
Nguyen, G. N. et al. A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells. Nat. Biotechnol. 39, 47–55 (2021).
Google Scholar
Wu, Z., Yang, H. & Colosi, P. Effect of genome size on AAV vector packaging. Mol. Ther. 18, 80–86 (2010).
Google Scholar
Chandler, M., Panigaj, M., Rolband, L. A. & Afonin, K. A. Challenges to optimizing RNA nanostructures for large scale production and controlled therapeutic properties. Nanomedicine 15, 1331–1340 (2020).
Google Scholar
Leborgne, C. et al. IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies. Nat. Med. 26, 1096–1101 (2020).
Google Scholar
Balwani, M. et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N. Engl. J. Med. 382, 2289–2301 (2020).
Google Scholar
Ray, K. K. et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N. Engl. J. Med. 382, 1507–1519 (2020).
Google Scholar
Garrelfs, S. F. et al. Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1. N. Engl. J. Med. 384, 1216–1226 (2021).
Google Scholar
Adams, D. et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 11–21 (2018).
Google Scholar
Parums, D. V. Editorial: first full regulatory approval of a COVID-19 vaccine, the BNT162b2 Pfizer-BioNTech vaccine, and the real-world implications for Public Health Policy. Med. Sci. Monit. 27, e934625 (2021).
Google Scholar
Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021).
Google Scholar
Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).
Google Scholar
Buck, J., Grossen, P., Cullis, P. R., Huwyler, J. & Witzigmann, D. Lipid-based DNA therapeutics: hallmarks of non-viral gene delivery. ACS Nano 13, 3754–3782 (2019).
Google Scholar
Vargason, A. M., Anselmo, A. C. & Mitragotri, S. The evolution of commercial drug delivery technologies. Nat. Biomed. Eng. 5, 951–967 (2021).
Google Scholar
Watts, J. K. & Corey, D. R. Silencing disease genes in the laboratory and the clinic. J. Pathol. 226, 365–379 (2012).
Google Scholar
Kosmas, C. E. et al. Inclisiran for the treatment of cardiovascular disease: a short review on the emerging data and therapeutic potential. Ther. Clin. Risk Manag. 16, 1031–1037 (2020).
Google Scholar
Chen, F., Alphonse, M. & Liu, Q. Strategies for nonviral nanoparticle-based delivery of CRISPR/Cas9 therapeutics. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 12, e1609 (2020).
Google Scholar
Hanna, J., Hossain, G. S. & Kocerha, J. The potential for microRNA therapeutics and clinical research. Front. Genet. 10, 478 (2019).
Google Scholar
Hong, D. S. et al. Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours. Br. J. Cancer 122, 1630–1637 (2020).
Google Scholar
van der Ree, M. H. et al. Miravirsen dosing in chronic hepatitis C patients results in decreased microRNA-122 levels without affecting other microRNAs in plasma. Aliment. Pharmacol. Ther. 43, 102–113 (2016).
Google Scholar
van der Ree, M. H. et al. Safety, tolerability, and antiviral effect of RG-101 in patients with chronic hepatitis C: a phase 1B, double-blind, randomised controlled trial. Lancet 389, 709–717 (2017).
Google Scholar
Regulus announces pipeline updates and advancements. Regulus http://ir.regulusrx.com/news-releases/news-release-details/regulus-announces-pipeline-updates-and-advancements (2017).
Wilson, R. C. & Doudna, J. A. Molecular mechanisms of RNA interference. Annu. Rev. Biophys. 42, 217–239 (2013).
Google Scholar
Liu, J., Valencia-Sanchez, M. A., Hannon, G. J. & Parker, R. MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nat. Cell Biol. 7, 719–723 (2005).
Google Scholar
Alnylam announces U.S. Food and Drug Administration acceptance of new drug application for investigational vutrisiran for the treatment of the polyneuropathy of hereditary ATTR amyloidosis. Alnylam https://investors.alnylam.com/press-release?id=25811 (2021).
HELIOS-A: 9-month results from the phase 3 study of vutrisiran in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Alnylam https://www.alnylam.com/wp-content/uploads/2021/04/Adams_HELIOS-A-9-Month-Results.pdf (2021).
Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).
Google Scholar
Adachi, H., Hengesbach, M., Yu, Y. T. & Morais, P. From antisense RNA to RNA modification: therapeutic potential of RNA-based technologies. Biomedicines 9, 550 (2021).
Google Scholar
Humphreys, S. C. et al. Emerging siRNA design principles and consequences for biotransformation and disposition in drug development. J. Med. Chem. 63, 6407–6422 (2020).
Google Scholar
Evers, M. M., Toonen, L. J. & van Roon-Mom, W. M. Antisense oligonucleotides in therapy for neurodegenerative disorders. Adv. Drug Deliv. Rev. 87, 90–103 (2015).
Google Scholar
Santos, R. D. et al. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials. Arterioscler. Thromb. Vasc. Biol. 35, 689–699 (2015).
Google Scholar
Benson, M. D. et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 22–31 (2018).
Google Scholar
Lim, K. R., Maruyama, R. & Yokota, T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des. Devel Ther. 11, 533–545 (2017).
Google Scholar
Frank, D. E. et al. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology 94, e2270–e2282 (2020).
Google Scholar
Finkel, R. S. et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med. 377, 1723–1732 (2017).
Google Scholar
Crooke, S. T. Molecular mechanisms of antisense oligonucleotides. Nucleic Acid Ther. 27, 70–77 (2017).
Google Scholar
Lim, K. H. et al. Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression. Nat. Commun. 11, 3501 (2020).
Google Scholar
Kilanowska, A. & Studzińska, S. In vivo and in vitro studies of antisense oligonucleotides — a review. RSC Adv. 10, 34501–34516 (2020).
Google Scholar
Bennett, C. F., Baker, B. F., Pham, N., Swayze, E. & Geary, R. S. Pharmacology of antisense drugs. Annu. Rev. Pharmacol. Toxicol. 57, 81–105 (2017).
Google Scholar
Burdick, A. D. et al. Sequence motifs associated with hepatotoxicity of locked nucleic acid — modified antisense oligonucleotides. Nucleic Acids Res. 42, 4882–4891 (2014).
Google Scholar
Yamamoto, T. et al. Highly potent GalNAc-conjugated tiny LNA anti-miRNA-122 antisense oligonucleotides. Pharmaceutics 13, 817 (2021).
Google Scholar
Shen, W. et al. Chemical modification of PS-ASO therapeutics reduces cellular protein-binding and improves the therapeutic index. Nat. Biotechnol. 37, 640–650 (2019).
Google Scholar
Miller, C. M. et al. Stabilin-1 and stabilin-2 are specific receptors for the cellular internalization of phosphorothioate-modified antisense oligonucleotides (ASOs) in the liver. Nucleic Acids Res. 44, 2782–2794 (2016).
Google Scholar
Merkle, T. et al. Precise RNA editing by recruiting endogenous ADARs with antisense oligonucleotides. Nat. Biotechnol. 37, 133–138 (2019).
Google Scholar
Qu, L. et al. Programmable RNA editing by recruiting endogenous ADAR using engineered RNAs. Nat. Biotechnol. 37, 1059–1069 (2019).
Google Scholar
Aquino-Jarquin, G. Novel engineered programmable systems for ADAR-mediated RNA editing. Mol. Ther. Nucleic Acids 19, 1065–1072 (2020).
Google Scholar
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).
Google Scholar
Gillmore, J. D. et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N. Engl. J. Med. 385, 493–502 (2021).
Google Scholar
Musunuru, K. et al. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature 593, 429–434 (2021).
Google Scholar
Rothgangl, T. et al. In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels. Nat. Biotechnol. 39, 949–957 (2021).
Google Scholar
Thompson, M. G. et al. Interim estimates of vaccine effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines in preventing SARS-CoV-2 infection among health care personnel, first responders, and other essential and frontline workers — eight U.S. locations, December 2020-March 2021. MMWR 70, 495–500 (2021).
Google Scholar
Dobrowolski, C., Paunovska, K., Hatit, M. Z. C., Lokugamage, M. P. & Dahlman, J. E. Therapeutic RNA delivery for COVID and other diseases. Adv. Health. Mater. 10, e2002022 (2021).
Translate Bio announces results from second interim data analysis from ongoing phase 1/2 clinical trial of MRT5005 in patients with cystic fibrosis (CF). Translate Bio https://investors.translate.bio/news-releases/news-release-details/translate-bio-announces-results-second-interim-data-analysis (2021).
Translate Bio announces pipeline program update. Translate Bio https://investors.translate.bio/news-releases/news-release-details/translate-bio-announces-pipeline-program-update (2021).
Arcturus Therapeutics announces first quarter 2021 company overview and financial results and provides new clinical data. Arcturus Therapeutics https://ir.arcturusrx.com/news-releases/news-release-details/arcturus-therapeutics-announces-first-quarter-2021-company (2021).
Krienke, C. et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science 371, 145–153 (2021).
Google Scholar
Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018).
Google Scholar
Luisi, K. et al. Development of a potent Zika virus vaccine using self-amplifying messenger RNA. Sci. Adv. 6, eaba5068 (2020).
Google Scholar
Leal, L. et al. Phase I clinical trial of an intranodally administered mRNA-based therapeutic vaccine against HIV-1 infection. AIDS 32, 2533–2545 (2018).
Google Scholar
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).
Google Scholar
Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).
Google Scholar
Conry, R. M. et al. Characterization of a messenger RNA polynucleotide vaccine vector. Cancer Res. 55, 1397–1400 (1995).
Google Scholar
Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020).
Google Scholar
Jimeno, A. et al. Abstract CT032: A phase 1/2, open-label, multicenter, dose escalation and efficacy study of mRNA-2416, a lipid nanoparticle encapsulated mRNA encoding human OX40L, for intratumoral injection alone or in combination with durvalumab for patients with advanced malignancies. Cancer Res. 80, CT032 (2020).
Zhang, H. X., Zhang, Y. & Yin, H. Genome editing with mRNA encoding ZFN, TALEN, and Cas9. Mol. Ther. 27, 735–746 (2019).
Google Scholar
Pardi, N. et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J. Controlled Rel. 217, 345–351 (2015).
Google Scholar
Finn, J. D. et al. A single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing. Cell Rep. 22, 2227–2235 (2018).
Google Scholar
Allergan and Editas Medicine announce dosing of first patient in landmark phase 1/2 clinical trial of CRISPR medicine AGN-151587 (EDIT-101) for the treatment of LCA10. Editas Medicine https://ir.editasmedicine.com/news-releases/news-release-details/allergan-and-editas-medicine-announce-dosing-first-patient (2020).
Hanlon, K. S. et al. High levels of AAV vector integration into CRISPR-induced DNA breaks. Nat. Commun. 10, 4439 (2019).
Google Scholar
Jiang, F. & Doudna, J. A. CRISPR-Cas9 structures and mechanisms. Annu. Rev. Biophys. 46, 505–529 (2017).
Google Scholar
Slaymaker, I. M. et al. Rationally engineered Cas9 nucleases with improved specificity. Science 351, 84–88 (2016).
Google Scholar
Kleinstiver, B. P. et al. Engineered CRISPR-Cas9 nucleases with altered PAM specificities. Nature 523, 481–485 (2015).
Google Scholar
Gilbert, L. A. et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154, 442–451 (2013).
Google Scholar
Thakore, P. I., Black, J. B., Hilton, I. B. & Gersbach, C. A. Editing the epigenome: technologies for programmable transcription and epigenetic modulation. Nat. Methods 13, 127–137 (2016).
Google Scholar
Nuñez, J. K. et al. Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing. Cell 184, 2503–2519.e2517 (2021).
Google Scholar
Porto, E. M., Komor, A. C., Slaymaker, I. M. & Yeo, G. W. Base editing: advances and therapeutic opportunities. Nat. Rev. Drug Discov. 19, 839–859 (2020).
Google Scholar
Mok, B. Y. et al. A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing. Nature 583, 631–637 (2020).
Google Scholar
Anzalone, A. V. et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 576, 149–157 (2019).
Google Scholar
Saito, M. et al. Dual modes of CRISPR-associated transposon homing. Cell 9, 2441–2453.e18 (2021).
Zetsche, B. et al. Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system. Cell 163, 759–771 (2015).
Google Scholar
Abudayyeh, O. O. et al. C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector. Science 353, aaf5573 (2016).
Google Scholar
Özcan, A. et al. Programmable RNA targeting with the single-protein CRISPR effector Cas7-11. Nature 597, 720–725 (2021).
Google Scholar
Cox, D. B. T. et al. RNA editing with CRISPR-Cas13. Science 358, 1019–1027 (2017).
Google Scholar
Abudayyeh, O. O. et al. A cytosine deaminase for programmable single-base RNA editing. Science 365, 382–386 (2019).
Google Scholar
Abbott, T. R. et al. Development of CRISPR as an antiviral strategy to combat SARS-CoV-2 and influenza. Cell 181, 865–876.e812 (2020).
Google Scholar
Blanchard, E. L. et al. Treatment of influenza and SARS-CoV-2 infections via mRNA-encoded Cas13a in rodents. Nat. Biotechnol. 39, 717–726 (2021).
Google Scholar
Miller, J. B. et al. Non-viral CRISPR/Cas gene editing in vitro and in vivo enabled by synthetic nanoparticle co-delivery of Cas9 mRNA and sgRNA. Angew. Chem. Int. Edn Engl. 56, 1059–1063 (2017).
Google Scholar
Jiang, C. et al. A non-viral CRISPR/Cas9 delivery system for therapeutically targeting HBV DNA and pcsk9 in vivo. Cell Res. 27, 440–443 (2017).
Google Scholar
Sago, C. D. et al. High-throughput in vivo screen of functional mRNA delivery identifies nanoparticles for endothelial cell gene editing. Proc. Natl Acad. Sci. USA 115, E9944–E9952 (2018).
Google Scholar
Yin, H. et al. Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing. Nat. Biotechnol. 35, 1179–1187 (2017).
Google Scholar
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).
Google Scholar
Rosenblum, D. et al. CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy. Sci. Adv. 6, eabc9450 (2020).
Google Scholar
Zhang, X. et al. Functionalized lipid-like nanoparticles for in vivo mRNA delivery and base editing. Sci. Adv. 6, eabc2315 (2020).
Google Scholar
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. USA 118, e2020401118 (2021).
Google Scholar
Yin, H. et al. Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat. Biotechnol. 34, 328–333 (2016).
Google Scholar
Lee, B. et al. Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours. Nat. Biomed. Eng. 2, 497–507 (2018).
Google Scholar
Lee, K. et al. Nanoparticle delivery of Cas9 ribonucleoprotein and donor DNA in vivo induces homology-directed DNA repair. Nat. Biomed. Eng. 1, 889–901 (2017).
Google Scholar
Wei, T., Cheng, Q., Min, Y.-L., Olson, E. N. & Siegwart, D. J. Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing. Nat. Commun. 11, 3232 (2020).
Google Scholar
Pausch, P. et al. CRISPR-CasΦ from huge phages is a hypercompact genome editor. Science 369, 333–337 (2020).
Google Scholar
Kim, D. Y. et al. Efficient CRISPR editing with a hypercompact Cas12f1 and engineered guide RNAs delivered by adeno-associated virus. Nat. Biotechnol. https://doi.org/10.1038/s41587-021-01009-z (2021).
Google Scholar
Xu, X. et al. Engineered miniature CRISPR-Cas system for mammalian genome regulation and editing. Mol. Cell 81, 4333–4345.e4 (2021).
Google Scholar
Kannan, S. et al. Compact RNA editors with small Cas13 proteins. Nat. Biotechnol. https://doi.org/10.1038/s41587-021-01030-2 (2021).
Google Scholar
Cheng, C. J., Tietjen, G. T., Saucier-Sawyer, J. K. & Saltzman, W. M. A holistic approach to targeting disease with polymeric nanoparticles. Nat. Rev. Drug Discov. 14, 239–247 (2015).
Google Scholar
Israelachvili, J. N., Mitchell, D. J. & Ninham, B. W. Theory of self-assembly of lipid bilayers and vesicles. Biochim. Biophys. Acta 470, 185–201 (1977).
Google Scholar
Kulkarni, J. A. et al. On the formation and morphology of lipid nanoparticles containing ionizable cationic lipids and siRNA. ACS Nano 12, 4787–4795 (2018).
Google Scholar
Herrera, M., Kim, J., Eygeris, Y., Jozic, A. & Sahay, G. Illuminating endosomal escape of polymorphic lipid nanoparticles that boost mRNA delivery. Biomater. Sci. 9, 4289–4300 (2021).
Google Scholar
Semple, S. C. et al. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 28, 172–176 (2010).
Google Scholar
Altınoglu, S., Wang, M. & Xu, Q. Combinatorial library strategies for synthesis of cationic lipid-like nanoparticles and their potential medical applications. Nanomedicine 10, 643–657 (2015).
Google Scholar
Zhang, Y., Sun, C., Wang, C., Jankovic, K. E. & Dong, Y. Lipids and lipid derivatives for RNA delivery. Chem. Rev. 121, 12181–12277 (2021).
Google Scholar
Love, K. T. et al. Lipid-like materials for low-dose, in vivo gene silencing. Proc. Natl Acad. Sci. USA 107, 1864–1869 (2010).
Google Scholar
Zimmermann, T. S. et al. RNAi-mediated gene silencing in non-human primates. Nature 441, 111–114 (2006).
Google Scholar
Dong, Y. et al. Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates. Proc. Natl Acad. Sci. USA 111, 3955–3960 (2014).
Google Scholar
Jayaraman, M. et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chem. Int. Edn Engl. 51, 8529–8533 (2012).
Google Scholar
Paunovska, K. et al. Nanoparticles containing oxidized cholesterol deliver mRNA to the liver microenvironment at clinically relevant doses. Adv. Mater. 31, 1807748 (2019).
Kauffman, K. J. et al. Rapid, single-cell analysis and discovery of vectored mRNA transfection in vivo with a loxP-flanked tdtomato reporter mouse. molecular therapy. Nucleic Acids 10, 55–63 (2018).
Google Scholar
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).
Google Scholar
Sedic, M. et al. Safety evaluation of lipid nanoparticle-formulated modified mRNA in the Sprague–Dawley rat and cynomolgus monkey. Vet. Pathol. 55, 341–354 (2018).
Google Scholar
ModernaTx. Compounds and compositions for intracellular delivery of therapeutic agents. US patent US20170210697A1 (2021).
Sabatine, M. S. et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376, 1713–1722 (2017).
Google Scholar
Beam Therapeutics announces updated preclinical data highlighting optimized LNP delivery approaches for in vivo base editing to the liver and other tissues. Beam Therapeutics https://investors.beamtx.com/news-releases/news-release-details/beam-therapeutics-announces-updated-preclinical-data (2021).
Kulkarni, J. A., Cullis, P. R. & van der Meel, R. Lipid nanoparticles enabling gene therapies: from concepts to clinical utility. Nucleic Acid. Ther. 28, 146–157 (2018).
Google Scholar
Cheng, X. & Lee, R. J. The role of helper lipids in lipid nanoparticles (LNPs) designed for oligonucleotide delivery. Adv. Drug Deliv. Rev. 99, 129–137 (2016).
Google Scholar
Dahlman, J. E. et al. In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight. Nat. Nano 9, 648–655 (2014).
Google Scholar
Khan, O. F. et al. Endothelial siRNA delivery in nonhuman primates using ionizable low-molecular weight polymeric nanoparticles. Sci. Adv. 4, eaar8409 (2018).
Google Scholar
Sago, C. D. et al. Nanoparticles that deliver RNA to bone marrow identified by in vivo directed evolution. J. Am. Chem. Soc. 140, 17095–17105 (2018).
Google Scholar
Paunovska, K. et al. Analyzing 2000 in vivo drug delivery data points reveals cholesterol structure impacts nanoparticle delivery. ACS Nano 12, 8341–8349 (2018).
Google Scholar
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).
Google Scholar
Mui, B. L. et al. Influence of polyethylene glycol lipid desorption rates on pharmacokinetics and pharmacodynamics of siRNA lipid nanoparticles. Mol. Ther. Nucleic acids 2, e139 (2013).
Google Scholar
Ryals, R. C. et al. The effects of PEGylation on LNP based mRNA delivery to the eye. PLoS ONE 15, e0241006 (2020).
Google Scholar
Suk, J. S., Xu, Q., Kim, N., Hanes, J. & Ensign, L. M. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv. Drug Deliv. Rev. 99, 28–51 (2016).
Google Scholar
Eygeris, Y., Patel, S., Jozic, A. & Sahay, G. Deconvoluting lipid nanoparticle structure for messenger RNA delivery. Nano Lett. 20, 4543–4549 (2020).
Google Scholar
Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401 (2016).
Google Scholar
Intellia Therapeutics presents preclinical proof of concept for CRISPR-based in vivo editing of bone marrow at Keystone eSymposium. Intellia Therapeutics https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-presents-preclinical-proof-concept-crispr (2021).
Rai, R., Alwani, S. & Badea, I. Polymeric nanoparticles in gene therapy: new avenues of design and optimization for delivery applications. Polymers 11, 745 (2019).
Google Scholar
Kamaly, N., Yameen, B., Wu, J. & Farokhzad, O. C. Degradable controlled-release polymers and polymeric nanoparticles: mechanisms of controlling drug release. Chem. Rev. 116, 2602–2663 (2016).
Google Scholar
Crucho, C. I. C. & Barros, M. T. Polymeric nanoparticles: A study on the preparation variables and characterization methods. Mater. Sci. Eng. C 80, 771–784 (2017).
Google Scholar
Zhong, H., Chan, G., Hu, Y., Hu, H. & Ouyang, D. A comprehensive map of FDA-approved pharmaceutical products. Pharmaceutics 10, 263 (2018).
Google Scholar
Xiao, B. et al. Combination therapy for ulcerative colitis: orally targeted nanoparticles prevent mucosal damage and relieve inflammation. Theranostics 6, 2250–2266 (2016).
Google Scholar
Harada-Shiba, M. et al. Polyion complex micelles as vectors in gene therapy — pharmacokinetics and in vivo gene transfer. Gene Ther. 9, 407–414 (2002).
Google Scholar
Ewe, A. et al. Optimized polyethylenimine (PEI)-based nanoparticles for siRNA delivery, analyzed in vitro and in an ex vivo tumor tissue slice culture model. Drug Deliv. Transl. Res. 7, 206–216 (2017).
Google Scholar
Gao, X. et al. The association of autophagy with polyethylenimine-induced cytotoxicity in nephritic and hepatic cell lines. Biomaterials 32, 8613–8625 (2011).
Google Scholar
Breunig, M., Lungwitz, U., Liebl, R. & Goepferich, A. Breaking up the correlation between efficacy and toxicity for nonviral gene delivery. Proc. Natl Acad. Sci. USA 104, 14454–14459 (2007).
Google Scholar
Ke, X. et al. Surface-functionalized PEGylated nanoparticles deliver messenger RNA to pulmonary immune cells. ACS Appl. Mater. Interf. 12, 35835–35844 (2020).
Google Scholar
Tan, L. et al. Optimization of an mRNA vaccine assisted with cyclodextrin–polyethyleneimine conjugates. Drug. Deliv. Transl. Res. 10, 678–689 (2020).
Google Scholar
Xiang, J. J. et al. IONP-PLL: a novel non-viral vector for efficient gene delivery. J. Gene Med. 5, 803–817 (2003).
Google Scholar
Yin, H. et al. Non-viral vectors for gene-based therapy. Nat. Rev. Genet. 15, 541–555 (2014).
Google Scholar
Choi, J. et al. Nonviral polymeric nanoparticles for gene therapy in pediatric CNS malignancies. Nanomedicine 23, 102115 (2020).
Google Scholar
Akinc, A., Lynn, D. M., Anderson, D. G. & Langer, R. Parallel synthesis and biophysical characterization of a degradable polymer library for gene delivery. J. Am. Chem. Soc. 125, 5316–5323 (2003).
Google Scholar
Green, J. J., Langer, R. & Anderson, D. G. A combinatorial polymer library approach yields insight into nonviral gene delivery. Acc. Chem. Res. 41, 749–759 (2008).
Google Scholar
Vandenbroucke, R. E. et al. Prolonged gene silencing in hepatoma cells and primary hepatocytes after small interfering RNA delivery with biodegradable poly(beta-amino esters). J. Gene Med. 10, 783–794 (2008).
Google Scholar
Anderson, D. G., Lynn, D. M. & Langer, R. Semi-automated synthesis and screening of a large library of degradable cationic polymers for gene delivery. Angew. Chem. Int. Edn Engl. 42, 3153–3158 (2003).
Google Scholar
Anderson, D. G., Akinc, A., Hossain, N. & Langer, R. Structure/property studies of polymeric gene delivery using a library of poly(beta-amino esters). Mol. Ther. 11, 426–434 (2005).
Google Scholar
Mastorakos, P. et al. Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy. Proc. Natl Acad. Sci. USA 112, 8720–8725 (2015).
Google Scholar
Su, X., Fricke, J., Kavanagh, D. G. & Irvine, D. J. In vitro and in vivo mRNA delivery using lipid-enveloped pH-responsive polymer nanoparticles. Mol. Pharm. 8, 774–787 (2011).
Google Scholar
Kozielski, K. L. et al. Cancer-selective nanoparticles for combinatorial siRNA delivery to primary human GBM in vitro and in vivo. Biomaterials 209, 79–87 (2019).
Google Scholar
Eltoukhy, A. A., Chen, D., Alabi, C. A., Langer, R. & Anderson, D. G. Degradable terpolymers with alkyl side chains demonstrate enhanced gene delivery potency and nanoparticle stability. Adv. Mater. 25, 1487–1493 (2013).
Google Scholar
Kaczmarek, J. C. et al. Polymer–lipid nanoparticles for systemic delivery of mRNA to the lungs. Angew. Chem. Int. Edn Engl. 55, 13808–13812 (2016).
Google Scholar
Xu, L., Zhang, H. & Wu, Y. Dendrimer advances for the central nervous system delivery of therapeutics. ACS Chem. Neurosci. 5, 2–13 (2014).
Google Scholar
Chahal, J. S. et al. Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose. Proc. Natl Acad. Sci. USA 113, E4133–E4142 (2016).
Google Scholar
Khan, O. F. et al. Ionizable amphiphilic dendrimer-based nanomaterials with alkyl-chain-substituted amines for tunable siRNA delivery to the liver endothelium in vivo. Angew. Chem. Int. Edn Engl. 53, 14397–14401 (2014).
Google Scholar
Bielinska, A. U., Kukowska-Latallo, J. F. & Baker, J. R. Jr The interaction of plasmid DNA with polyamidoamine dendrimers: mechanism of complex formation and analysis of alterations induced in nuclease sensitivity and transcriptional activity of the complexed DNA. Biochim. Biophys. Acta 1353, 180–190 (1997).
Google Scholar
Sonawane, N. D., Szoka, F. C. Jr & Verkman, A. S. Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J. Biol. Chem. 278, 44826–44831 (2003).
Google Scholar
Yoo, J., Park, C., Yi, G., Lee, D. & Koo, H. Active targeting strategies using biological ligands for nanoparticle drug delivery systems. Cancers 11, 640 (2019).
Google Scholar
Nel, A. E. et al. Understanding biophysicochemical interactions at the nano-bio interface. Nat. Mater. 8, 543–557 (2009).
Google Scholar
Dawson, K. A. & Yan, Y. Current understanding of biological identity at the nanoscale and future prospects. Nat. Nanotechnol. 16, 229–242 (2021).
Google Scholar
Schöttler, S. et al. Protein adsorption is required for stealth effect of poly(ethylene glycol)- and poly(phosphoester)-coated nanocarriers. Nat. Nanotechnol. 11, 372–377 (2016).
Google Scholar
Salvati, A. et al. Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nat. Nanotechnol. 8, 137–143 (2013).
Google Scholar
Akinc, A. et al. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nat. Nanotechnol. 14, 1084–1087 (2019).
Google Scholar
Akinc, A. et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol. Ther. 18, 1357–1364 (2010).
Google Scholar
Miao, L. et al. Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver. Nat. Commun. 11, 2424 (2020).
Google Scholar
Sago, C. D. et al. Modifying a commonly expressed endocytic receptor retargets nanoparticles in vivo. Nano Lett. 18, 7590–7600 (2018).
Google Scholar
Chen, S. et al. Influence of particle size on the in vivo potency of lipid nanoparticle formulations of siRNA. J. Control. Rel. 235, 236–244 (2016).
Google Scholar
Nakamura, T. et al. The effect of size and charge of lipid nanoparticles prepared by microfluidic mixing on their lymph node transitivity and distribution. Mol. Pharm. 17, 944–953 (2020).
Google Scholar
Reinhard, K. et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science 367, 446–453 (2020).
Google Scholar
Nair, J. K. et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J. Am. Chem. Soc. 136, 16958–16961 (2014).
Google Scholar
Prakash, T. P. et al. Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res. 42, 8796–8807 (2014).
Google Scholar
Agarwal, S. et al. Impact of serum proteins on the uptake and RNA interference activity of N-acetylgalactosamine-conjugated small interfering RNAs. Nucleic Acid Ther. 31, 309–315 (2021).
Google Scholar
Foster, D. J. et al. Advanced siRNA designs further improve in vivo performance of GalNAc-siRNA conjugates. Mol. Ther. 26, 708–717 (2018).
Google Scholar
Nair, J. K. et al. Impact of enhanced metabolic stability on pharmacokinetics and pharmacodynamics of GalNAc-siRNA conjugates. Nucleic Acids Res. 45, 10969–10977 (2017).
Google Scholar
Zanardi, T. A. et al. Safety, pharmacokinetic, and pharmacodynamic evaluation of a 2′-(2-methoxyethyl)-d-ribose antisense oligonucleotide-triantenarry N-acetyl-galactosamine conjugate that targets the human transmembrane protease serine 6. J. Pharmacol. Exp. Ther. 377, 51–63 (2021).
Google Scholar
Janas, M. M. et al. The nonclinical safety profile of GalNAc-conjugated RNAi therapeutics in subacute studies. Toxicol. Pathol. 46, 735–745 (2018).
Google Scholar
Biscans, A. et al. Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo. Nucleic Acids Res. 47, 1082–1096 (2019).
Google Scholar
Osborn, M. F. et al. Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways. Nucleic Acids Res. 47, 1070–1081 (2019).
Google Scholar
Nagata, T. et al. Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood–brain barrier and knock down genes in the rodent CNS. Nat. Biotechnol. https://doi.org/10.1038/s41587-021-00972-x (2021).
Google Scholar
Zhou, J. & Rossi, J. Aptamers as targeted therapeutics: current potential and challenges. Nat. Rev. Drug Discov. 16, 181–202 (2017).
Google Scholar
Yoon, S., Wu, X., Armstrong, B., Habib, N. & Rossi, J. J. An RNA aptamer targeting the receptor tyrosine kinase PDGFRα induces anti-tumor effects through STAT3 and p53 in glioblastoma. Mol. Ther. Nucleic Acids 14, 131–141 (2019).
Google Scholar
Sugo, T. et al. Development of antibody-siRNA conjugate targeted to cardiac and skeletal muscles. J. Controlled Rel. 237, 1–13 (2016).
Google Scholar
Avidity corporate presentation. Avidity Biosciences https://aviditybiosciences.investorroom.com/events-and-presentations (2021).
Kedmi, R. et al. A modular platform for targeted RNAi therapeutics. Nat. Nanotechnol. 13, 214–219 (2018).
Google Scholar
Veiga, N. et al. Cell specific delivery of modified mRNA expressing therapeutic proteins to leukocytes. Nat. Commun. 9, 4493 (2018).
Google Scholar
Dammes, N. et al. Conformation-sensitive targeting of lipid nanoparticles for RNA therapeutics. Nat. Nanotechnol. https://doi.org/10.1038/s41565-021-00928-x (2021).
Google Scholar
Li, Q. et al. Engineering caveolae-targeted lipid nanoparticles to deliver mRNA to the lungs. ACS Chem. Biol. 15, 830–836 (2020).
Google Scholar
Zhuang, X. et al. mRNA vaccines encoding the HA protein of influenza A H1N1 virus delivered by cationic lipid nanoparticles induce protective immune responses in mice. Vaccines 8, 123 (2020).
Google Scholar
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).
Google Scholar
Paunovska, K., Loughrey, D., Sago, C. D., Langer, R. & Dahlman, J. E. Using large datasets to understand nanotechnology. Adv. Mater. 31, e1902798 (2019).
Google Scholar
Lokugamage, M. P., Sago, C. D. & Dahlman, J. E. Testing thousands of nanoparticles in vivo using DNA barcodes. Curr. Opin. Biomed. Eng. 7, 1–8 (2018).
Google Scholar
Yaari, Z. et al. Theranostic barcoded nanoparticles for personalized cancer medicine. Nat. Commun. 7, 13325 (2016).
Google Scholar
Dahlman, J. E. et al. Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics. Proc. Natl Acad. Sci. USA 114, 2060–2065 (2017).
Google Scholar
Lokugamage, M. P., Sago, C. D., Gan, Z., Krupczak, B. R. & Dahlman, J. E. Constrained nanoparticles deliver siRNA and sgRNA to T cells in vivo without targeting ligands. Adv. Mater. 31, e1902251 (2019).
Google Scholar
Lokugamage, M. P. et al. Mild innate immune activation overrides efficient nanoparticle-mediated RNA delivery. Adv. Mater. 32, 1904905 (2019).
Riley, R. S. et al. Ionizable lipid nanoparticles for in utero mRNA delivery. Sci. Adv. 7, eaba1028 (2021).
Google Scholar
Havel, P. J., Kievit, P., Comuzzie, A. G. & Bremer, A. A. Use and importance of nonhuman primates in metabolic disease research: current state of the field. ILAR J. 58, 251–268 (2017).
Google Scholar
Paunovska, K. et al. Increased PIP3 activity blocks nanoparticle mRNA delivery. Sci. Adv. 6, eaba5672 (2020).
Google Scholar
Li, R. et al. Therapeutically reprogrammed nutrient signalling enhances nanoparticulate albumin bound drug uptake and efficacy in KRAS-mutant cancer. Nat. Nanotechnol. 16, 830–839 (2021).
Google Scholar
Patel, S. et al. Boosting intracellular delivery of lipid nanoparticle-encapsulated mRNA. Nano Lett. 17, 5711–5718 (2017).
Google Scholar
Yin, W. et al. Plasma lipid profiling across species for the identification of optimal animal models of human dyslipidemia. J. Lipid Res. 53, 51–65 (2012).
Google Scholar
Rampado, R., Crotti, S., Caliceti, P., Pucciarelli, S. & Agostini, M. Recent advances in understanding the protein corona of nanoparticles and in the formulation of “stealthy” nanomaterials. Front. Bioeng. Biotechnol. 8, 166 (2020).
Google Scholar
Delprato, A. et al. Systems genetic analysis of hippocampal neuroanatomy and spatial learning in mice. Genes Brain Behav. 14, 591–606 (2015).
Google Scholar
Harrill, A. H. et al. A mouse diversity panel approach reveals the potential for clinical kidney injury due to DB289 not predicted by classical rodent models. Toxicol. Sci. 130, 416–426 (2012).
Google Scholar
Church, R. J. et al. A systems biology approach utilizing a mouse diversity panel identifies genetic differences influencing isoniazid-induced microvesicular steatosis. Toxicol. Sci. 140, 481–492 (2014).
Google Scholar
Leist, S. R. et al. Influenza H3N2 infection of the collaborative cross founder strains reveals highly divergent host responses and identifies a unique phenotype in CAST/EiJ mice. BMC Genomics 17, 143 (2016).
Google Scholar
Jaxpheno2 project protocol: morphometric (organ weight) survey of 11 strains of mice (2006). Mouse Phenome Database at the Jackson Laboratory https://phenome.jax.org/projects/Jaxpheno2/protocol?method=organ+weights (2006).
Sugimoto, K. et al. Background data on organ weights and histopathological lesions in Cej:CD(SD)IGS rats for 4-, 13- and 26-weeks repeated-dose toxicity studies. Biological reference data on CD(SD)IGS rats. In IGS Databook 2000 79–87 (Charles River Laboratory, 2000).
Durbin, P. W., Jeung, N., Williams, M. H., Kullgren, B. & Parrott, M. W. Weights of bones and tissues at maturity and growth of the skeleton of rhesus (Macaca mullata and cynomolgus (Macaca fascicularis) monkeys. escholarship https://escholarship.org/content/qt6kw7682s/qt6kw7682s.pdf (1996).
Molina, D. K. & DiMaio, V. J. Normal organ weights in men. Part II — the brain, lungs, liver, spleen, and kidneys. Am. J. Forensic Med. Pathol. 33, 368–372 (2012).
Google Scholar
Molina, D. K. & DiMaio, V. J. Normal organ weights in women. Part II — the brain, lungs, liver, spleen, and kidneys. Am. J. Forensic Med. Pathol. 36, 182–187 (2015).
Google Scholar
Molina, D. K. & DiMaio, V. J. Normal organ weights in women. Part I — the heart. Am. J. Forensic Med. Pathol. 36, 176–181 (2015).
Google Scholar
Molina, D. K. & DiMaio, V. J. Normal organ weights in men. Part I — the heart. Am. J. Forensic Med. Pathol. 33, 362–367 (2012).
Google Scholar
Hatit, M. Z. C. et al. Species-dependent in vivo mRNA delivery and cellular responses to nanoparticles. Nat. Nanotechnol. https://doi.org/10.1038/s41565-021-01030-y (2021).
Google Scholar
Zhang, X., Goel, V. & Robbie, G. J. Pharmacokinetics of patisiran, the first approved RNA interference therapy in patients with hereditary transthyretin-mediated amyloidosis. J. Clin. Pharmacol. 60, 573–585 (2019).
Google Scholar
Zhang, X. et al. Patisiran pharmacokinetics, pharmacodynamics, and exposure-response analyses in the phase 3 APOLLO trial in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. J. Clin. Pharmacol. 60, 37–49 (2020).
Google Scholar
Center for Drug Evaluation and Research application number: 210922Orig1s000. FDA https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210922Orig1s000MultiR.pdf (2018).
Maier, M. A. et al. Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. Mol. Ther. 21, 1570–1578 (2013).
Google Scholar
Cheng, Z., Al Zaki, A., Hui, J. Z., Muzykantov, V. R. & Tsourkas, A. Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science 338, 903–910 (2012).
Google Scholar
Gilleron, J. et al. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat. Biotechnol. 31, 638–646 (2013).
Google Scholar
Wittrup, A. et al. Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown. Nat. Biotechnol. 33, 870–876 (2015).
Google Scholar
Alberer, M. et al. Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial. Lancet 390, 1511–1520 (2017).
Google Scholar
Zhao, P. et al. Long-term storage of lipid-like nanoparticles for mRNA delivery. Bioact. Mater. 5, 358–363 (2020).
Google Scholar
Gerhardt, A. et al. A thermostable, flexible RNA vaccine delivery platform for pandemic response. Preprint at bioRxiv https://doi.org/10.1101/2021.02.01.429283 (2021).
Google Scholar
Besin, G. et al. Accelerated blood clearance of lipid nanoparticles entails a biphasic humoral response of B-1 followed by B-2 lymphocytes to distinct antigenic moieties. Immunohorizons 3, 282–293 (2019).
Google Scholar
Machin, N. & Ragni, M. V. An investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B. J. Blood Med. 9, 135–140 (2018).
Google Scholar
Habtemariam, B. A. et al. Single-dose pharmacokinetics and pharmacodynamics of transthyretin targeting N-acetylgalactosamine–small interfering ribonucleic acid conjugate, vutrisiran, in healthy subjects. Clin. Pharmacol. Ther. 109, 372–382 (2021).
Google Scholar
Wang, Y., Yu, R. Z., Henry, S. & Geary, R. S. Pharmacokinetics and clinical pharmacology considerations of GalNAc(3)-conjugated antisense oligonucleotides. Expert Opin. Drug Metab. Toxicol. 15, 475–485 (2019).
Google Scholar
Ferguson, C. M., Echeverria, D., Hassler, M., Ly, S. & Khvorova, A. Cell type impacts accessibility of mRNA to silencing by RNA interference. Mol. Ther. Nucleic Acids 21, 384–393 (2020).
Google Scholar
Segel, M. et al. Mammalian retrovirus-like protein PEG10 packages its own mRNA and can be pseudotyped for mRNA delivery. Science 373, 882 (2021).
Google Scholar
Herrmann, I. K., Wood, M. J. A. & Fuhrmann, G. Extracellular vesicles as a next-generation drug delivery platform. Nat. Nanotechnol. 16, 748–759 (2021).
Google Scholar
Dhuri, K. et al. Antisense oligonucleotides: an emerging area in drug discovery and development. J. Clin. Med. 9, 2004 (2020)
Google Scholar
Hung, G. et al. Characterization of target mRNA reduction through in situ RNA hybridization in multiple organ systems following systemic antisense treatment in animals. Nucleic Acid. Ther. 23, 369–378 (2013).
Google Scholar
CureVac provides update on phase 2b/3 trial of first-generation COVID-19 vaccine candidate, CVnCoV. CureVac https://www.curevac.com/en/2021/06/16/curevac-provides-update-on-phase-2b-3-trial-of-first-generation-covid-19-vaccine-candidate-cvncov/ (2021).
McKenzie, L. K., El-Khoury, R., Thorpe, J. D., Damha, M. J. & Hollenstein, M. Recent progress in non-native nucleic acid modifications. Chem. Soc. Rev. 50, 5126–5164 (2021).
Google Scholar
Orlandini von Niessen, A. G. et al. Improving mRNA-based therapeutic gene delivery by expression-augmenting 3′ UTRs identified by cellular library screening. Mol. Ther. 27, 824–836 (2019).
Google Scholar
Jain, R. et al. MicroRNAs enable mRNA therapeutics to selectively program cancer cells to self-destruct. Nucleic Acid Ther. 28, 285–296 (2018).
Google Scholar
Hrkach, J. et al. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci. Transl. Med. 4, 128ra139 (2012).
Chen, Z. et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 483, 613–617 (2012).
Google Scholar
Kojima, N., Turner, I. & Klausner, J. D. The Covid-19 vaccine-development multiverse. N. Engl. J. Med. 384, 681–682 (2021).
Google Scholar
Levine-Tiefenbrun, M. et al. Initial report of decreased SARS-CoV-2 viral load after inoculation with the BNT162b2 vaccine. Nat. Med. 27, 790–792 (2021).
Google Scholar
Dagan, N. et al. BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting. N. Engl. J. Med. 384, 1412–1423 (2021).
Google Scholar
Lindsay, K. E. et al. Visualization of early events in mRNA vaccine delivery in non-human primates via PET-CT and near-infrared imaging. Nat. Biomed. Eng. 3, 371–380 (2019).
Google Scholar
Pardi, N. et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J. Exp. Med. 215, 1571–1588 (2018).
Google Scholar
Laczkó, D. et al. A single immunization with nucleoside-modified mRNA vaccines elicits strong cellular and humoral immune responses against SARS-CoV-2 in mice. Immunity 53, 724–732.e727 (2020).
Google Scholar
Wu, K. et al. Serum neutralizing activity elicited by mRNA-1273 vaccine. N. Engl. J. Med. https://doi.org/10.1056/NEJMc2102179 (2021).
Google Scholar
Callaway, E. & Ledford, H. How to redesign COVID vaccines so they protect against variants. Nature 590, 15–16 (2021).
Google Scholar
Hacisuleyman, E. et al. Vaccine breakthrough infections with SARS-CoV-2 variants. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2105000 (2021).
Google Scholar
Han, B. A., Kramer, A. M. & Drake, J. M. Global patterns of zoonotic disease in mammals. Trends Parasitol. 32, 565–577 (2016).
Google Scholar
