Vogel, A. B. et al. BNT162b vaccines protect rhesus macaques from SARS-CoV-2. Nature 592, 283–289 (2021).
Google Scholar
Corbett, K. S. et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567–571 (2020).
Google Scholar
Rijkers, G. T. et al. Antigen Presentation of mRNA-Based and Virus-Vectored SARS-CoV-2 Vaccines. Vaccines (Basel) 9, https://doi.org/10.3390/vaccines9080848 (2021).
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
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
Rotshild, V., Hirsh-Raccah, B., Miskin, I., Muszkat, M. & Matok, I. Comparing the clinical efficacy of COVID-19 vaccines: a systematic review and network meta-analysis. Sci Rep 11, 22777 (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
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
Brenner, S., Jacob, F. & Meselson, M. An unstable intermediate carrying information from genes to ribosomes for protein synthesis. Nature 190, 576–581 (1961).
Google Scholar
Pardi, N., Hogan, M. J. & Weissman, D. Recent advances in mRNA vaccine technology. Curr Opin Immunol 65, 14–20 (2020).
Google Scholar
Sahin, U., Kariko, K. & Tureci, O. mRNA-based therapeutics–developing a new class of drugs. Nat Rev Drug Discov 13, 759–780 (2014).
Google Scholar
Verbeke, R., Hogan, M. J., Loré, K. & Pardi, N. Innate immune mechanisms of mRNA vaccines. Immunity 55, 1993–2005 (2022).
Google Scholar
Ramanathan, A., Robb, G. B. & Chan, S. H. mRNA capping: biological functions and applications. Nucleic Acids Res 44, 7511–7526 (2016).
Google Scholar
Pasquinelli, A. E., Dahlberg, J. E. & Lund, E. Reverse 5’ caps in RNAs made in vitro by phage RNA polymerases. RNA 1, 957–967 (1995).
Google Scholar
Jemielity, J. et al. Novel “anti-reverse” cap analogs with superior translational properties. RNA 9, 1108–1122 (2003).
Google Scholar
Pardi, N., Muramatsu, H., Weissman, D. & Karikó, K. In vitro transcription of long RNA containing modified nucleosides. Methods Mol Biol 969, 29–42 (2013).
Google Scholar
Henderson, J. M. et al. Cap 1 Messenger RNA Synthesis with Co-transcriptional CleanCap(®) Analog by In Vitro Transcription. Curr Protoc 1, e39 (2021).
Google Scholar
Grudzien, E. et al. Novel cap analogs for in vitro synthesis of mRNAs with high translational efficiency. RNA 10, 1479–1487 (2004).
Google Scholar
Vlatkovic, I. et al. Ribozyme Assays to Quantify the Capping Efficiency of In Vitro-Transcribed mRNA. Pharmaceutics 14, 328 (2022).
Google Scholar
Leppek, K., Das, R. & Barna, M. Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them (vol 19, pg 158, 2018). Nat Rev Mol Cell Bio 19, 673–673 (2018).
Google Scholar
Babendure, J. R., Babendure, J. L., Ding, J. H. & Tsien, R. Y. Control of mammalian translation by mRNA structure near caps. Rna 12, 851–861 (2006).
Google Scholar
Lawson, T. G. et al. Influence of 5’ proximal secondary structure on the translational efficiency of eukaryotic mRNAs and on their interaction with initiation factors. Journal of Biological Chemistry 261, 13979–13989 (1986).
Google Scholar
Warren, L. et al. Highly Efficient Reprogramming to Pluripotency and Directed Differentiation of Human Cells with Synthetic Modified mRNA. Cell Stem Cell 7, 618–630 (2010).
Google Scholar
Mayr, C. Regulation by 3’-Untranslated Regions. Annu Rev Genet 51, 171–194 (2017).
Google Scholar
Navarro, E., Mallen, A. & Hueso, M. Dynamic Variations of 3’UTR Length Reprogram the mRNA Regulatory Landscape. Biomedicines 9, https://doi.org/10.3390/biomedicines9111560 (2021).
Shaw, G. & Kamen, R. A conserved AU sequence from the 3’ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46, 659–667 (1986).
Google Scholar
Chen, C. Y. & Shyu, A. B. AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem Sci 20, 465–470 (1995).
Google Scholar
Schwanhausser, B. et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011).
Google Scholar
Tanguay, R. L. & Gallie, D. R. Translational efficiency is regulated by the length of the 3’ untranslated region. Mol Cell Biol 16, 146–156 (1996).
Google Scholar
Kariko, K., Buckstein, M., Ni, H. & Weissman, D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165–175 (2005).
Google Scholar
Karikó, K. et al. Incorporation of Pseudouridine Into mRNA Yields Superior Nonimmunogenic Vector With Increased Translational Capacity and Biological Stability. Molecular Therapy 16, 1833–1840 (2008).
Google Scholar
Karikó, K., Muramatsu, H., Ludwig, J. & Weissman, D. Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA. Nucleic Acids Research 39, e142–e142 (2011).
Google Scholar
Andries, O. et al. N(1)-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice. J Control Release 217, 337–344 (2015).
Google Scholar
Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat Rev Mater 6, 1078–1094 (2021).
Google Scholar
Blakney, A. K., McKay, P. F., Yus, B. I., Aldon, Y. & Shattock, R. J. Inside out: optimization of lipid nanoparticle formulations for exterior complexation and in vivo delivery of saRNA. Gene Therapy 26, 363–372 (2019).
Google Scholar
Lokugamage, M. P. et al. Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs. Nature Biomedical Engineering 5, 1059–1068 (2021).
Google Scholar
Álvarez-Benedicto, E. et al. Optimization of phospholipid chemistry for improved lipid nanoparticle (LNP) delivery of messenger RNA (mRNA). Biomaterials Science 10, 549–559 (2022).
Google Scholar
Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nature Reviews Materials 2, 17056 (2017).
Google Scholar
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).
Google Scholar
Han, X. et al. An ionizable lipid toolbox for RNA delivery. Nat Commun 12, 7233 (2021).
Google Scholar
Semple, S. C. et al. Rational design of cationic lipids for siRNA delivery. Nat Biotechnol 28, 172–176 (2010).
Google Scholar
Xia, X. Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines. Vaccines (Basel) 9, https://doi.org/10.3390/vaccines9070734 (2021).
Hatit, M. Z. C. et al. Nanoparticle stereochemistry-dependent endocytic processing improves in vivo mRNA delivery. Nature Chemistry 15, 508–515 (2023).
Google Scholar
Dong, Y. et al. Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates. Proceedings of the National Academy of Sciences 111, 3955–3960 (2014).
Google Scholar
Muramatsu, H. et al. Lyophilization provides long-term stability for a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine. Mol Ther 30, 1941–1951 (2022).
Google Scholar
Plotkin, J. B. & Kudla, G. Synonymous but not the same: the causes and consequences of codon bias. Nature Reviews Genetics 12, 32–42 (2011).
Google Scholar
Hia, F. et al. Codon bias confers stability to human mRNAs. EMBO Rep 20, e48220 (2019).
Google Scholar
Courel, M. et al. GC content shapes mRNA storage and decay in human cells. eLife 8, e49708 (2019).
Google Scholar
Patel, P., Ibrahim, N. M. & Cheng, K. The Importance of Apparent pKa in the Development of Nanoparticles Encapsulating siRNA and mRNA. Trends Pharmacol Sci 42, 448–460 (2021).
Google Scholar
Cullis, P. R. & Hope, M. J. Lipid Nanoparticle Systems for Enabling Gene Therapies. Mol Ther 25, 1467–1475 (2017).
Google Scholar
Hassett, K. J. et al. Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines. Mol Ther Nucleic Acids 15, 1–11 (2019).
Google Scholar
Buschmann, M. D. et al. Nanomaterial Delivery Systems for mRNA Vaccines. Vaccines (Basel) 9, https://doi.org/10.3390/vaccines9010065 (2021).
Miao, L. et al. Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver. Nat Commun 11, 2424 (2020).
Google Scholar
Connors, J. et al. Lipid nanoparticles (LNP) induce activation and maturation of antigen presenting cells in young and aged individuals. Communications Biology 6, 188 (2023).
Google Scholar
Ndeupen, S. et al. The mRNA-LNP platform’s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory. iScience 24, 103479 (2021).
Google Scholar
Kobiyama, K. & Ishii, K. J. Making innate sense of mRNA vaccine adjuvanticity. Nat Immunol 23, 474–476 (2022).
Google Scholar
Alameh, M. G. et al. Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses. Immunity 54, 2877–2892.e2877 (2021).
Google Scholar
Dienz, O. et al. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells. J Exp Med 206, 69–78 (2009).
Google Scholar
Sidman, C. L., Marshall, J. D., Shultz, L. D., Gray, P. W. & Johnson, H. M. γ-Interferon is one of several direct B cell-maturing lymphokines. Nature 309, 801–804 (1984).
Google Scholar
Maeda, K., Mehta, H., Drevets, D. A. & Coggeshall, K. M. IL-6 increases B-cell IgG production in a feed-forward proinflammatory mechanism to skew hematopoiesis and elevate myeloid production. Blood 115, 4699–4706 (2010).
Google Scholar
Snapper, C. M. & Paul, W. E. Interferon-gamma and B Cell Stimulatory Factor-1 Reciprocally Regulate Ig Isotype Production. Science 236, 944–947 (1987).
Google Scholar
Blakney, A. K. et al. Polymeric and lipid nanoparticles for delivery of self-amplifying RNA vaccines. Journal of Controlled Release 338, 201–210 (2021).
Google Scholar
Zeng, Y., Escalona-Rayo, O., Knol, R., Kros, A. & Slutter, B. Lipid nanoparticle-based mRNA candidates elicit potent T cell responses. Biomater Sci 11, 964–974 (2023).
Google Scholar
Hubler, M. J. & Kennedy, A. J. Role of lipids in the metabolism and activation of immune cells. J Nutr Biochem 34, 1–7 (2016).
Google Scholar
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).
Google Scholar
Granados-Riveron, J. T. & Aquino-Jarquin, G. Engineering of the current nucleoside-modified mRNA-LNP vaccines against SARS-CoV-2. Biomed Pharmacother 142, 111953 (2021).
Google Scholar
Mauger, D. M. et al. mRNA structure regulates protein expression through changes in functional half-life. Proceedings of the National Academy of Sciences 116, 24075–24083 (2019).
Google Scholar
Gu, W. et al. The role of RNA structure at 5’ untranslated region in microRNA-mediated gene regulation. Rna 20, 1369–1375 (2014).
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
Mitschka, S. & Mayr, C. Context-specific regulation and function of mRNA alternative polyadenylation. Nat Rev Mol Cell Biol 23, 779–796 (2022).
Google Scholar
Castro-Chavez, F. Most Used Codons per Amino Acid and per Genome in the Code of Man Compared to Other Organisms According to the Rotating Circular Genetic Code. Neuroquantology 9, https://doi.org/10.14704/nq.2011.9.4.500 (2011).
Davis, D. R. Stabilization of RNA stacking by pseudouridine. Nucleic Acids Research 23, 5020–5026 (1995).
Google Scholar
Morais, P., Adachi, H. & Yu, Y.-T. The Critical Contribution of Pseudouridine to mRNA COVID-19 Vaccines. Frontiers in Cell and Developmental Biology 9, https://doi.org/10.3389/fcell.2021.789427 (2021).
Baiersdörfer, M. et al. A Facile Method for the Removal of dsRNA Contaminant from In Vitro-Transcribed mRNA. Mol Ther Nucleic Acids 15, 26–35 (2019).
Google Scholar
