
Pardi, N. & Krammer, F. mRNA vaccines for infectious diseases — advances, challenges and opportunities. Nat. Rev. Drug Discov. 23, 838–861 (2024).
COVID-19, vaccinations (broken down by manufacturer). Our World in Data https://ourworldindata.org/grapher/covid-vaccine-doses-by-manufacturer (accessed 25 May 2025).
Warne, N. et al. Delivering 3 billion doses of Comirnaty in 2021. Nat. Biotechnol. 41, 183–188 (2023).
Chaudhary, N., Weissman, D. & Whitehead, K. A. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat. Rev. Drug Discov. 20, 817–838 (2021).
Gupta, A., Rudra, A., Reed, K., Langer, R. & Anderson, D. G. Advanced technologies for the development of infectious disease vaccines. Nat. Rev. Drug Discov. https://doi.org/10.1038/s41573-024-01041-z (2024).
Rosa, S. S., Prazeres, D. M. F., Azevedo, A. M. & Marques, M. P. C. mRNA vaccines manufacturing: challenges and bottlenecks. Vaccine 39, 2190–2200 (2021).
Roozen, G. V. T., Roukens, A. H. E. & Roestenberg, M. COVID-19 vaccine dose sparing: strategies to improve vaccine equity and pandemic preparedness. Lancet Glob. Health 10, e570–e573 (2022).
Yassini, P. et al. Interim analysis of a phase 1 randomized clinical trial on the safety and immunogenicity of the mRNA-1283 SARS-CoV-2 vaccine in adults. Hum. Vaccin. Immunother. 19, 2190690 (2023).
Verbeke, R., Hogan, M. J., Loré, K. & Pardi, N. Innate immune mechanisms of mRNA vaccines. Immunity 55, 1993–2005 (2022).
Hassett, K. J. et al. Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines. Mol. Ther. Nucleic Acids 15, 1–11 (2019).
Public assessment report authorisation for temporary supply COVID-19 mRNA vaccine BNT162b2 (BNT162b2 RNA) concentrate for solution for injection. MHRA https://assets.publishing.service.gov.uk/media/63529601e90e07768265c115/COVID-19_mRNA_Vaccine_BNT162b2__UKPAR___PFIZER_BIONTECH_ext_of_indication_11.6.2021.pdf (accessed 25 May 2025).
Oda, Y. et al. Immunogenicity and safety of a booster dose of a self-amplifying RNA COVID-19 vaccine (ARCT-154) versus BNT162b2 mRNA COVID-19 vaccine: a double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet Infect. Dis. https://doi.org/10.1016/S1473-3099(23)00650-3 (2024).
Sabnis, S. et al. A novel amino lipid series for mRNA delivery: improved endosomal escape and sustained pharmacology and safety in non-human primates. Mol. Ther. 26, 1509–1519 (2018).
Miao, L. et al. Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation. Nat. Biotechnol. 37, 1174–1185 (2019).
Li, B. et al. Enhancing the immunogenicity of lipid-nanoparticle mRNA vaccines by adjuvanting the ionizable lipid and the mRNA. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-023-01082-6 (2023).
Zhang, Y. et al. STING agonist-derived LNP-mRNA vaccine enhances protective immunity against SARS-CoV-2. Nano Lett. 23, 2593–2600 (2023).
Han, X. et al. Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines. Nat. Nanotechnol. 18, 1105–1114 (2023).
Yan, J. et al. Nanomaterials-mediated co-stimulation of toll-like receptors and CD40 for antitumor immunity. Adv. Mater. 34, 2207486 (2022).
Pulendran, B., S. Arunachalam, P. & O’Hagan, D. T. Emerging concepts in the science of vaccine adjuvants. Nat. Rev. Drug Discov. 20, 454–475 (2021).
Goldman, R. L. et al. Understanding structure activity relationships of Good HEPES lipids for lipid nanoparticle mRNA vaccine applications. Biomaterials 301, 122243 (2023).
Fenton, O. S. et al. Bioinspired alkenyl amino alcohol ionizable lipid materials for highly potent in vivo mRNA delivery. Adv. Mater. 28, 2939–2943 (2016).
Akinc, A. et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat. Biotechnol. 26, 561–569 (2008).
Love, K. T. et al. Lipid-like materials for low-dose, in vivo gene silencing. Proc. Natl Acad. Sci. USA 107, 1864–1869 (2010).
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).
Whitehead, K. A. et al. Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity. Nat. Commun. 5, 4277 (2014).
Chen, J. et al. Combinatorial design of ionizable lipid nanoparticles for muscle-selective mRNA delivery with minimized off-target effects. Proc. Natl Acad. Sci. USA 120, e2309472120 (2023).
Tilstra, G. et al. Iterative design of ionizable lipids for intramuscular mRNA delivery. J. Am. Chem. Soc. 145, 2294–2304 (2023).
Han, X. et al. Optimization of the activity and biodegradability of ionizable lipids for mRNA delivery via directed chemical evolution. Nat. Biomed. Eng. 8, 1412–1424 (2024).
Li, B. et al. Effects of local structural transformation of lipid-like compounds on delivery of messenger RNA. Sci. Rep. 6, 22137 (2016).
Miller, J. B., Kos, P., Tieu, V., Zhou, K. & Siegwart, D. J. Development of cationic quaternary ammonium sulfonamide amino lipids for nucleic acid delivery. ACS Appl. Mater. Interfaces 10, 2302–2311 (2018).
Cornebise, M. et al. Discovery of a novel amino lipid that improves lipid nanoparticle performance through specific interactions with mRNA. Adv. Funct. Mater. 32, 2106727 (2022).
Fukami, T. & Yokoi, T. The emerging role of human esterases. Drug Metab. Pharmacokinet. 27, 466–477 (2012).
Brotzel, F., Ying, C. C. & Mayr, H. Nucleophilicities of primary and secondary amines in water. J. Org. Chem. 72, 3679–3688 (2007).
Heyes, J., Palmer, L., Bremner, K. & MacLachlan, I. Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids. J. Control. Release 107, 276–287 (2005).
Semple, S. C. et al. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 28, 172–176 (2010).
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).
Whitehead, K. A. et al. In vitro–in vivo translation of lipid nanoparticles for hepatocellular siRNA delivery. ACS Nano 6, 6922–6929 (2012).
Jayaraman, M. et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chem. Int. Ed. 51, 8529–8533 (2012).
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).
Maier, M. A. et al. Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. Mol. Ther. 21, 1570–1578 (2013).
Ndeupen, S. et al. The mRNA-LNP platform’s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory. iScience 24, 103479 (2021).
Hassett, K. J. et al. mRNA vaccine trafficking and resulting protein expression after intramuscular administration. Mol. Ther. Nucleic Acids 35, 102083 (2024).
Trougakos, I. P. et al. Adverse effects of COVID-19 mRNA vaccines: the spike hypothesis. Trends Mol. Med. 28, 542–554 (2022).
Efe, C. et al. Liver injury after SARS-CoV-2 vaccination: features of immune-mediated hepatitis, role of corticosteroid therapy and outcome. Hepatology 76, 1576–1586 (2022).
Pateev, I., Seregina, K., Ivanov, R. & Reshetnikov, V. Biodistribution of RNA vaccines and of their products: evidence from human and animal studies. Biomedicines 12, 59 (2023).
Zhang, D. et al. Simplified quantification method for in vivo SPECT/CT imaging of asialoglycoprotein receptor with 99mTc-p(VLA-co-VNI) to assess and stage hepatic fibrosis in mice. Sci. Rep. 6, 25377 (2016).
Welsher, K., Sherlock, S. P. & Dai, H. Deep-tissue anatomical imaging of mice using carbon nanotube fluorophores in the second near-infrared window. Proc. Natl Acad. Sci. USA 108, 8943–8948 (2011).
Broudic, K. et al. Nonclinical safety evaluation of a novel ionizable lipid for mRNA delivery. Toxicol. Appl. Pharm. 451, 116143 (2022).
Corbett, K. S. et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567–571 (2020).
Pecetta, S. & Rappuoli, R. mRNA, the beginning of a new influenza vaccine game. Proc. Natl Acad. Sci. USA 119, e2217533119 (2022).
Russell, C. A. et al. Seasonal influenza vaccine performance and the potential benefits of mRNA vaccines. Hum. Vaccin. Immunother. 20, 2336357 (2024).
Fink, A. L., Engle, K., Ursin, R. L., Tang, W.-Y. & Klein, S. L. Biological sex affects vaccine efficacy and protection against influenza in mice. Proc. Natl Acad. Sci. USA 115, 12477–12482 (2018).
Watanabe, H., Numata, K., Ito, T., Takagi, K. & Matsukawa, A. Innate immune response in th1- and th2-dominant mouse strains. Shock 22, 460–466 (2004).
Plotkin, S. A. Correlates of protection induced by vaccination. Clin. Vaccin. Immunol. 17, 1055–1065 (2010).
Khoury, D. S. et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat. Med. 27, 1205–1211 (2021).
Liu, H. et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507, 519–522 (2014).
Fenton, O. S. et al. Customizable lipid nanoparticle materials for the delivery of siRNAs and mRNAs. Angew. Chem. Int. Ed. 57, 13582–13586 (2018).
Liang, F. et al. Efficient targeting and activation of antigen-presenting cells in vivo after modified mRNA vaccine administration in rhesus macaques. Mol. Ther. 25, 2635–2647 (2017).
Haensler, J. & Szoka, F. C. Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. Bioconjug. Chem. 4, 372–379 (1993).
Bus, T., Traeger, A. & Schubert, U. S. The great escape: how cationic polyplexes overcome the endosomal barrier. J. Mater. Chem. B 6, 6904–6918 (2018).
Freeman, E. C., Weiland, L. M. & Meng, W. S. Modeling the proton sponge hypothesis: examining proton sponge effectiveness for enhancing intracellular gene delivery through multiscale modeling. J. Biomater. Sci. Polym. Ed. 24, 398–416 (2013).
Nguyen, J. & Szoka, F. C. Nucleic acid delivery: the missing pieces of the puzzle?. Acc. Chem. Res. 45, 1153–1162 (2012).
Patel, S. et al. Brief update on endocytosis of nanomedicines. Adv. Drug Deliv. Rev. 144, 90–111 (2019).
Hafez, I. M., Maurer, N. & Cullis, P. R. On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids. Gene Ther. 8, 1188–1196 (2001).
Finger, S., Schwieger, C., Arouri, A., Kerth, A. & Blume, A. Interaction of linear polyamines with negatively charged phospholipids: the effect of polyamine charge distance. Biol. Chem. 395, 769–778 (2014).
Aty, H. A. et al. Machine learning platform for determining experimental lipid phase behaviour from small angle X-ray scattering patterns by pre-training on synthetic data. Digit. Discov. 1, 98–107 (2022).
Li, B. et al. Accelerating ionizable lipid discovery for mRNA delivery using machine learning and combinatorial chemistry. Nat. Mater. 23, 1002–1008 (2024).
Witten, J. et al. Artificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy. Nat. Biotechnol. https://doi.org/10.1038/s41587-024-02490-y (2024).
Best, R. B. et al. Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ1 and χ2 dihedral angles. J. Chem. Theory Comput. 8, 3257–3273 (2012).
Mackerell, A. D. Empirical force fields for biological macromolecules: overview and issues. J. Comput. Chem. 25, 1584–1604 (2004).
Venable, R. M., Brown, F. L. H. & Pastor, R. W. Mechanical properties of lipid bilayers from molecular dynamics simulation. Chem. Phys. Lipids 192, 60–74 (2015).
Leonard, A. N., Wang, E., Monje-Galvan, V. & Klauda, J. B. Developing and testing of lipid force fields with applications to modeling cellular membranes. Chem. Rev. 119, 6227–6269 (2019).
Klauda, J. B. et al. Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J. Phys. Chem. B 114, 7830–7843 (2010).
Brooks, B. R. et al. CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. J. Comput. Chem. 4, 187–217 (1983).
Brooks, B. R. et al. CHARMM: the biomolecular simulation program. J. Comput. Chem. 30, 1545–1614 (2009).
Hwang, W. et al. CHARMM at 45: enhancements in accessibility, functionality, and speed. J. Phys. Chem. B 128, 9976–10042 (2024).
Smith, P., Ziolek, R. M., Gazzarrini, E., Owen, D. M. & Lorenz, C. D. On the interaction of hyaluronic acid with synovial fluid lipid membranes. Phys. Chem. Chem. Phys. 21, 9845–9857 (2019).
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