Token is not live yet. Please beware of scams.
-1.5 C
New York

Degradable cyclic amino alcohol ionizable lipids as vectors for potent influenza mRNA vaccines

Date:

Node: 4536703
  • Pardi, N. & Krammer, F. mRNA vaccines for infectious diseases — advances, challenges and opportunities. Nat. Rev. Drug Discov. 23, 838–861 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Verbeke, R., Hogan, M. J., Loré, K. & Pardi, N. Innate immune mechanisms of mRNA vaccines. Immunity 55, 1993–2005 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, Y. et al. STING agonist-derived LNP-mRNA vaccine enhances protective immunity against SARS-CoV-2. Nano Lett. 23, 2593–2600 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Han, X. et al. Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines. Nat. Nanotechnol. 18, 1105–1114 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yan, J. et al. Nanomaterials-mediated co-stimulation of toll-like receptors and CD40 for antitumor immunity. Adv. Mater. 34, 2207486 (2022).

    Article 
    CAS 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Goldman, R. L. et al. Understanding structure activity relationships of Good HEPES lipids for lipid nanoparticle mRNA vaccine applications. Biomaterials 301, 122243 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Akinc, A. et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat. Biotechnol. 26, 561–569 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Whitehead, K. A. et al. Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity. Nat. Commun. 5, 4277 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tilstra, G. et al. Iterative design of ionizable lipids for intramuscular mRNA delivery. J. Am. Chem. Soc. 145, 2294–2304 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, B. et al. Effects of local structural transformation of lipid-like compounds on delivery of messenger RNA. Sci. Rep. 6, 22137 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 

    Google Scholar
     

  • Fukami, T. & Yokoi, T. The emerging role of human esterases. Drug Metab. Pharmacokinet. 27, 466–477 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Brotzel, F., Ying, C. C. & Mayr, H. Nucleophilicities of primary and secondary amines in water. J. Org. Chem. 72, 3679–3688 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Semple, S. C. et al. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 28, 172–176 (2010).

    Article 
    CAS 
    PubMed 

    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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Whitehead, K. A. et al. In vitro–in vivo translation of lipid nanoparticles for hepatocellular siRNA delivery. ACS Nano 6, 6922–6929 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 

    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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Maier, M. A. et al. Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. Mol. Ther. 21, 1570–1578 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hassett, K. J. et al. mRNA vaccine trafficking and resulting protein expression after intramuscular administration. Mol. Ther. Nucleic Acids 35, 102083 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Trougakos, I. P. et al. Adverse effects of COVID-19 mRNA vaccines: the spike hypothesis. Trends Mol. Med. 28, 542–554 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Broudic, K. et al. Nonclinical safety evaluation of a novel ionizable lipid for mRNA delivery. Toxicol. Appl. Pharm. 451, 116143 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Corbett, K. S. et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567–571 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pecetta, S. & Rappuoli, R. mRNA, the beginning of a new influenza vaccine game. Proc. Natl Acad. Sci. USA 119, e2217533119 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Russell, C. A. et al. Seasonal influenza vaccine performance and the potential benefits of mRNA vaccines. Hum. Vaccin. Immunother. 20, 2336357 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Plotkin, S. A. Correlates of protection induced by vaccination. Clin. Vaccin. Immunol. 17, 1055–1065 (2010).

    Article 
    CAS 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu, H. et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507, 519–522 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fenton, O. S. et al. Customizable lipid nanoparticle materials for the delivery of siRNAs and mRNAs. Angew. Chem. Int. Ed. 57, 13582–13586 (2018).

    Article 
    CAS 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Haensler, J. & Szoka, F. C. Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. Bioconjug. Chem. 4, 372–379 (1993).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nguyen, J. & Szoka, F. C. Nucleic acid delivery: the missing pieces of the puzzle?. Acc. Chem. Res. 45, 1153–1162 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Patel, S. et al. Brief update on endocytosis of nanomedicines. Adv. Drug Deliv. Rev. 144, 90–111 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 

    Google Scholar
     

  • Li, B. et al. Accelerating ionizable lipid discovery for mRNA delivery using machine learning and combinatorial chemistry. Nat. Mater. 23, 1002–1008 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mackerell, A. D. Empirical force fields for biological macromolecules: overview and issues. J. Comput. Chem. 25, 1584–1604 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brooks, B. R. et al. CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. J. Comput. Chem. 4, 187–217 (1983).

    Article 
    CAS 

    Google Scholar
     

  • Brooks, B. R. et al. CHARMM: the biomolecular simulation program. J. Comput. Chem. 30, 1545–1614 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hwang, W. et al. CHARMM at 45: enhancements in accessibility, functionality, and speed. J. Phys. Chem. B 128, 9976–10042 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar