Enhancing the immunogenicity of lipid-nanoparticle mRNA vaccines by adjuvanting the ionizable lipid and the mRNA

Bowen Li^#^{1

2

3

4

5}, Allen Yujie Jiang^#^{1

2}, Idris Raji^#^{1

2}, Caroline Atyeo^{6

7}, Theresa M Raimondo^{1

2}, Akiva G R Gordon^{1

2}, Luke H Rhym^{1

2}, Tahoura Samad^{1

8}, Corina MacIsaac^{1

9}, Jacob Witten^{1

2}, Haseeb Mughal^{1

10}, Taras M Chicz⁶, Yue Xu³, Ryan P McNamara⁶, Sangeeta Bhatia^{1

8

9

10

11

12

13

14

15}, Galit Alter⁶, Robert Langer^{1

2

8

9}, Daniel G Anderson^{16

17

18

19

20}

Affiliations

¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
⁴ Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
⁵ Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
⁶ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
⁷ Division of Medical Sciences, Harvard University, Boston, MA, USA.
⁸ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁹ Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹¹ Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹² Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹³ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
¹⁴ Wyss Institute at Harvard, Cambridge, MA, USA.
¹⁵ Howard Hughes Medical Institute, Cambridge, MA, USA.
¹⁶ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
¹⁷ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
¹⁸ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA. dgander@mit.edu.
¹⁹ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
²⁰ Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.

^# Contributed equally.

PMID: 37679571
DOI: 10.1038/s41551-023-01082-6

Enhancing the immunogenicity of lipid-nanoparticle mRNA vaccines by adjuvanting the ionizable lipid and the mRNA

Bowen Li et al. Nat Biomed Eng. 2025 Feb.

. 2025 Feb;9(2):167-184.

doi: 10.1038/s41551-023-01082-6. Epub 2023 Sep 7.

Authors

Affiliations

¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
⁴ Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
⁵ Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
⁶ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
⁷ Division of Medical Sciences, Harvard University, Boston, MA, USA.
⁸ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁹ Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹¹ Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹² Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹³ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
¹⁴ Wyss Institute at Harvard, Cambridge, MA, USA.
¹⁵ Howard Hughes Medical Institute, Cambridge, MA, USA.
¹⁶ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
¹⁷ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
¹⁸ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA. dgander@mit.edu.
¹⁹ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
²⁰ Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.

^# Contributed equally.

PMID: 37679571
DOI: 10.1038/s41551-023-01082-6

Erratum in

Author Correction: Enhancing the immunogenicity of lipid-nanoparticle mRNA vaccines by adjuvanting the ionizable lipid and the mRNA.
Li B, Jiang AY, Raji I, Atyeo C, Raimondo TM, Gordon AGR, Rhym LH, Samad T, MacIsaac C, Witten J, Mughal H, Chicz TM, Xu Y, McNamara RP, Bhatia S, Alter G, Langer R, Anderson DG. Li B, et al. Nat Biomed Eng. 2025 Feb;9(2):280. doi: 10.1038/s41551-025-01347-2. Nat Biomed Eng. 2025. PMID: 39820560 No abstract available.

Abstract

To elicit optimal immune responses, messenger RNA vaccines require intracellular delivery of the mRNA and the careful use of adjuvants. Here we report a multiply adjuvanted mRNA vaccine consisting of lipid nanoparticles encapsulating an mRNA-encoded antigen, optimized for efficient mRNA delivery and for the enhanced activation of innate and adaptive responses. We optimized the vaccine by screening a library of 480 biodegradable ionizable lipids with headgroups adjuvanted with cyclic amines and by adjuvanting the mRNA-encoded antigen by fusing it with a natural adjuvant derived from the C3 complement protein. In mice, intramuscular or intranasal administration of nanoparticles with the lead ionizable lipid and with mRNA encoding for the fusion protein (either the spike protein or the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) increased the titres of antibodies against SARS-CoV-2 tenfold with respect to the vaccine encoding for the unadjuvanted antigen. Multiply adjuvanted mRNA vaccines may improve the efficacy, safety and ease of administration of mRNA-based immunization.

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Conflict of interest statement

Competing interests: B.L., A.Y.J. and D.G.A. have filed a patent for the use of C3d in mRNA vaccines. D.G.A receives research funding from Sanofi/Translate Bio and is a co-founder of Orna Therapeutics. R.L. co-founded Moderna and serves on its board. He has been an advisor for Hopewell Therapeutics and Combined Therapeutics. For a list of entities with which R.L. is or has been recently involved, compensated or uncompensated, refer to the ‘Competing Interests’ section of the supplementary information (accurate as of July 2023). The other authors declare no competing interests.

References

1. Corbett, K. S. et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567–571 (2020). - PubMed - PMC
1. Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020). - PubMed
1. Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021). - PubMed
1. Vogel, A. B. et al. BNT162b vaccines protect rhesus macaques from SARS-CoV-2. Nature 592, 283–289 (2021). - PubMed
1. Barbier, A. J., Jiang, A. Y., Zhang, P., Wooster, R. & Anderson, D. G. The clinical progress of mRNA vaccines and immunotherapies. Nat. Biotechnol. 40, 840–854 (2022). - PubMed

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Enhancing the immunogenicity of lipid-nanoparticle mRNA vaccines by adjuvanting the ionizable lipid and the mRNA

Affiliations

Enhancing the immunogenicity of lipid-nanoparticle mRNA vaccines by adjuvanting the ionizable lipid and the mRNA

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

References

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous