4.8 Article

Enzyme-Catalyzed One-Step Synthesis of Ionizable Cationic Lipids for Lipid Nanoparticle-Based mRNA COVID-19 Vaccines

Journal

ACS NANO
Volume 16, Issue 11, Pages 18936-18950

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acsnano.2c07822

Keywords

ionizable lipids; lipid nanoparticle; gene delivery; COVID-19 vaccines; mRNA therapeutics

Funding

  1. National Science Foundation
  2. American Heart Association
  3. Gustavus and Louise Pfeiffer Research Foundation
  4. Foundation of National Facility for Translational Medicine (Shanghai)
  5. Shanghai Jiao Tong University Scientific and Technological Innovation Funds
  6. Interdisciplinary Program of Shanghai Jiao Tong University
  7. [2001606]
  8. [19AIREA34380849]
  9. [TMSK-2020-008]
  10. [2019TPA10]
  11. [ZH2018ZDA36]
  12. [190020006]

Ask authors/readers for more resources

Ionizable cationic lipid-containing lipid nanoparticles (LNPs) are important non-viral gene delivery platforms, and the developed AA3-DLin LNPs show excellent mRNA delivery efficacy and strong immunogenicity in COVID-19 vaccines.
Ionizable cationic lipid-containing lipid nanoparticles (LNPs) are the most clinically advanced non-viral gene delivery platforms, holding great potential for gene therapeutics. This is exemplified by the two COVID-19 vaccines employing mRNA-LNP technology from Pfizer/ BioNTech and Moderna. Herein, we develop a chemical library of ionizable cationic lipids through a one-step chemical-biological enzyme-catalyzed esterification method, and the synthesized ionizable lipids were further prepared to be LNPs for mRNA delivery. Through orthogonal design of experiment methodology screening, the top-performing AA3-DLin LNPs show outstanding mRNA delivery efficacy and long-term storage capability. Furthermore, the AA3-DLin LNP COVID-19 vaccines encapsulating SARSCoV-2 spike mRNAs successfully induced strong immunogenicity in a BALB/c mouse model demonstrated by the antibody titers, virus challenge, and T cell immune response studies. The developed AA3-DLin LNPs are an excellent mRNA delivery platform, and this study provides an overall perspective of the ionizable cationic lipids, from aspects of lipid design, synthesis, screening, optimization, fabrication, characterization, and application.

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