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

Document Type

Article

Publication Date

11-22-2022

Abstract

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 SARS-CoV-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.

Identifier

85140839169 (Scopus)

Publication Title

ACS Nano

External Full Text Location

https://doi.org/10.1021/acsnano.2c07822

e-ISSN

1936086X

ISSN

19360851

PubMed ID

36269150

First Page

18936

Last Page

18950

Issue

11

Volume

16

Grant

TMSK-2020-008

Fund Ref

National Science Foundation

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