TY - JOUR
T1 - Enzyme-Catalyzed One-Step Synthesis of Ionizable Cationic Lipids for Lipid Nanoparticle-Based mRNA COVID-19 Vaccines
AU - Li, Zhongyu
AU - Zhang, Xue Qing
AU - Ho, William
AU - Li, Fengqiao
AU - Gao, Mingzhu
AU - Bai, Xin
AU - Xu, Xiaoyang
N1 - Funding Information:
X.X. acknowledges funding from National Science Foundation (2001606) and American Heart Association grant #19AIREA34380849. This research is also supported by the Gustavus and Louise Pfeiffer Research Foundation Award. X.-Q.Z. recognizes funding from the Foundation of National Facility for Translational Medicine (Shanghai) (TMSK-2020-008) and Shanghai Jiao Tong University Scientific and Technological Innovation Funds (2019TPA10) and the Interdisciplinary Program of Shanghai Jiao Tong University [ZH2018ZDA36 (19 × 190020006)].
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/11/22
Y1 - 2022/11/22
N2 - 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.
AB - 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.
KW - COVID-19 vaccines
KW - gene delivery
KW - ionizable lipids
KW - lipid nanoparticle
KW - mRNA therapeutics
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U2 - 10.1021/acsnano.2c07822
DO - 10.1021/acsnano.2c07822
M3 - Article
C2 - 36269150
AN - SCOPUS:85140839169
SN - 1936-0851
VL - 16
SP - 18936
EP - 18950
JO - ACS Nano
JF - ACS Nano
IS - 11
ER -