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

Zhongyu Li, Xue Qing Zhang, William Ho, Fengqiao Li, Mingzhu Gao, Xin Bai, Xiaoyang Xu

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)18936-18950
Number of pages15
JournalACS Nano
Issue number11
StatePublished - Nov 22 2022

All Science Journal Classification (ASJC) codes

  • General Materials Science
  • General Engineering
  • General Physics and Astronomy


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


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