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

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Enzyme-Catalyzed One-Step Synthesis of Ionizable Cationic Lipids for Lipid Nanoparticle-Based mRNA COVID-19 Vaccines
ACS Nano ( IF 15.8 ) Pub Date : 2022-10-21 , DOI: 10.1021/acsnano.2c07822
Zhongyu Li ₁ , Xue-Qing Zhang ₂ , William Ho ₁ , Fengqiao Li ₁ , Mingzhu Gao ₂ , Xin Bai ₂ , Xiaoyang Xu _{1,

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Affiliation

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.

中文翻译：

酶催化一步合成可电离阳离子脂质，用于基于脂质纳米颗粒的 mRNA COVID-19 疫苗

可电离的含阳离子脂质的脂质纳米粒子（LNP）是临床上最先进的非病毒基因递送平台，在基因治疗方面具有巨大的潜力。辉瑞/BioNTech 和 Moderna 的两种采用 mRNA-LNP 技术的 COVID-19 疫苗就是例证。在此，我们通过一步化学-生物酶催化酯化方法开发了可电离阳离子脂质的化学库，并将合成的可电离脂质进一步制备成用于mRNA递送的LNP。通过正交设计的实验方法筛选，性能最佳的AA3-DLin LNP表现出出色的mRNA递送功效和长期储存能力。此外，抗体滴度、病毒攻击和 T 细胞免疫反应研究证明，封装 SARS-CoV-2 刺突 mRNA 的 AA3-DLin LNP COVID-19 疫苗在 BALB/c 小鼠模型中成功诱导了强免疫原性。所开发的AA3-DLin LNPs是一个优秀的mRNA递送平台，本研究从脂质设计、合成、筛选、优化、制造、表征和应用方面提供了可电离阳离子脂质的整体视角。

更新日期：2022-10-21

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