Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, New Jersey07102, United States.
Engineering Research Center of Cell & Therapeutic Antibody Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai200240, P. R. China.
ACS Nano. 2022 Nov 22;16(11):18936-18950. doi: 10.1021/acsnano.2c07822. Epub 2022 Oct 21.
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.
含可离子化阳离子脂质的脂质纳米颗粒 (LNPs) 是最具临床应用前景的非病毒基因传递平台，在基因治疗方面具有巨大潜力。辉瑞/生物技术公司和 Moderna 公司采用 mRNA-LNP 技术的两种 COVID-19 疫苗就是很好的例子。在此，我们通过一步化学-生物酶催化酯化法开发了可离子化阳离子脂质的化学文库，合成的可离子化脂质进一步被制备成用于 mRNA 传递的 LNPs。通过正交设计实验方法学筛选，表现最佳的 AA3-DLin LNPs 显示出优异的 mRNA 传递效率和长期储存能力。此外，包封 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烈的免疫原性，抗体滴度、病毒挑战和 T 细胞免疫反应研究证明了这一点。所开发的 AA3-DLin LNPs 是一种优秀的 mRNA 传递平台，本研究从脂质设计、合成、筛选、优化、制备、表征和应用等方面全面介绍了可离子化阳离子脂质。
