Han Xuexiang, Alameh Mohamad-Gabriel, Gong Ningqiang, Xue Lulu, Ghattas Majed, Bojja Goutham, Xu Junchao, Zhao Gan, Warzecha Claude C, Padilla Marshall S, El-Mayta Rakan, Dwivedi Garima, Xu Ying, Vaughan Andrew E, Wilson James M, Weissman Drew, Mitchell Michael J
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Key Laboratory of RNA Innovation, Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Nat Chem. 2024 Oct;16(10):1687-1697. doi: 10.1038/s41557-024-01557-2. Epub 2024 Jul 9.
Lipid nanoparticles (LNPs) are widely used for mRNA delivery, with cationic lipids greatly affecting biodistribution, cellular uptake, endosomal escape and transfection efficiency. However, the laborious synthesis of cationic lipids limits the discovery of efficacious candidates and slows down scale-up manufacturing. Here we develop a one-pot, tandem multi-component reaction based on the rationally designed amine-thiol-acrylate conjugation, which enables fast (1 h) and facile room-temperature synthesis of amidine-incorporated degradable (AID) lipids. Structure-activity relationship analysis of a combinatorial library of 100 chemically diverse AID-lipids leads to the identification of a tail-like amine-ring-alkyl aniline that generally affords efficacious lipids. Experimental and theoretical studies show that the embedded bulky benzene ring can enhance endosomal escape and mRNA delivery by enabling the lipid to adopt a more conical shape. The lead AID-lipid can not only mediate local delivery of mRNA vaccines and systemic delivery of mRNA therapeutics, but can also alter the tropism of liver-tropic LNPs to selectively deliver gene editors to the lung and mRNA vaccines to the spleen.
脂质纳米颗粒（LNPs）被广泛用于mRNA递送，阳离子脂质对生物分布、细胞摄取、内体逃逸和转染效率有很大影响。然而，阳离子脂质繁琐的合成过程限制了有效候选物的发现，并减缓了扩大规模生产的速度。在此，我们基于合理设计的胺-硫醇-丙烯酸酯共轭反应开发了一种一锅串联多组分反应，能够快速（1小时）且简便地在室温下合成含脒的可降解（AID）脂质。对100种化学性质不同的AID脂质组合文库进行构效关系分析，鉴定出一种尾状胺-环-烷基苯胺，它通常能提供有效的脂质。实验和理论研究表明，嵌入的大体积苯环可使脂质呈现更锥形的形状，从而增强内体逃逸和mRNA递送。先导AID脂质不仅可以介导mRNA疫苗的局部递送和mRNA治疗药物的全身递送，还可以改变肝靶向LNPs的趋向性，以选择性地将基因编辑器递送至肺部，并将mRNA疫苗递送至脾脏。
