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.

脂质纳米粒子（LNP）广泛用于 mRNA 递送，阳离子脂质极大地影响生物分布、细胞摄取、内体逃逸和转染效率。然而，阳离子脂质的费力合成限制了有效候选物的发现并减慢了规模化生产。在这里，我们开发了一种基于合理设计的胺-硫醇-丙烯酸酯缀合的一锅串联多组分反应，该反应能够快速（1小时）且轻松地在室温下合成脒掺入的可降解（AID）脂质。对 100 种化学上不同的 AID-脂质的组合库进行结构-活性关系分析，鉴定出通常提供有效脂质的尾状胺-环烷基苯胺。实验和理论研究表明，嵌入的大苯环可以通过使脂质呈圆锥形来增强内体逃逸和 mRNA 递送。主要的 AID-脂质不仅可以介导 mRNA 疫苗的局部递送和 mRNA 治疗剂的全身递送，而且还可以改变亲肝 LNP 的趋向性，以选择性地将基因编辑器递送到肺，并将 mRNA 疫苗递送到脾。