美国宾夕法尼亚大学Mitchell, Michael J.团队报道了用于体内多用途mRNA递送的酰胺结合可降解脂质的快速和容易合成。相关研究成果于2024年7月9日发表于国际顶尖学术期刊《自然—化学》。

脂质纳米颗粒（LNPs）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者的发现，并减缓了规模化生产。

该文中，研究人员开发了一种基于合理设计的胺-硫醇-丙烯酸酯偶联的一锅串联多组分反应，这使得能够在室温下快速（1小时）、简便地合成掺入脒的可降解（AID）脂质。对100种化学多样的AID脂质的组合文库进行结构-活性关系分析，从而鉴定出一种通常能提供有效脂质的类尾胺-环烷基苯胺。

实验和理论研究表明，嵌入的大体积苯环可以使脂质呈更圆锥形，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治疗剂的全身递送，还可以改变嗜肝LNPs的向性，选择性地将基因编辑物递送到肺，将mRNA病毒疫苗递送到脾。

附：英文原文

Title: Fast and facile synthesis of amidine-incorporated degradable lipids for versatile mRNA delivery in vivo

Author: 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.

Issue&Volume: 2024-07-09

Abstract: 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 (1h) 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.

DOI: 10.1038/s41557-024-01557-2

Source: https://www.nature.com/articles/s41557-024-01557-2