Piperazine-derived ionizable lipids for enhanced mRNA delivery and cancer immunotherapy  

作　　者：Kai Xu Yujia Xu Jin Sun Xinwei Cheng Chenxi Lu Wenzhong Chen Bingfang He Tianyue Jiang 

机构地区：[1]School of Pharmaceutical Sciences,Nanjing Tech University,Nanjing 211816,China [2]Department of Nano Formulation,Nanjing GeneLeap Biotechnology,Nanjing 210061,China

出　　处：《Nano Research》2024年第8期7357-7364,共8页纳米研究（英文版）

基　　金：supported by the National Key Research and Development Program of China(No.2019YFA0905200);the National Natural Science Foundation of China(No.82072045);the Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.KYCX23_1504).

摘　　要：Messenger ribonucleic acid(mRNA)-based therapeutics hold great prospects in disease treatment and lipid nanoparticles(LNPs)are the most extensively applied non-viral platform for RNA delivery in clinics.Despite the clinical success of LNPs as vehicles have been achieved,developing LNPs with enhanced mRNA transmembrane delivery and transfection efficiency in a non-toxic manner is highly desirable and challenging.In this study,we designed a series of new ionizable amino lipids with piperazinederived headgroups and constructed a group of LNPs to promote the transfection activity of mRNA cargos.Among them,LNP formulated with lipid 10(L10-LNP)can efficiently package mRNA and perform superior transfection efficiency both in vitro and in vivo,which is mainly attributed to the improved intracellular uptake and effective endosomal escape.We verified that a single administration of L10-LNP packaging interleukin(IL)-12 mRNA induced tumor shrink and even regression by robust activation of immune effector CD8^(+)T cells and stimulating the generation of IFN-γwithout causing systemic toxicity,which provides a promising platform for clinical cancer immunotherapy.

关 键 词：ionizable lipid lipid nanoparticle piperazine-derived lipid mRNA therapeutics cancer immunotherapy 

分 类 号：R730.51[医药卫生—肿瘤]