LPA_(1) antagonist-derived LNPs deliver A20 mRNA and promote anti-fibrotic activities  

作　　者：Jingyue Yan Diana D.Kang Chang Wang Xucheng Hou Shi Du Siyu Wang Yonger Xue Zhengwei Liu Haoyuan Li Yichen Zhong Binbin Deng David W.McComb Yizhou Dong 

机构地区：[1]Division of Pharmaceutics&Pharmacology,College of Pharmacy,The Ohio State University,Columbus,OH 43210,USA [2]Icahn Genomics Institute,Precision Immunology Institute,Department of Immunology and Immunotherapy,Department of Oncological Sciences,Tisch Cancer Institute,Biomedical Engineering and Imaging Institute,Friedman Brain Institute,Icahn School of Medicine at Mount Sinai,New York,NY 10029,USA [3]Center for Electron Microscopy and Analysis,The Ohio State University,Columbus,OH 43212,USA [4]Department of Materials Science and Engineering,The Ohio State University,Columbus,OH 43210,USA

出　　处：《Nano Research》2024年第10期9095-9102,共8页纳米研究（英文版）

基　　金：the Maximizing Investigators’Research Award(No.R35GM119679);the National Institute of General Medical Sciences(No.R35GM144117);the support from the Professor Sylvan G.Frank Graduate Fellowship;the Presidential Fellowship.

摘　　要：Activated fibroblasts are major mediators of pulmonary fibrosis.Fibroblasts are generally found in the connective tissue but upon activation can generate excess extracellular matrix(ECM)in the lung interstitial section.Therefore,fibroblasts are one of the most targeted cells for treating idiopathic pulmonary fibrosis(IPF).Here,we develop an anti-fibrotic platform that can modulate both the lysophosphatidic acid receptor 1(LPA_(1))and the inflammatory pathway through tumor necrosis factorα-induced protein 3(TNFAIP3,also known as A20)in fibroblasts.First,we synthesized a series of LPA_(1) antagonists,AM095 and AM966,derived amino lipids(LA lipids)which were formulated into LA-lipid nanoparticles(LA-LNPs)encapsulating mRNA.Specifically,LA5-LNPs,with AM966 head group and biodegradable acetal lipid tails,showed efficient A20 mRNA delivery to lung fibroblasts in vitro(80.2%±1.5%)and ex vivo(17.2%±0.4%).When treated to primary mouse lung fibroblasts(MLF),this formulation inhibited fibroblast migration and collagen production,thereby slowing the progression of IPF.Overall,LA5-LNPs encapsulated with A20 mRNA is a novel platform offering a potential approach to regulate fibroblast activation for the treatment of IPF.

关 键 词：lysophosphatidic acid receptor 1(LPA_(1))antagonist tumor necrosis factorα-induced protein 3(A20) lung fibrosis lipid nanoparticles MRNA 

分 类 号：TB383[一般工业技术—材料科学与工程]