文献类型：期刊文献

英文题名：Boosting mRNA Therapeutics: pHLIP Enhances Endosomal Escape and Gene Expression in Lipid Nanoparticle

作者：Liu, Caixia[1];Zhang, Kaixiang[2,3];Ge, Ruijie[2];Wang, Wenya[4];Liu, Xueting[3];Li, Xuan[2];Hao, Pei[5,6,7];Li, Honglin[1,8]

机构：[1]Lingang Lab, Shanghai 200031, Peoples R China;[2]Chinese Acad Sci, CAS Ctr Excellence Mol Plant Sci, Key Lab Synthet Biol, State Key Lab Plant Trait Design, Shanghai 200032, Peoples R China;[3]East China Univ Sci Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[4]ChemPartner PharmaTech Co Ltd, Shanghai 200237, Peoples R China;[5]Chinese Acad Sci, Shanghai Inst Immun & Infect, Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China;[6]Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;[7]Univ Chinese Acad Sci, Beijing 100049, Peoples R China;[8]East China Normal Univ, Innovat Ctr AI & Drug Discovery, Sch Pharm, Shanghai 200062, Peoples R China

年份：2026

卷号：15

期号：5

外文期刊名：ADVANCED HEALTHCARE MATERIALS

收录：;EI(收录号：20254419398940);WOS:【SCI-EXPANDED(收录号:WOS:001600887700001)】；

基金：We hope to thank Prof. Yangyang Yang at East China University of Science of Technology for her support with assembling lipid nanoparticle experiments, and Dr. Huiqing Yu at Shanghai Institute of Materia Medica, Chinese Academy of Sciences for her assistance with animal experiments. This work was supported in part by the National Key Research and Development Program of China (2022YFC3400501), the National Natural Science Foundation of China (grant Nos. 82425104, 32270695], and the Shanghai Post-doctoral Excellence Program (No. 2023013). C. Liu, K. Zhang and R. Ge contributed equally to this work.

语种：英文

外文关键词：endosomal escape; lipid nanoparticles; mRNA delivery; mRNA vaccine; pHLIP

摘要：Messenger RNA (mRNA) has emerged as a transformative technology for combating viral pandemics and malignancies, with lipid nanoparticle (LNP)-based mRNA vaccines playing a pivotal role in the COVID-19 pandemic. However, current LNP face challenges such as low endosomal escape efficiency (<5%), leading to cargo waste and increased costs. To address this, pHLIP-incorporated LNP (mRNA@LNP-pHLIP), leveraging the pH-dependent membrane-insertion properties of pHLIP is developed to enhance endosomal escape. pHLIP undergoes a conformational change in acidic environments, enabling it to insert into endosomal membranes and promote the release of mRNA into the cytosol. In vitro studies demonstrate a three to fivefold increase in mRNA expression across multiple cell lines, while in vivo experiments show sustained and higher protein expression in mice. Applied to a monkeypox vaccine encoding A35R and M1R antigens, mRNA@LNP-pHLIP elicited stronger immune responses, highlighting its potential for next-generation mRNA therapeutics and vaccines.