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However, current LNP face challenges such as low endosomal escape efficiency (&lt;5%), leading to cargo waste and increased costs. To address this, pHLIP\u2010incorporated LNP (mRNA@LNP\u2010pHLIP), leveraging the pH\u2010dependent membrane\u2010insertion 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\u2010pHLIP elicited stronger immune responses, highlighting its potential for next\u2010generation mRNA therapeutics and vaccines.<\/jats:p>","DOI":"10.1002\/adhm.202502567","type":"journal-article","created":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T05:41:45Z","timestamp":1761370905000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Boosting mRNA Therapeutics: pHLIP Enhances Endosomal Escape and Gene Expression in Lipid Nanoparticle"],"prefix":"10.1002","volume":"15","author":[{"given":"Caixia","family":"Liu","sequence":"first","affiliation":[{"name":"Lingang Laboratory  Shanghai 200031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaixiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Synthetic Biology, State Key Laboratory of Plant Trait Design, CAS Center for Excellence in Molecular Plant Sciences Chinese Academy of Sciences  Shanghai 200032 China"},{"name":"State Key Laboratory of Bioreactor Engineering East China University of Science of Technology  Shanghai 200237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruijie","family":"Ge","sequence":"additional","affiliation":[{"name":"Key Laboratory of Synthetic Biology, State Key Laboratory of Plant Trait Design, CAS Center for Excellence in Molecular Plant Sciences Chinese Academy of Sciences  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenya","family":"Wang","sequence":"additional","affiliation":[{"name":"ChemPartner PharmaTech Co., Ltd.  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