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Adv."],"published-print":{"date-parts":[[2026,7,3]]},"abstract":"<jats:p>\n                    Lipid nanoparticles (LNPs), composed of ionizable lipids, phospholipids, cholesterol, and PEGylated lipids, have been successfully used in messenger RNA (mRNA) vaccine development. Despite substantial progress, endosomal entrapment after cellular internalization is still a critical bottleneck limiting the vaccine efficacy. While the efforts to optimize lipid p\n                    <jats:italic toggle=\"yes\">K<\/jats:italic>\n                    <jats:sub>a<\/jats:sub>\n                    , spatial conformation, and LNP composition have been made, further fine-tuning of these parameters shows diminishing returns in improving effectiveness. Here, we propose a previously unreported parameter, programmable mechanical movement. LNPs are expected to destabilize endosomal membranes through conducting mechanical movements under specific inputs, achieving robust endosomal escape. Specifically, we demonstrate a light-emitting diode (LED)\u2013driven movable lipid (i.e., phenylazothiazole lipid) capable of performing mechanical movements. We integrate the movable lipids into the BNT162b2 formulation from Pfizer-BioNTech. Upon LED irradiation, the movable lipids within LNPs function as molecular rotors, thereby facilitating endosomal membrane destabilization. This strategy has achieved exciting preclinical results in enhancing mRNA-LNP cancer vaccine efficacy.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aef1695","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T17:59:22Z","timestamp":1782928762000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["Mechanical movements generated by movable lipids break endosomal barriers for enhanced mRNA therapeutics"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1643-6222","authenticated-orcid":true,"given":"Zilu","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Advanced Drug Delivery and Release Systems, Institute of Pharmaceutics, School of Pharmacy, Zhejiang University, Hangzhou 310058, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1249-9642","authenticated-orcid":true,"given":"Jie","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3665-8431","authenticated-orcid":true,"given":"Jiayu","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Advanced Medicals and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Tianjin 300192, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0501-8424","authenticated-orcid":true,"given":"Yumiao","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daohan","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Advanced Drug Delivery and Release Systems, Institute of Pharmaceutics, School of Pharmacy, Zhejiang University, Hangzhou 310058, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengfei","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Advanced Drug Delivery and Release Systems, Institute of Pharmaceutics, School of Pharmacy, Zhejiang University, Hangzhou 310058, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8106-0460","authenticated-orcid":true,"given":"Zhuoting","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Advanced Drug Delivery and Release Systems, Institute of Pharmaceutics, School of Pharmacy, Zhejiang University, Hangzhou 310058, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5360-2249","authenticated-orcid":true,"given":"Juanjuan","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Advanced Drug Delivery and Release Systems, Institute of Pharmaceutics, School of Pharmacy, Zhejiang University, Hangzhou 310058, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6773-3546","authenticated-orcid":true,"given":"Jinquan","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9029-8805","authenticated-orcid":true,"given":"Fan","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Advanced Medicals and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Tianjin 300192, 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