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Current clinically advanced lipid nanoparticles (LNPs) primarily bind mRNA through electrostatic interactions, with limited exploration of other intermolecular forces that can benefit multiple delivery processes. Here, we design zinc\u2010coordinated lipids (Zn\u2010CL) to formulate LNPs, enabling high mRNA delivery efficacy in vivo. The zinc\u2010coordinated moieties in ionizable lipids show strong affinity toward phosphate groups, yielding tight yet reversible mRNA encapsulation. In addition, due to the abundance of phosphate groups in biological membranes, Zn\u2010CL lipids engage them to boost enhanced cellular uptake. Once inside endosomes, competitive binding of zinc\u2010coordinated moieties to the membranes strengthens endosomal destabilization and weakens Zn\u2011CL\/mRNA interactions, enabling efficient endosomal escape as well as rapid cytosolic mRNA release and resolving the long\u2011standing paradox between stable encapsulation and efficient release. As a result, zinc coordination introduction simultaneously solves multiple mRNA delivery obstacles, ultimately leading to 29\u2010fold higher mRNA translation than FDA\u2010approved SM\u2010102 LNPs in vivo. Notably, this coordination strategy is extendable to other metal ions, with cobalt\u2010coordinated lipids facilitating spleen\u2010targeted mRNA delivery. These findings highlight the substantial potential of metal\u2010coordinated lipids as a versatile platform for enhancing mRNA therapeutic delivery.<\/jats:p>","DOI":"10.1002\/anie.202515406","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T03:43:40Z","timestamp":1761018220000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Zinc\u2010Coordinated Lipids: Facilitators for Enhanced mRNA Delivery Efficacy"],"prefix":"10.1002","volume":"64","author":[{"given":"Yiran","family":"Zhang","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Sciences Liangzhu Laboratory Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kexin","family":"Su","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences Liangzhu Laboratory Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Shi","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences Liangzhu Laboratory Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqi","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences Liangzhu Laboratory Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Yan","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences Liangzhu Laboratory Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences Liangzhu Laboratory Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zichuan","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences Liangzhu Laboratory Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Bioengineering College of Chemical and Biological Engineering Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengfei","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences Liangzhu Laboratory Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8405-6743","authenticated-orcid":false,"given":"Shuai","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences Liangzhu Laboratory Zhejiang University  Hangzhou 310058 China"},{"name":"Eye Center of the Second Affiliated Hospital of Zhejiang University School of Medicine Zhejiang University  Hangzhou 310009 China"},{"name":"State Key Laboratory of Advanced Drug Delivery and Release Systems Zhejiang University  Hangzhou 310058 China"},{"name":"Zhejiang Key Laboratory of Pain Perception and Neuromodulation  Hangzhou 310009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,20]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"crossref","unstructured":"N.Pardi M. 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