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Here, this challenge is addressed through rationally engineering compensatory forces between mRNA and LNP, leveraging short\u2010range intermolecular interactions (van der Waals, hydrogen bonding) to dynamically balance long\u2010range Coulombic binding. Guided by a computational\u2010experimental framework, a \u201ccontact number\u201d metric is developed to decipher mRNA and LNP binding hierarchies, enabling the strategic incorporation of short\u2010range\u2010interaction motifs (e.g., urea, carbamate) into ionizable lipid (IL) structures. These designs achieve optimal mRNA encapsulation while promoting endosomal escape and cytosolic release, resulting in enhanced mRNA translation. Compared to commercial mRNA vaccine counterparts, the engineered LNP (OT13\u2010LNP) induces a 1.7\u2010fold increase in antigen\u2010specific T cell responses and 77.9% tumor inhibition in melanoma. In hepatic gene editing, OT13\u2010LNPs achieve comparable transthyretin (TTR) on\u2010target editing efficiency to ALC0315\u2010LNPs (0.5\u00a0mg kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    ), but elicit a markedly stronger silencing effect, reducing serum TTR levels by over 90% compared with \u224858% for ALC0315\u2010LNPs. This study may highlights the potential of compensatory\u2010force engineering for next\u2010generation mRNA therapeutics in oncology, gene editing, and infectious diseases.\n                  <\/jats:p>","DOI":"10.1002\/adma.202512235","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T07:31:39Z","timestamp":1763364699000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Resolving the mRNA Encapsulation\u2010Release Trade\u2010off via Compensatory Forces in Engineered Ionizable Lipids"],"prefix":"10.1002","volume":"38","author":[{"given":"Weixiang","family":"Gao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Biopharmaceutical Preparation and Delivery Institute of Process Engineering Chinese Academy of Sciences  Beijing 100190 P. R. China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 P. R. 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