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While clinically approved lipids like ALC\u20100315 demonstrate robust hepatic tropism, their inherent liver\u2010targeting bias substantially limits therapeutic applications requiring extrahepatic delivery. Furthermore, the complex safety validation requirements for novel lipid architectures present significant barriers to clinical translation. Hence, a simple nitrogen\u2010to\u2010sulfur (N\u2010to\u2010S) switching strategy is proposed in the head group of marketed vectors to modulate the tissue distribution of LNP\u2010mRNA. Proof\u2010of\u2010concept studies with ALC\u20100315\u2010derived S\u2010ALC\u20100315 reveal that this atomic\u2010level modification fundamentally redirected delivery tropism from hepatic to pulmonary tissues. Notably, formulation optimization demonstrates that combining S\u2010ALC\u20100315 with its parent lipid at a 1:2 molar ratio generated LNPs with spleen targeting. Consequently, this method promotes the generation of antigen\u2010specific cytotoxic T lymphocytes (CTL), and has produced significant anti\u2010tumor effects in two tumor models while maintaining safety. This research underscores the N\u2010to\u2010S lipid modification as a promising platform for tailoring organ targeting and accelerating clinical translation.<\/jats:p>","DOI":"10.1002\/adma.202509471","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T00:52:20Z","timestamp":1765587140000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Reprogramming mRNA Delivery Tropism via Nitrogen\u2010To\u2010Sulfur Substitution in Ionizable Lipids"],"prefix":"10.1002","volume":"38","author":[{"given":"Xing","family":"Duan","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine Frontiers Science Center for Disease\u2010related Molecular Network State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University  Chengdu 610041 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