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While cationic polymers hold promise as genetic vectors, their poor in vivo efficacy and numerous variants highlight the urgent need for a universal functionalization strategy to bolster their delivery capabilities. Here, we present a versatile strategy to transform low\u2010cost commercial cationic polymers into phospholipidated and alkylated polymers (PAPs), enabling efficient and organ\u2010selective mRNA delivery in vivo. This straightforward post\u2010functionalization method can be readily broadened to a diverse array of existing cationic polymers, enhancing their cellular uptake, endosomal escape, and mRNA release functionalities. Consequently, PAPs facilitate up to 30,500\u2010fold higher mRNA expression compared to their unmodified counterparts in vivo. Notably, the one\u2010component PAPs enable spleen\u2010specific mRNA delivery, with their vaccine application validated in a mouse melanoma model following intravenous administration. Better still, PAPs can synergize with different helper lipids to formulate four\u2010component lipid nanoparticles (LNPs), achieving respective lung\u2010 and liver\u2010specific mRNA delivery. Noteworthy is that these organ\u2010selective mRNA delivery systems significantly outperform previous polymer and LNP benchmarks. This transformation strategy for cationic polymers represents a generalized methodology to give highly effective mRNA carriers, highlighting substantial potential for clinical translation of mRNA therapies with organ\u2010targeting requirements.<\/jats:p>","DOI":"10.1002\/anie.202500306","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T07:34:58Z","timestamp":1739259298000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["A Versatile Strategy to Transform Cationic Polymers for Efficient and Organ\u2010Selective mRNA Delivery"],"prefix":"10.1002","volume":"64","author":[{"given":"Lixin","family":"Lin","sequence":"first","affiliation":[{"name":"Eye Center of the Second Affiliated Hospital of Zhejiang University School of Medicine College of Pharmaceutical Sciences, Liangzhu Laboratory, State Key Laboratory of Advanced Drug Delivery and Release Systems Zhejiang University  Hangzhou 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