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While optimization efforts focus on ionizable and helper lipids, the role of trace PEG\u2010lipids remains underexplored. To address this, we constructed a 45\u2010member PEG\u2010lipid library via Ugi\/Passerini reactions, keeping the PEG chain constant at 2\u00a0kDa while systematically diversifying the hydrophobic tail and linker structures. High\u2010throughput screening identified Pr\u2010182\u2010BNT (P1B LNP) as a lead candidate. P1B LNPs enable highly efficient and selective mRNA delivery to skeletal muscle while drastically minimizing hepatic off\u2010targeting. This precise tropism originates from enhanced muscle cell uptake and optimized membrane interactions, driven by the lipid's unique branched, asymmetric tail. In Ai9 reporter mice, P1B LNPs drive potent muscle\u2010specific gene editing and reduce off\u2010target recombination. As an RSV mRNA vaccine, they elicit robust antigen\u2010specific IgG titers and expands polyfunctional CD8\n                    <jats:sup>+<\/jats:sup>\n                    IFN\u2010\u03b3\n                    <jats:sup>+<\/jats:sup>\n                    T cells, indicating a Th1\u2010skewed response. By re\u2010engineering only the trace PEG\u2010lipid, this work overcomes a key targeting limitation of classical LNPs and establishes a translatable platform for safer, more effective mRNA vaccines and therapeutics.\n                  <\/jats:p>","DOI":"10.1002\/smll.74730","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T09:57:48Z","timestamp":1784800668000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hydrophobic Tail and Linker Diversification of PEG\u2010Lipids Unlocks Precise Muscle Tropism of mRNA\u2010Lipid Nanoparticles"],"prefix":"10.1002","volume":"22","author":[{"given":"Bingqian","family":"Ou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Advanced Separation Membrane Materials Zhejiang Key Laboratory of Advanced Polymer Materials Modification and Application Technology, College of Materials Science and Engineering Zhejiang University of Technology  Hangzhou P. 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