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We report a modular platform of sterol\u2010containing ionizable lipids designed to probe how sterol motifs and branched dialkyl tails govern in vivo performance. Each lipid incorporates a sterol\u2010derived (e.g., cholesterol) tail and a dialkyl tail with tunable branching and spatial arrangement, enabling systematic control over packing behavior, protonation characteristics, and nanoparticle assembly. The resulting LNPs exhibited favorable apparent pKa values (6.2\u20136.8), encapsulation efficiencies higher than 90%, and strong transfection potency. Our lead LNP (L1\u2010aCho\u2010e3 LNP) exhibited higher transfection efficiency than the benchmark SM\u2010102 LNP. Incorporation of cationic (DOTAP) or anionic (DOPA) lipids as fifth components further demonstrated reorienting biodistribution from liver to lung or spleen. Finally, mRNA\n                    <jats:sup>H1N1<\/jats:sup>\n                    @L1\u2010aCho\u2010e3 LNPs elicited robust antibody responses and full protection against lethal H1N1 challenge. These results reveal how rational sterol tail design can be applied to create ionizable lipids with tunable structural functional properties for next\u2010generation mRNA therapeutics.\n                  <\/jats:p>","DOI":"10.1002\/smtd.70796","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T09:33:17Z","timestamp":1782466397000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial Tail Design in Ionizable Lipids Enhances the Safety and Efficacy of mRNA Delivery"],"prefix":"10.1002","volume":"10","author":[{"given":"Haiyang","family":"Li","sequence":"first","affiliation":[{"name":"Biomedical Division State Key Laboratory of Luminescent Materials and Devices Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates School of Materials Science and Engineering South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongyu","family":"Tian","sequence":"additional","affiliation":[{"name":"Institute of Infectious Diseases Shenzhen Bay Laboratory  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weining","family":"Kong","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Animal Science Peking Union Medicine College Chinese Academy of Medical Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Weiss","sequence":"additional","affiliation":[{"name":"General Therapeutics, Inc.  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