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Here, we report a retinoic\u2010acid\u2010inspired ionizable lipid platform for spleen\u2010selective functional mRNA expression. Systematic variation of the ionizable scaffold, linker architecture, and retinoid\u2010derived hydrophobic domain generated a modular 40\u2010member library of retinoic\u2010acid\u2010derived ionizable lipids (RAILs). Paired in vitro and in vivo screening identified AT4\u201013CRA LNPs as the lead formulation, with the highest spleen\u2010to\u2010liver reporter\u2010expression ratio and approximately 15.1\u2010fold higher splenic expression than the tested Dlin\u2010MC3\/18PA selective organ targeting (SORT) formulation. Enhanced reporter expression was not explained by total cellular uptake alone and was accompanied by reduced lysosomal mRNA retention and attenuated TNF\u2010\u03b1\/NF\u2010\u03baB\u2010associated activation. Serum\u2010corona proteomics revealed an immunoglobulin heavy\u2010chain\u2010 and J\u2010chain\u2010associated profile distinct from the apolipoprotein\u2010associated profile of 18PA\u2010containing SORT LNPs. In Ai9 reporter mice and an OVA mRNA vaccination model, AT4\u201013CRA LNPs promoted functional expression in splenic macrophages and dendritic cells, enhanced antigen\u2010specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cell and antibody responses, and improved prophylactic protection against B16F10\u2010OVA tumor challenge. These findings establish retinoid\u2010derived hydrophobic\u2010domain engineering as a chemically defined route to spleen\u2010selective, inflammation\u2010restrained, antigen\u2010presenting\u2010cell\u2010centered mRNA cancer vaccination.\n                  <\/jats:p>","DOI":"10.1002\/anie.3823572","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T16:59:03Z","timestamp":1786553943000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Retinoic\u2010Acid\u2010Derived Ionizable Lipids Enable Spleen\u2010Selective Antigen Expression for mRNA Cancer Vaccination"],"prefix":"10.1002","volume":"65","author":[{"given":"Kai","family":"Jiang","sequence":"first","affiliation":[{"name":"Hefei National Research Center for Physical Sciences At the Microscale and State Key Laboratory of Precision and Intelligent Chemistry University of Science and Technology of China  Hefei Anhui 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