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Here, we report a modular engineering strategy that incorporates FDA\u2010approved corticosteroids into LNP formulations, creating a new class of steroid LNPs with tunable anti\u2010inflammatory properties. Through systematic screening of steroid and cholesterol substitution ratios, we establish structure\u2013property relationships governing mRNA encapsulation efficiency, physicochemical characteristics, and inflammation suppression. Triamcinolone (TRI) emerges as our lead steroid, with 50% cholesterol substitution in SM\u2010102 LNPs preserving physicochemical characteristics. Importantly, we show that optimal substitution ratios are ionizable lipid\u2010dependent\u201480% for MC3 and 50% for SM\u2010102 and ALC\u20100315\u2014revealing fundamental design principles for these dual\u2010functional LNPs. In an endotoxemia mouse model, TRI LNPs administered intramuscularly maintain mRNA delivery efficacy while reducing inflammatory cytokines by \u223c4\u2010fold compared to SM\u2010102 LNPs. In a multiple sclerosis mouse model, TRI LNPs delivering therapeutic mRNA promote antigen\u2010specific tolerance in spinal cord tissue and protect against paralysis. Compared to SM\u2010102 LNPs, TRI LNPs reduce inflammatory cytokines by \u223c3\u2010fold and prolong protection against paralysis. Together, our work introduces a generalizable materials design strategy for engineering LNPs with tunable immunomodulatory properties to expand their therapeutic utility.<\/jats:p>","DOI":"10.1002\/adma.74301","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T10:15:40Z","timestamp":1786011340000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ionizable Lipid\u2010Dependent Optimization of Steroid Lipid Nanoparticles With Tunable Immunomodulatory Properties"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7372-8893","authenticated-orcid":false,"given":"Ajay S.","family":"Thatte","sequence":"first","affiliation":[{"name":"Department of Bioengineering University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin E.","family":"Nachod","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Baena","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna","family":"Muscat\u2010Rivera","sequence":"additional","affiliation":[{"name":"Division of Infectious Disease Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Penn Institute for RNA Innovation Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley","family":"Chaboub","sequence":"additional","affiliation":[{"name":"Division of Infectious Disease Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Penn Institute for RNA Innovation Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah C.","family":"Safford","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6455-8183","authenticated-orcid":false,"given":"Hannah C.","family":"Geisler","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah M.","family":"Yamagata","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melgious J. 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