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To address this delivery challenge, we developed a new class of LNPs\u2014termed\n                    <jats:bold>C<\/jats:bold>\n                    h\n                    <jats:bold>O<\/jats:bold>\n                    lesterol alte\n                    <jats:bold>RE<\/jats:bold>\n                    d lipid nanoparticles (\n                    <jats:bold>CORE<\/jats:bold>\n                    LNPs)\u2014designed to shift mRNA expression away from the liver and toward the spleen, a central organ for systemic immune activation. To do so, we interfaced material synthesis with computational characterization to develop a series of novel cholesterol analogs which were incorporated alongside formulation components used for mRNA delivery. These were then optimized through design of experiment to generate 78 discrete formulations and were assessed for their physical properties, cellular uptake, and endosomal escape capabilities in vitro. Importantly, in vivo studies demonstrated that\n                    <jats:bold>CORE<\/jats:bold>\n                    LNPs were well\u2010tolerated and achieved highly selective mRNA expression in the spleen following intravenous administration. These results suggest that interfacing synthesis with computational characterization of novel cholesterol derivatives may modulate both nanoparticle behavior and organ\u2010level targeting, offering a promising strategy for developing spleen\u2010specific mRNA therapies for vaccination and immune modulation.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202505862","type":"journal-article","created":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T08:09:24Z","timestamp":1774685364000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CORE: Cholesterol Altered Lipid Nanoparticles for Splenic Expression of mRNA Payloads"],"prefix":"10.1002","volume":"15","author":[{"given":"Eshan A.","family":"Narasipura","sequence":"first","affiliation":[{"name":"Division of Pharmacoengineering and Molecular Pharmaceutics Eshelman School of Pharmacy University of North Carolina At Chapel Hill  Chapel Hill North Carolina 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