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However, conventional LNP formulations face several limitations, including poor endosomal escape and ApoE\u2010mediated liver tropism. Here, a novel class of LNPs, endogenous corticosteroid\u2010derived LNPs (cortico LNPs), is introduced in which the cholesterol component is replaced with endogenous corticosteroids, resulting in redirection from the liver to the spleen. Multiple corticosteroids and their precursors, including corticosterone, 11\u2010deoxycortisol, 11\u2010deoxycorticosterone, progesterone, 11\u03b2\u2010hydroxyprogesterone, and pregnenolone, are investigated due to their critical roles in immune regulation, stress response, and metabolism. Among these, corticosterone\u2010 and progesterone\u2010LNPs demonstrate robust protein expression in vivo with remarkable spleen selectivity of 97% and 99%, respectively. Additionally, these LNPs display superior safety profiles compared to the clinical SM\u2010102 formulation. It is proposed that the adsorption of \u03b22\u2010glycoprotein I (\u03b22\u2010GPI) on the LNP surface mediates the spleen\u2010specific delivery. Notably, this approach is also compatible with other clinically approved ionizable lipids, such as MC3 and ALC\u20100315, underscoring the versatility of corticosteroid modifications in optimizing organ tropism across different LNP platforms. These findings highlight the therapeutic potential of cortico LNPs to reprogram organ distribution and enhance gene targeting beyond the liver, representing an exciting advancement in the development of precision immunotherapy and gene therapy.<\/jats:p>","DOI":"10.1002\/smll.202503034","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T13:46:33Z","timestamp":1753451193000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Endogenous Corticosteroid Derived Lipid Nanoparticles (Cortico LNPs) Enable Selective mRNA Delivery to the Spleen"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3874-148X","authenticated-orcid":false,"given":"Ivan","family":"Isaac","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Nevada Las Vegas  Las Vegas NV 89154 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