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However, targetable tissues currently in preclinical development are limited to liver following systemic intravenous (IV) administration because predictable delivery of siRNA to non\u2010liver tissues remains an unsolved challenge. Here, evidence of durable extrahepatic gene silencing enabled by siRNA Selective ORgan Targeting lipid nanoparticles (siRNA SORT LNPs) to the kidneys, lungs, and spleen is provided. LNPs excel at dose\u2010dependent silencing of tissue\u2010enriched endogenous targets resulting in 60%\u201380% maximal knockdown after a single IV injection and up to 88% downregulation of protein expression in mouse lungs after two doses. To examine knockdown potency and unbiased organ targeting, B6.129\n                    <jats:sup>TdTom\/EGFP<\/jats:sup>\n                    mice that constitutively express the TdTomato transgene across all cell types are utilized to demonstrate 58%, 45%, and 15% reduction in TdTomato fluorescence in lungs, spleen, and kidneys, respectively. Finally, physiological relevance of siRNA SORT LNP\u2010mediated gene silencing is established via acute suppression of endogenous Tie2 which induces lung\u2010specific phenotypic alteration of vascular endothelial barrier. Due to plethora of extrahepatic diseases that may benefit from RNAi interventions, it is anticipated that the findings will expand preclinical landscape of therapeutic targets beyond the liver.\n                  <\/jats:p>","DOI":"10.1002\/adma.202313791","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T08:35:53Z","timestamp":1718958953000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":87,"title":["Expanding RNAi to Kidneys, Lungs, and Spleen via Selective ORgan Targeting (SORT) siRNA Lipid Nanoparticles"],"prefix":"10.1002","volume":"36","author":[{"given":"Amogh","family":"Vaidya","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Department of Biochemistry Simmons Comprehensive Cancer Center Program in Genetic Drug Engineering The University of Texas Southwestern Medical Center Dallas TX 75235 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