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However, a major limitation lies in their preferential accumulation in the liver following intravenous administration, making most targets hard\u2010to\u2010reach. In this study, a novel platform called endogenous targeting lipid nanoparticles (ENDO), containing cholecalciferol (vitamin D3) as a fifth component is reported, that selectively delivers mRNA to the pancreas \u2013 a target previously inaccessible through intravenous administration. The top formulation, C\u2010CholF3, demonstrates an unprecedented 99% pancreas selectivity with robust and sustained protein expression for up to 3 days in a dose\u2010dependent manner with minimal toxicity that makes it suitable for repeat administration. This organ\u2010specific delivery is proposed to be mediated by an endogenous targeting mechanism involving the Vitamin D receptor (VDR). C\u2010CholF3 also enables selective pancreatic delivery of plasmid DNA and circular mRNA, underscoring its versatility and therapeutic potential. Furthermore, C\u2010CholF3 exhibits pancreas\u2010specific gene editing in the Ai14 transgenic mouse model, showing high expression of tdTomato in the \u03b2 cells. These findings highlight its potential for translational applications in protein replacement and CRISPR\/Cas9\u2010mediated gene editing for currently incurable pancreatic diseases, including pancreatic cancer and diabetes.<\/jats:p>","DOI":"10.1002\/adma.202507657","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T12:43:22Z","timestamp":1749732202000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Reengineering Endogenous Targeting Lipid Nanoparticles (ENDO) for Systemic Delivery of mRNA to Pancreas"],"prefix":"10.1002","volume":"37","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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