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Upadacitinib (UPA), a selective Janus kinase 1 (JAK1) inhibitor, has demonstrated clinical efficacy in UC, but its therapeutic application is often constrained by adverse effects arising from systemic drug exposure. This underscores the need for advanced, site-specific delivery systems that enhance local efficacy while minimizing systemic toxicity. Here, we developed a colon-targeted natural lipid nanoparticle formulation of UPA (UPA-nLNP) to improve therapeutic performance and safety. UPA-nLNP was prepared by thin-film hydration using digalactosyldiacylglycerol (DGDG), monogalactosyldiacylglycerol (MGDG), and phosphatidic acid (PA), mimicking the lipid composition of ginger-derived exosomal particles, and was characterized for particle size, surface charge, and encapsulation efficiency. The formulation exhibited excellent mucus-penetrating capability and was evaluated in a dextran sulfate sodium (DSS)-induced acute colitis model in C57BL\/6 mice following oral administration (5 mg\/kg). Pharmacokinetic analysis demonstrated increased colonic accumulation with reduced systemic exposure compared to free UPA. Treatment with UPA-nLNP improved body weight recovery, reduced disease biomarkers, and suppressed key proinflammatory cytokines in the colon, with no evidence of systemic toxicity. This innovative strategy holds strong potential to enhance the clinical utility of JAK1 inhibitors by providing a safer and more effective therapeutic approach for ulcerative colitis.<\/jats:p>","DOI":"10.3390\/ijms27093758","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T12:04:42Z","timestamp":1776945882000},"page":"3758","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Oral Colon-Targeted Lipid Nanoparticles Enhance Upadacitinib Delivery and Efficacy in a Murine Model of Ulcerative Colitis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2068-7759","authenticated-orcid":false,"given":"Rabeya Jafrin","family":"Mow","sequence":"first","affiliation":[{"name":"Digestive Disease Research Group, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodi","family":"Shi","sequence":"additional","affiliation":[{"name":"Digestive Disease Research Group, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Arts & Sciences, Georgia State University, Atlanta, GA 30303, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siming","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Arts & Sciences, Georgia State University, Atlanta, GA 30303, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Merlin","sequence":"additional","affiliation":[{"name":"Digestive Disease Research Group, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA"},{"name":"Atlanta Veterans Affairs Medical Center, Decatur, GA 30302, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0805-1008","authenticated-orcid":false,"given":"Chunhua","family":"Yang","sequence":"additional","affiliation":[{"name":"Digestive Disease Research Group, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA"},{"name":"Atlanta Veterans Affairs Medical Center, Decatur, GA 30302, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.mayocp.2018.09.013","article-title":"Mechanisms of Disease: Inflammatory Bowel Diseases","volume":"94","author":"Ramos","year":"2019","journal-title":"Mayo Clin. 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