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Herein, ursodeoxycholic acid (UDCA)\u2010decorated zwitterionic nanoparticles (NPs) (UC\u2010CMs@ins) are designed to overcome these barriers, target the liver, and respond to glycemia, thereby achieving oral one\u2010time\u2010per\u2010day therapy. UC\u2010CMs@ins show excellent mucus permeability through the introduction of zwitterion (carboxy betaine, CB). Furthermore, UC\u2010CMs@ins possess superior cellular internalization via proton\u2010assisted amino acid transporter 1 (PAT1, CB\u2010receptor) and apical sodium\u2010dependent bile acid transporter (ASBT, UDCA\u2010receptor) pathways. Moreover, UC\u2010CMs@ins exhibit excellent endolysosomal escape ability and improve the basolateral release of insulin into the bloodstream via the ileal bile acid\u2010binding protein and the heteromeric organic solute transporter (OST\u03b1\u2010 OST\u03b2) routes compared with non\u2010UDCA\u2010decorated C\u2010CMs@ins. Therefore, CB and UDCA jointly overcome mucus and intestinal barriers. Additionally, UC\u2010CMs@ins prevent insulin degradation in the gastrointestinal tract for crosslinked structure, improve insulin accumulation in the liver for UDCA introduction, and effectively regulate glycemia for \u201cclosed\u2010loop\u201d glucose control. Surprisingly, oral ingestion of UC\u2010CMs@ins shows a superior effect on glycemia (\u224822\u00a0h, normoglycemia) and improves postprandial glycemic levels in diabetic mice, illustrating the enormous potential of the prepared NPs as a platform for oral insulin administration in diabetes treatment.<\/jats:p>","DOI":"10.1002\/adhm.202302677","type":"journal-article","created":{"date-parts":[[2024,1,21]],"date-time":"2024-01-21T07:28:11Z","timestamp":1705822091000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Ursodeoxycholic Acid\u2010Decorated Zwitterionic Nanoparticles for Orally Liver\u2010Targeted Close\u2010Looped Insulin Delivery"],"prefix":"10.1002","volume":"13","author":[{"given":"Yuhong","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Engineering School of Engineering China Pharmaceutical University  Nanjing 211198 P. R. 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