Ursodeoxycholic Acid‐Decorated Zwitterionic Nanoparticles for Orally Liver‐Targeted Close‐Looped Insulin Delivery

Abstract Oral insulin therapies targeting the liver and further simulating close‐looped secretion face significant challenges due to multiple trans‐epithelial barriers. Herein, ursodeoxycholic acid (UDCA)‐decorated zwitterionic nanoparticles (NPs) (UC‐CMs@ins) are designed to overcome these barriers, target the liver, and respond to glycemia, thereby achieving oral one‐time‐per‐day therapy. UC‐CMs@ins show excellent mucus permeability through the introduction of zwitterion (carboxy betaine, CB). Furthermore, UC‐CMs@ins possess superior cellular internalization via proton‐assisted amino acid transporter 1 (PAT1, CB‐receptor) and apical sodium‐dependent bile acid transporter (ASBT, UDCA‐receptor) pathways. Moreover, UC‐CMs@ins exhibit excellent endolysosomal escape ability and improve the basolateral release of insulin into the bloodstream via the ileal bile acid‐binding protein and the heteromeric organic solute transporter (OSTα‐ OSTβ) routes compared with non‐UDCA‐decorated C‐CMs@ins. Therefore, CB and UDCA jointly overcome mucus and intestinal barriers. Additionally, UC‐CMs@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 “closed‐loop” glucose control. Surprisingly, oral ingestion of UC‐CMs@ins shows a superior effect on glycemia (≈22 h, 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.