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

Oral insulin therapies targeting the liver and further simulating close‐looped secretion face significant challenges due to multiple trans‐epithelial barriers. Herein, we designed ursodeoxycholic acid (UDCA)‐decorated zwitterionic nanoparticles (UC‐CMs@ins) to overcome these barriers, target the liver, and respond to blood glycemia, thereby achieving oral one‐time‐per‐day therapy. UC‐CMs@ins showed excellent penetration of the intestinal mucus through the introduction of zwitterion (carboxy betaine, CB) introduction. Furthermore, UC‐CMs@ins possessed 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 exhibited excellent endolysosomal escape ability and improved the basolateral release of insulin into the bloodstream via the Golgi apparatus, ileal bile acid‐binding protein (IBABP), and the heteromeric organic solute transporter (OSTα‐ OSTβ) routes compared with non‐UDCA‐decorated C‐CMs@ins. Therefore, CB and UDCA jointly overcame mucus and intestinal barriers. Additionally, UC‐CMs@ins prevented insulin degradation in the gastrointestinal tract for crosslinked structure, improved insulin accumulation in the liver for UDCA introduction, and effectively regulated blood glucose for “closed‐loop” glucose control. Surprisingly, oral ingestion of UC‐CMs@ins showed a superior effect on blood glucose (∼ 22 h, normoglycemia), as well as improved postprandial glycemic levels (PGLs) in diabetic mice, illustrating the enormous potential of the prepared nanoparticles as a platform for oral insulin administration in diabetes treatment.

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