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. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.