An environment-responsive platform based on acid-resistant metal organic framework for efficient oral insulin delivery

Oral insulin delivery is considered a revolutionary alternative to daily subcutaneous injections in terms of compliance and convenience. However, significant challenges remain in terms of inactivation in gastrointestinal environment and limited permeation across the intestinal epithelium. Herein, we used acid-resistant metal-organic framework (PCN-222) to load insulin and modified the exterior with sodium dodecyl sulfate (SDS) to achieve efficient oral insulin delivery. The PCN-222 nanocarrier with ordered mesoporous cage structure and suitable pore size achieved a high insulin loading of 75 %. The SDS on the surface of nanocarrier reduces its hydrophilicity while reversibly altering cell morphology and increasing epithelial cell permeability, thereby promoting intestinal epithelial absorption. The constructed particle (I@P@S) was encapsulated in sodium alginate (SA) microspheres to protect it from gastric acid degradation and releases it upon entry into the intestinal tract. Through an uptake pathway dominated by clathrin-mediated endocytosis, the released I@P@S realized efficient intestinal permeability and controlled insulin release under physiological conditions due to the phosphate sensitivity of PCN-222, leading to an in vivo bioavailability of 12.9 %. This work provides a valuable reference for the design of oral insulin delivery systems.