pH‐Responsive Sodium Alginate Micro‐Nano Hydrogels for Oral Insulin Delivery: Enhancing Therapeutic Efficacy and Reducing Hypoglycemic Risk

ABSTRACT Oral insulin administration offers significant advantages of accurate dosage, convenient administration, and improved patient compliance compared to subcutaneous injection. However, existing oral insulin formulations struggle to overcome the physiological barrier in the gastrointestinal tract, leading to low bioavailability and uncontrolled burst release. In this research, an insulin delivery system (SC@AP@INS) with a micro‐nano structure was developed using nano‐micelles (AP) based insulin delivery system cross‐linked with pH‐responsive sodium alginate hydrogel. In vitro experiment indicated that AP micelle promotes the speedy penetration of mucus and enhances the absorption of insulin. SC@AP@INS overcomes the gastrointestinal barrier, protects insulin from severe gastric conditions, and achieves a pH‐responsive drug release in the intestine. In streptozotocin (STZ)‐induced type 1 diabetic SD rats, the oral administration of SC@AP@INS exhibited a sustained and safer hypoglycemic effect than subcutaneous injection, while achieving an oral bioavailability of 12.91%. Additionally, SC@AP@INS effectively regulates the blood sugar of diabetic rats for a long time by simulating the action process of endogenous insulin. In vitro experiments and in vivo experiments show that the hydrogel has excellent biological safety. Taken together, the SC@AP@INS hydrogel has the advantages of convenient preparation and high utilization, conferring it with great potential for oral protein delivery.