Bioinspired pH-Responsive Microalgal Hydrogels for Oral Insulin Delivery with Both Hypoglycemic and Insulin Sensitizing Effects

The oral form of insulin is more convenient and has better patient compliance than subcutaneous or intravenous insulin. Current oral insulin preparations, however, cannot overcome the enzyme barrier, chemical barrier, and epithelial barrier of the gastrointestinal tract completely. In this study, a microalgae-based oral insulin delivery strategy (CV@INS@ALG) was developed using Chlorella vulgaris (CV)-based insulin delivery system cross-linking with sodium alginate (ALG). CV@INS@ALG could overcome the gastrointestinal barrier, protect insulin from harsh gastric conditions, and achieve a pH-responsive drug release in the intestine. CV@INS@ALG might contribute to two mechanisms of insulin absorption, including direct insulin release from the delivery system and endocytosis by M cells and macrophages. In the streptozotocin (STZ)-induced type 1 diabetic mouse model, CV@INS@ALG showed a more effective and long-lasting hypoglycemic effect than direct insulin injection and did not cause any damage to the intestinal tract. Additionally, the long-term oral administration of the carrier CV@ALG effectively ameliorated gut microbiota disorder, and significantly increased the abundance of probiotic Akkermansia in db/db type 2 diabetic mice, thereby enhancing the insulin sensitivity of mice. Microalgal insulin delivery systems could be degraded and metabolized in the intestinal tract after oral administration, showing good biodegradability and biosafety. This insulin delivery strategy based on microalgal biomaterials provides a natural, efficient, and multifunctional solution for oral insulin delivery.