Liver‐Target and Glucose‐Responsive Polymersomes toward Mimicking Endogenous Insulin Secretion with Improved Hepatic Glucose Utilization

Abstract Oral insulin therapy that targets the liver and further mimics glucose‐responsive secretion holds promise for correcting defects in glucose metabolism caused by peripheral delivery. This work describes the construction of polymersomes (Pep‐PMS), which are composed of glucose‐responsive polymers decorated with peptides that readily bind to the ganglioside‐monosialic acid (GM1) receptor in the intestinal epithelium. Pep‐PMS are efficiently transported across the intestinal epithelium through GM1‐mediated transcytosis, leading to their abundant accumulation in the liver. Moreover, Pep‐PMS can efficiently encapsulate insulin in euglycemia and release them in hyperglycemia. Under hyperglycemic conditions, the Pep‐PMS dissociate to release the encapsulated insulin in response to glucose oxidase (GOx)‐induced H₂O₂. Surprisingly, the postprandial blood glucose levels of diabetic rats treated with Pep‐PMS can be maintained even after being challenged by glucose administration. Hepatic glucose uptake and glycogen production are also elevated after treating diabetic rats with Pep‐PMS, which is similar to glucose utilization in normal rats. Oral delivery systems that target the liver and serve as a reservoir for glucose‐responsive insulin secretion may improve the therapeutic effect in people with diabetes.