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

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.