Oral delivery of insulin via bitter melon-derived extracellular vesicles: a novel strategy for effective hypoglycemia.

Bitter melon is an edible crop, widely recognized for its hypoglycemic effects. Extracellular vesicles, as key signaling mediators produced by living cells, retain the bioactive components of their parent plants and possess the ability to traverse biological barriers to facilitate intercellular communication. On this basis, bitter melon-derived extracellular vesicles (BMEVs) were isolated. Subsequent mechanistic investigations revealed that BMEVs promote glycogen synthesis and glucose consumption via the Akt-FoxO1-PEPCK pathway. Subsequently, insulin (INS) was loaded into BMEVs to develop an oral INS delivery system (BMEVs@INS). This system protects INS from gastrointestinal degradation and facilitates its translocation across the intestinal barrier, thereby enabling safe and efficient systemic delivery. This system exhibited significant hypoglycemic effects in both type 1 and type 2 diabetic models. BMEVs also ameliorated non-alcoholic fatty liver disease (NAFLD) in T2D mice, which is a common comorbidity of type 2 diabetes. In the safety assessment, favorable biocompatibility of BMEVs@INS was confirmed at both the cellular and animal levels. Through this strategy, a foundation was established for the use of plant-derived vesicles in oral INS delivery, and significant promise for future application was demonstrated.