Nanocarriers for On-Demand Insulin Aspart Delivery: Integrated Control of Postprandial and Basal Glycemia in Type 2 Diabetic Mice

Type 2 diabetes mellitus demands coordinated control of fasting and postprandial glycemia, and current clinical rapid-acting insulin aspart (IAsp) suffers from short action duration and hypoglycemia-related risks. We describe a glucose-sensitive insulin delivery system based on rigid amphiphilic methoxy poly(ethylene glycol)-polysalicylate (mPEG-PSA) copolymers synthesized by controlled ring-opening polymerization of salicylic acid O-carboxyanhydride, with a structure substantially different from conventional aliphatic polyesters. The 100–150 nm nanoparticles possessed favorable colloidal stability, ∼85% encapsulation efficiency and ∼20% drug loading, and IAsp bioactivity was well preserved. In vitro release followed glucose-dependent kinetics tuned by PSA hydrophobicity. In streptozotocin-induced diabetic mice, IAsp@mPEG-PSA restored euglycemia within 0.5 h and maintained normoglycemia for up to 10 h without hypoglycemia, outperforming free IAsp and mPEG-PLA formulations in this animal model. The nanosystem realized glucose-activated on-demand insulin release to suppress repeated glucose spikes, accomplishing combined postprandial and basal glycemic regulation in rodents. This study presents mPEG-PSA as a promising polymeric candidate for glucose-responsive insulin delivery.