Biocompatible Nanogels Synthesized via RAFT Polymerization for Long‐Acting Onset‐Controllable Glucose‐Responsive Insulin Delivery in Diabetic Mice

ABSTRACT Glucose‐responsive insulin delivery (GRID) nanocarriers that can respond to glucose fluctuations rapidly and deliver insulin autonomously for long‐acting normoglycemic control with low risk of hypoglycemia are highly desirable but still unattained for diabetic care. Herein, we report a class of biocompatible nanogels with controllable onset of glucose response for self‐regulated insulin delivery. The narrowly distributed nanogels are prepared via controlled polymerization using the poly[oligo(ethylene glycol) methyl ether methacrylate (M n = 500)] (pMEO 9 MA) as macro‐chain transfer agents copolymerized with 4‐vinylphenylboronic acid (VPBA) and a crosslinker. The nanogels can be freeze‐dried and easily redispersed in an aqueous phase with excellent colloidal stability. The pMEO 9 MA chain length and pMEO 9 MA/VPBA ratio enable tuning both particle size and the onset of glucose responsiveness of the nanogels. A single injection of the insulin‐loaded nanogels can maintain normoglycemia in diabetic mice for up to 18 h. Importantly, the dose increase in the nanogel‐insulin prolongs the duration of normoglycemia but does not cause hypoglycemia in diabetic mice, benefiting from the reversible on‐off insulin delivery at the desirable glucose threshold. The nanogels exhibit no cytotoxicity or organ toxicity after repeated dosing in vivo. These results highlight great promise for developing swelling‐based nanogels for long‐acting GRID systems.