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

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 (Mn = 500)] (pMEO9MA) 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 pMEO9MA chain length and pMEO9MA/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.