Glucose Oxidase‐Immobilized Dually‐Crosslinked Nanogels for Rapid‐Responsive Insulin Delivery

Abstract Despite the potential benefits of close‐looped insulin delivery systems in regulating glycemic homeostasis and effectively alleviating diabetes, they still encounter challenges such as limited effectiveness in preventing low glycemic episodes due to sluggish glucose response, and issues with the instability of enzymes and carriers. In this study, dually‐crosslinked and glucose oxidase (GOx)‐immobilized insulin nanogels (DC‐NGs@Ins) are developed for rapid‐responsive and sustained hypoglycemic therapy. The DC‐NGs@Ins with the phenylborate ester linker enabled the insulin release in a close‐looped fashion, and moreover, immobilized GOx‐generated hydrogen peroxide (H 2 O 2 ) by consuming the glucose, which can further bind to phenylborate ester for enhancing glucose response and accelerating the insulin release. The dually‐crosslinked structure (phenylboronic ester and UV‐crosslinking) effectively minimized the initial burst release of insulin, thus preventing the potential risk of hypoglycemia. More interestingly, GOx immobilized in the nanogels mitigated GOx leakage and enhanced its multiple utilization compared to free GOx. In vivo study demonstrated that DC‐NGs@Ins effectively maintained glycemic levels (BGLs) below 200 mg dL −1 for at least 8 h compared to singly‐crosslinked nanogels (SC‐NGs@Ins). Therefore, this intelligent insulin delivery system shows potential applications in diabetes treatment.