An Engineered Nanosugar Enables Rapid and Sustained Glucose‐Responsive Insulin Delivery in Diabetic Mice

Abstract Glucose‐responsive insulin‐delivery platforms that are sensitive to dynamic glucose concentration fluctuations and provide both rapid and prolonged insulin release have great potential to control hyperglycemia and avoid hypoglycemia diabetes. Here, biodegradable and charge‐switchable phytoglycogen nanoparticles capable of glucose‐stimulated insulin release are engineered. The nanoparticles are “nanosugars” bearing glucose‐sensitive phenylboronic acid groups and amine moieties that allow effective complexation with insulin (≈95% loading capacity) to form nanocomplexes. A single subcutaneous injection of nanocomplexes shows a rapid and efficient response to a glucose challenge in two distinct diabetic mouse models, resulting in optimal blood glucose levels (below 200 mg dL^–1) for up to 13 h. The morphology of the nanocomplexes is found to be key to controlling rapid and extended glucose‐regulated insulin delivery in vivo. These studies reveal that the injected nanocomplexes enabled efficient insulin release in the mouse, with optimal bioavailability, pharmacokinetics, and safety profiles. These results highlight a promising strategy for the development of a glucose‐responsive insulin delivery system based on a natural and biodegradable nanosugar.