Diabetes requires precise insulin management to maintain glycemic control and prevent severe complications. Glucose-responsive delivery systems envision an autonomous approach to improve insulin therapy. Here, a glucose-sensitive insulin delivery system comprising hyaluronic acid conjugated with a diboronate glucose binder as a carrier for diol-modified insulin is shown. This approach seeks improved precision in insulin delivery, leveraging bidentate glucose binding to achieve enhanced glucose affinity and specificity. Modification of insulin with a diol motif preserves its native conformation and function. These insulin formulations correct blood glucose in diabetic mice, including glucose-responsive function when subjected to a glucose challenge. However, the absence of secondary interactions, such as electrostatic complexation, ultimately limits the duration of function relative to that of previous platforms. Integrating complementary interactions alongside dynamic-covalent glucose binders therefore enhances the functional duration and therapeutic efficacy in the design of glucose-responsive polymeric carriers, offering design insights into the development of new carriers for glucose-responsive insulin delivery.

Czech Academy of Sciences Institute of Organic Chemistry and Biochemistry Prague 16610 Czech Republic

Department of Chemical and Biomolecular Engineering University of Notre Dame Notre Dame Indiana 46556 United States

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