A glucose-responsive dual-nanoparticle-hydrogel-based microneedle patch for co-delivery of insulin and exendin-4.

Combination therapy is one of the key strategies for managing type 2 diabetes mellitus (T2DM). The combined administration of insulin and exendin-4 can improve glycemic control, reduce the risk of hypoglycemia, and alleviate weight gain in T2DM patients. However, the co-administration of these two drugs is currently restricted to subcutaneous injection, which undoubtedly imposes pain and treatment burden on patients. Herein, we developed a dual-nanoparticle-hydrogel-based microneedle (MN) patch for the co-delivery of insulin and exendin-4. Insulin-loaded nanoparticles (iNPs) formed by weaker boronic ester bonds and exendin-4-loaded nanoparticles (eNPs) formed by stronger boronic ester bonds were co-encapsulated within a glucose-sensitive hydrogel for the fabrication of an MN patch. This design enabled the MN patch to dynamically release these two drugs in response to different blood glucose levels (BGLs). Under normoglycemic conditions, insulin was predominantly released to maintain fasting blood glucose homeostasis. In the case of postprandial hyperglycemia, both insulin and exendin-4 were released simultaneously, thereby exerting a synergistic and highly effective hypoglycemic effect. In vivo studies in T2DM mice demonstrated that the MN patch treatment effectively reduced BGLs, maintained normal blood glucose control for more than 28 hours without hypoglycemia risk, and improved glucose tolerance. In summary, this MN patch exhibits excellent therapeutic effects and clinical translation potential, offering a promising strategy for the long-term and safe treatment of T2DM.