Cascade reaction hydrogel with enzyme-catalyzed endogenous glucose for diabetic wound healing

The complex microenvironment of diabetic wounds, combined with the emergence of antibiotic-resistant bacteria under biofilms, makes it challenging for antibiotics or single treatment strategies to effectively treat infected wounds. To sustainably improve the wound microenvironment, we developed a hydrogel (Hyd-GZA) with controlled nitric oxide (NO) release based on a cascade reaction. This hydrogel contains an acid-sensitive cascade reactor (GOx@ZIF-90-Arg) loaded with glucose oxidase (GOx) and the NO donor l-arginine (l-Arg). Under hyperglycemic environments, GOx@ZIF-90-Arg catalyzes glucose to produce gluconic acid and hydrogen peroxide (H₂O₂). H₂O₂ not only induces oxidative stress in bacteria, but also oxidizes Arg to produce NO, which disperses and removes the biofilm. Simultaneously, the accumulation of gluconic acid lowers the local pH, stimulating the acid-responsive ZIF-90 to release zinc ions (Zn²⁺), synergistically eradicating bacteria. In addition, a diabetic whole skin defect model demonstrated that Hyd-GZA effectively promoted macrophage shift to M2 phenotype, regulated the expression of inflammatory factors, stimulated vascular regeneration and granulation tissue formation under the synergistic effect of Zn²⁺ and NO. Overall, Hyd-GZA, with its powerful ability to remodel the wound microenvironment, offers a novel strategy for treating diabetic wounds infected with bacterial biofilms.