Cascade Nanozyme-Loaded Sprayable Hydrogels for Fibroblast Rejuvenation and Diabetic Wound Regeneration

Abstract

Multifunctional composite wound dressings hold significant promise for diabetic wound healing. However, the detrimental role of the advanced glycation end-products (AGEs)-reactive oxygen species (ROS) cycle in impeding wound repair remains underexplored. To disrupt this pathological cycle, zeolitic imidazolate framework-8 (ZIF-8) encapsulated cerium dioxide (CeO₂) and adsorbed glucose oxidase (GOx) nanozyme particles ((ZIF-8@CeO₂)@GOx, zcg) were loaded into a methacrylic anhydride-modified gelatin (GelMA) hydrogel to form a sprayable dressing, zcg/GelMA (zcgG). Physicochemical characterization revealed that GOx catalyzes glucose oxidation, triggering ZIF-8 acid-mediated decomposition to release zinc ions and CeO₂ nanoparticles, thereby enabling a cascade of glucose depletion, antioxidant, and antiglycation functions. In vitro antimicrobial and cytotoxicity experiments optimized the zcg concentration in GelMA. Under oxidative and hyperglycemic culture conditions, we validated the zcg mechanism of blocking the AGEs-ROS cycle, restoring fibroblast mitochondrial membrane potential, and subsequently suppressing cellular senescence. In a bacterial-infected diabetic rat skin wound model, the zcgG group demonstrated substantially reduced inflammatory levels, a 68% decrease in AGEs, and a 1.9-fold increase in collagen deposition compared to blank controls. Within 2 weeks, the zcgG group achieved complete wound closure, while the control group retained 28% of the initial wound area. This work provides preliminary evidence for the feasibility of using cascade nanozymes to break the AGEs-ROS cycle and promote wound healing.