Complementary Antioxidant Strategy for Diabetic Wound Healing: Myricetin and Ceria Nanozymes for Enhanced Reactive Oxygen Species Management

Diabetic wounds are characterized by persistent oxidative stress, hypoxia, and chronic inflammation, leading to delayed healing and high risk of recurrence. Conventional antioxidants such as polyphenols can rapidly scavenge reactive oxygen species (ROS) but show short-lived and unstable activity, whereas inorganic nanozymes provide longer-term catalysis but respond more slowly to acute oxidative bursts. Here, a multifunctional hydrogel dressing (PBX@CCM) was constructed by integrating myricetin (MYR)-loaded ceria nanozymes (CCMNRs) into a dynamically crosslinked polyvinyl alcohol/borax/xanthan gum (PBX) network to achieve complementary antioxidant therapy for diabetic wounds. CCMNRs combined the rapid ROS-scavenging ability of MYR with the sustained, auto-regenerative redox cycling of Ce3+/Ce4+, enabling dual-action antioxidant behavior with multi-enzyme-mimicking activities, efficient ·OH and H2O2 clearance, oxygen generation, and inhibition of advanced glycation end products formation. PBX@CCM hydrogel exhibited a porous structure and self-healing properties, suitable rheological behavior, and good cytocompatibility and hemocompatibility. In lipopolysaccharide-stimulated macrophages, PBX@CCM reduced intracellular ROS levels and promoted M1-to-M2 polarization, indicating antioxidant and immunomodulatory effects. In a streptozotocin-induced diabetic rat model with full-thickness wounds, PBX@CCM significantly accelerated wound closure with improved tissue regeneration. These results demonstrate that PBX@CCM hydrogel provides a rapid-and-sustained antioxidant platform with immune regulation, offering a promising strategy for the treatment of diabetic wounds.