Breaking the Vicious Cycle: Nanozyme-Driven Multimodal Therapeutics for Diabetic Wound Regeneration

Diabetic wounds are a global health burden characterized by persistent non-healing and high infection risk. The hyperglycemic microenvironment triggers oxidative stress, microbial dysbiosis, and impaired angiogenesis, thereby disrupting the normal wound-healing process. Despite recent advancements, diabetic ulcers remain resistant to healing, leading to high amputation rates, which require novel treatments. Conventional therapies often fail to adequately address these multifaceted issues. Nanozymes, engineered nanoparticles that exhibit enzyme-like activities, are promising alternatives to natural enzymes for managing diabetic wounds. They offer sustained catalytic control over glucose, hydrogen peroxide (H₂O₂), and reactive oxygen species (ROS) in chronic wounds. Their stability, tailorable catalytic profiles, and responsiveness to microenvironmental cues enable precise, on-demand intervention at the wound site. This review focuses on glucose oxidase (Gox)-, superoxide dismutase (SOD)-, catalase (CAT)-, and peroxidase (POD)-mimicking nanozymes, analyzing their roles in (i) glycemic control, (ii) ROS neutralization, (iii) antimicrobial activity, and (iv) pro-angiogenic signaling. It also examines advanced delivery platforms that enhance therapeutic efficacy and discusses design principles for multienzyme cascade systems. Finally, translational challenges related to biocompatibility and regulatory compliance are critically assessed. A roadmap integrating artificial intelligence-driven multimodal therapy with personalized precision medicine further optimizes the clinical applications of nanozyme in treating chronic diabetic wounds.