Multi‐Enzyme Mimetic Microneedles with Spatiotemporal Control: Eradicating Biofilms, Resolving Oxidative Stress, and Revascularizing Diabetic Wounds

Diabetic wound healing remains clinically challenging due to persistent oxidative stress and dysregulated inflammation caused by the pathological microenvironment, particularly excessive reactive oxygen species (ROS). A near-infrared (NIR)-responsive multifunctional microneedle system (Res@ZIF-67/Ce_0.1Mn_0.9-MMON, RZCM) integrating antioxidant, antibacterial, and angiogenic functionalities is developed. The microneedle substrate incorporates Ce_0.1Mn_0.9-MMON nanoparticles that synergistically exert antibacterial effects through peroxidase-mimetic activity and NIR-induced photothermal hyperthermia, while concurrently mimicking superoxide dismutase and catalase activities to scavenge ROS and alleviate hypoxia. The microneedle tips encapsulate pH-responsive Res@ZIF-67 nanoparticles that release cobalt ions (Co²⁺) and resveratrol in acidic environments, cooperatively stabilizing hypoxia-inducible factor 1α (HIF-1α) under normoxic conditions to promote angiogenesis. In vivo evaluations demonstrate that RZCM accelerates diabetic wound healing through coordinated mechanisms: photothermal bacterial eradication, ROS scavenging (85.7% reduction), macrophage M2 polarization (2.3 fold increase), HIF-1α-mediated neovascularization (2.1 fold higher CD31 density), and enhanced collagen remodeling (78.4% increased collagen I/III ratio). This multifunctional system achieves complete epithelialization within 14 days, outperforming conventional treatments. By integrating multi-enzyme mimetic nanomaterials with microenvironment-responsive drug delivery, RZCM establishes a novel therapeutic paradigm for chronic wound management, demonstrating significant translational potential for diabetic wound care through synergistic regulation of oxidative, inflammatory, and angiogenic pathways.