Dual-mode-driven nanozyme nanomotors for active tissue penetration and gas-mediated microenvironment regulation in...

The spatially heterogeneous and dynamically evolving pathological microenvironment of diabetic wounds, characterized by excessive oxidative/inflammatory stress, deep-tissue hypoxia and irregularly shaped wounds, remains a major delivery challenge for topical nanotherapeutics, as passive diffusion limits both surface coverage and access to deeper tissue. Here, we report a dual-mode-driven nanozyme nanomotor, Fe₃O₄@CeO₂@polydopamine@L-arginine (FCPA), that combines active tissue penetration with reactive oxygen species (ROS)-responsive nitric oxide (NO) release and O₂ generation for diabetic wound microenvironment regulation. In this system, the heterogeneous ROS distribution promotes redistribution of FCPA across the wound surface, whereas external magnetic actuation enables controllable penetration into deeper wound tissue. In vitro, FCPA markedly reduced intracellular ROS levels, increased NO/O₂ levels, modulated macrophage polarization, and restored oxidative stress-impaired proliferation, migration, and angiogenesis-related functions with partial involvement of the peroxisome proliferator-activated receptor gamma (PPARγ)/endothelial nitric oxide synthase (eNOS) pathway. In a diabetic full-thickness wound model, magnetically actuated FCPA achieved 95.7% wound closure by day 14, with reduced inflammation and ROS levels, enhanced angiogenesis, collagen deposition, and re-epithelialization. Overall, this work demonstrates a nanotherapeutic strategy that integrates ROS-responsive surface distribution, magnetically-controlled deep penetration, and gas-mediated microenvironment regulation, providing a promising therapeutic platform for diabetic wound repair.