Oxygen-Vacancy-Engineered Self-Regenerative Nanozymes in Dual-Signal-Responsive Dynamic Hydrogels: A Closed-Loop Therapeutic Strategy for Diabetic Wound Microenvironment Remodeling.

Abstract

Diabetic wounds are trapped in a self-perpetuating pathological triad of hypoxia, infection, and oxidative stressdisrupting physiological wound healing and causing recalcitrant nonhealing ulcerswhile conventional therapies, limited by static interventions and simplistic co-delivery, fail to adapt to the spatiotemporally heterogeneous wound microenvironment and break this cycle; to address this, we engineered a microenvironment-responsive closed-loop hydrogel dressing by integrating Cu-doped oxygen-vacancy molybdenum oxide nanozymes (MoO_3- _x(Cu)) and curcumin (Cur) into an oxidized alginatehyaluronic acid matrix: MoO_3- _x(Cu) forms a self-regenerative defect synergy via Mo⁵⁺/Mo⁶⁺-Cu⁺/Cu²⁺ dual redox cycles (oxygen vacancies (Vo) regenerate Cu²⁺→Cu⁺, Cu⁺ stabilizes Vo, decomposing 98.7% endogenous H₂O₂ into O₂ in 24 h with sustained catalysis), Cur acts as a catalytic cofactor (chelating Cu²⁺) and antimicrobial (disrupting bacterial membranes) for > 99.9% biofilm inhibition, and the pH-responsive Schiff base-crosslinked hydrogel (activated by diabetic wounds' alkaline pH 79) accelerates Schiff base hydrolysis to release nanozymes/Cur and boost MoO_3- _x(Cu)'s catalytic efficiency by 1.8-fold, dynamically matching wound microenvironment demands.