Bioinspired Cascade-Catalytic Scaffold to Prevent Adverse Remodeling of Heart Valve under Pathological Conditions via Conversion of •O ₂ ^– into NO

In situ tissue-engineered heart valves (TEHVs) face significant challenges in patients with compromised endogenous repair capacity, particularly those with diabetic comorbidities. To address this issue, we developed a bimetallic nanozyme-functionalized scaffold capable of restoring •O 2 – /NO homeostasis through a bioinspired cascade catalytic reaction that modulates the adverse repair microenvironment. The nanozyme, composed of polyphenol-coordinated iridium (Ir)/ruthenium (Ru), exhibited tunable superoxide dismutase (SOD)- and endothelial nitric oxide synthase (eNOS)-like activities by adjusting the Ir/Ru ratio. The scaffold was further modified with a sulfonated polymer via in situ radical polymerization, forming an anticoagulant and pro-endothelial cell (EC) adhesion interface. In the diabetic microenvironment, the scaffold first mimicked SOD activity to convert •O 2 – into H 2 O 2 and subsequently exhibited eNOS-like activity to catalyze the reaction between H 2 O 2 and endogenous arginine for NO generation, ultimately inhibiting EC apoptosis and promoting EC proliferation and migration. Additionally, the nanozyme coating effectively scavenged hyperglycemia-induced •O 2 – overproduction in macrophages, mitigating inflammatory responses. In vivo implantation in diabetic rabbit vascular models demonstrated that the functionalized scaffold significantly enhanced endothelialization and prevented excessive collagen deposition. This catalytic strategy to restore •O 2 – /NO balance offers a promising approach for advancing in situ heart valve tissue engineering under pathological conditions, particularly in diabetic patients.