Pathologically responsive ZnSrMo-LDH/Cu nanozymes with cascade antioxidant and angiogenic functions for myocardial ischemia-reperfusion treatment

Rationale: Myocardial ischemia-reperfusion (MI/R) injury induces apoptosis, metabolic dysregulation, and ventricular remodeling through complex pathological mechanisms. Although nanozyme engineering has the potential for antioxidation, reoxygenation, and pro-vascularization, achieving responsive modulation of the pathological microenvironment remains significantly challenging. Methods: A layered double hydroxide (LDH)-based nanozyme (ZnSrMo-LDH/Cu) was synthesized via a low-temperature hydrothermal/isomorphic substitution method for MI/R treatment. The reactive oxygen species (ROS) scavenging ability and responsive ion release performance of ZnSrMo-LDH/Cu were evaluated through various spectroscopic characterization methods. The biosafety and therapeutic efficiency of ZnSrMo-LDH/Cu-BSA nanozymes were assessed by in vitro and in vivo experiments. Results: ZnSrMo-LDH/Cu demonstrated cascade superoxide dismutase (SOD) and catalase (CAT) activities, effectively overcoming acidic microenvironment limitations to maintain CAT activity rather than peroxidase (POD) activity while scavenging ROS to generate oxygen, with a ROS scavenging capacity 2.97 times that of Fe 3 O 4 . Moreover, the acid-triggered Sr 2+ release promoted vascular regeneration and synergistically improved the ischemic-hypoxic microenvironment. Consequently, after bovine serum albumin (BSA) modification, ZnSrMo-LDH/Cu-BSA demonstrated excellent cytoprotective effects, reducing the cardiomyocyte apoptosis rates to 9.4% ( in vitro ) and 20.7% ( in vivo ) of the levels in the MI/R group. In vivo studies further validated that ZnSrMo-LDH/Cu-BSA enhanced cardiac function and attenuated ventricular remodeling by inhibiting oxidative stress and promoting angiogenesis. Mechanistically, ZnSrMo-LDH/Cu-BSA provided a cardioprotective effect by inhibiting the TGF-β signaling pathway, thereby alleviating cell damage caused by MI/R. Conclusions: The pathologically responsive LDH-based nanozyme represents a promising avenue for MI/R treatment.