Metal-site engineering in Prussian blue analogues tunes catalytic selectivity for radiation-induced heart disease therapy

Nanozymes with multi-enzyme activity offer substantial potential for treating diseases associated with reactive oxygen species (ROS). However, poor catalytic selectivity and uncontrolled reactivity often impair their therapeutic efficacy in diseased tissues and may even exacerbate oxidative damage. Here, we present a metal-site engineering strategy in Prussian blue analogues (PBAs) to achieve selective antioxidant catalysis. Through systematic screening of five PBAs, we identified ZnCu-PBA as an optimal candidate, which exhibited markedly enhanced catalase (CAT)-like activity while effectively suppressed peroxidase (POD)-like activity. Density functional theory (DFT) calculations revealed that Zn incorporation tuned the electronic structure of Cu active sites, shifting the catalytic preference from •OH generation toward O 2 production. ZnCu-PBA additionally displayed intrinsic superoxide dismutase (SOD)-like activity. Owing to its CAT- and SOD-like activities, ZnCu-PBA effectively eliminated excess ROS, thereby attenuating X-ray-induced injury in H9C2 cells in vitro. Moreover, ZnCu-PBA exhibited exceptional cardioprotective effects in vivo against X-ray-induced cardiac injury. Mechanistically, it scavenged excessive ROS and alleviated oxidative stress, thereby attenuating the DNA damage response and suppressing the p53-p21 signaling and NF-κB-mediated pro-inflammatory signaling, ultimately mitigating cardiac dysfunction and myocardial fibrosis. This study demonstrates the therapeutic potential of selective antioxidant nanozymes for radiation-induced heart disease (RIHD) and provides a rational strategy for regulating nanozyme catalytic selectivity.