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The vicious cycle between reactive oxygen species (ROS) rupture and mitochondrial damage is a central pathological driver of myocardial infarction (MI). Effectively promoting ROS clearance while enhancing mitochondrial phagocytosis to achieve dual restoration of redox homeostasis and energy metabolism is key to treating myocardial infarction. To this end, we have developed a bioinspired sesame-like cube doped with selenium Prussian blue nanozymes (SP), with active sites of Se0/Fe2/Fe3. By utilizing the superoxide dismutase (SOD)-like activity of the nanozymes, superoxide anions (·O2–) are converted into hydrogen peroxide (H2O2). Simultaneously, the catalase (CAT)-mimicking activity of the material further breaks down H2O2 to produce oxygen (O2), while selenium-enhanced electron transfer synergistically activates PINK1/Parkin-mediated mitochondrial clearance.
Subsequently, the nanozyme was integrated into a hydrogel, forming SP@Gel through dynamic Schiff base crosslinking between aldehyde-modified hyaluronic acid and amine-functionalized nanozymes. After being injected into the blocked myocardium, this hydrogel can continuously release the nanozyme. The SP@Gel exhibits excellent capability in promoting ROS clearance and alleviating oxidative damage, thereby improving myocardial redox homeostasis. Additionally, SP@Gel enhances cardiac mitophagy flux and regulates this process via the PTEN-induced kinase 1 (PINK1)/Parkin/microtubule-associated protein 1 light chain 3β (LC3B) pathway, promoting the restoration of mitochondrial structure and energy metabolism. These findings were further validated through metabolomics analysis. SP@Gel injection mediates remodeling of the myocardial infarction microenvironment, significantly reducing infarct size, inhibiting fibrosis, promoting angiogenesis, and notably improving cardiac function. This integrated nanozyme-hydrogel system represents a promising therapeutic strategy for myocardial infarction, achieving synergistic treatment through dual regulation of oxidative stress and mitochondrial quality control.
