Biomimetic Selenium-Encrusted Prussian Blue Nanozyme for Myocardial Infarction by Coordinated Enhancement of Mitophagy and Reactive Oxygen Species Scavenging

The vicious cycle between reactive oxygen species (ROS) burst and impaired mitochondria represents a core pathological driver in myocardial infarction (MI). Synergistically promoting ROS scavenging and enhancing mitophagy to achieve dual restoration of redox homeostasis and energy metabolism are crucial for the effective treatment of MI. To address this, we developed a biomimetic sesame cube-shaped selenium-doped Prussian blue nanozyme (SP) featuring Se⁰/Fe²⁺/Fe³⁺ active sites. By leveraging the superoxide dismutase (SOD)-like activity of the nanozyme, superoxide anions (·O₂^-) are converted into hydrogen peroxide (H₂O₂). Simultaneously, the material's catalase (CAT)-mimetic activity further decomposes the resulting H₂O₂ into oxygen (O₂) while cooperatively activating PINK1/Parkin-mediated mitophagy <i>via</i> selenium-enhanced electron transport. The nanozyme was subsequently integrated into a hydrogel to form the SP@Gel through dynamic Schiff base cross-linking between aldehyde-modified hyaluronic acid and amine-functionalized nanozyme. Upon injection into the infarcted myocardium, this hydrogel enables the sustained release of nanozymes. The SP@Gel exhibits excellent capabilities in promoting ROS scavenging and mitigating oxidative damage, thereby improving myocardial redox homeostasis. Furthermore, the SP@Gel enhances cardiac mitophagic flux and regulates this process via the PTEN-induced putative kinase 1 (PINK1)/Parkin/microtubule-associated protein 1 light chain 3 beta (LC3B) pathway, facilitating the restoration of mitochondrial structure and energy metabolism. These findings were further validated by metabolomics analyses. SP@Gel injection mediated remodeling of the MI microenvironment, resulting in significantly reduced infarct size, suppressed fibrosis, enhanced angiogenesis, and substantially improved cardiac function. This integrated nanozyme-hydrogel system represents a promising therapeutic strategy for MI, achieving synergistic treatment through the dual regulation of oxidative stress and mitochondrial quality control.