A Covalent Resveratrol‐Polyoxometalate Hybrid for Synergistic Disassembly of Prion Protein Fragment 106–126 Aggregates and Catalytic Scavenging of Reactive Oxygen Species

ABSTRACT Prion diseases are fatal neurodegenerative disorders driven by pathogenic prion protein aggregation and persistent oxidative stress. To simultaneously target these interconnected pathological processes, we designed an organic‐inorganic hybrid, Res‐MnMo ₆ , by covalently grafting a resveratrol‐derived ligand onto an Anderson‐type polyoxometalate (POM) cluster. Res‐MnMo ₆ confers potent dual functionality, achieving 93% disassembly of preformed PrP106‐126 aggregates and effectively alleviating associated cytotoxicity and oxidative damage. Unlike conventional sacrificial antioxidants, the covalent integration fundamentally redirects the reactive oxygen species (ROS)‐scavenging mechanism toward a catalytic redox pathway, enabling sustained antioxidant activity. Notably, the ligand‐induced electronic redistribution within the POM scaffold enhances the catalytic efficiency by lowering the kinetic barriers of the rate‑determining steps in both superoxide (·O ₂ ⁻ ) and hydroxyl radical (·OH) scavenging reactions, leading to a long‐lasting catalytic ROS‑elimination performance.