Ultrasound-driven redox cycling in Cu-doped Mn Prussian blue nanozymes amplifies ferroptosis and immune activation

Multi-enzyme nanozymes that integrate catalytic regulation and physical stimulation are highly desirable for efficient ferroptosis therapy. This study reports a hollow Cu–Mn Prussian blue nanozyme (CMP) that couples multi-enzyme activity with ultrasound (U) responsiveness for redox-activated tumor therapy. The incorporation of Cu creates a mixed-valence catalytic network that facilitates rapid electron transfer and synergistic peroxidase-, catalase-, and glutathione (GSH) oxidase-like reactions. The hollow architecture improves mass diffusion and substrate accessibility, whereas U irradiation accelerates charge separation and exposes the internal active sites, leading to amplified hydroxyl radical (•OH) generation, GSH depletion, and O₂ production. Furthermore, the mitochondrial respiration inhibitor atovaquone is integrated to form a composite system (CMPA), which disrupts electron transport and adenosine triphosphate synthesis, thereby increasing intracellular O₂ availability and reinforcing reactive oxygen species accumulation. Consequently, CMPA + U achieved a 90.9% tumor suppression rate without systemic toxicity. Overall, this study establishes a general strategy for constructing U-responsive redox-catalytic nanozymes that couple multi-enzyme catalysis with ferroptosis-immune synergistic therapy.