Hybrid Ultrasound‐Enhanced and Self‐Cascade‐Catalysis‐Mediated System with Lewis Acid Active Centers for Treating MRSA‐Infected Osteomyelitis

Conventional nanoenzymes for treating methicillin-resistant Staphylococcus aureus (MRSA)-infected osteomyelitis face serious limitations, including instability caused by valence cycling and impaired reactive oxygen species (ROS) generation by hypoxia. Here, we present Lewis acid nanoenzymes (Cu/ZM-Ca), which avoids valence cycling by through electron-pair-mediated hydrogen peroxide (H₂O₂) cleavage, exhibiting higher stability compared to compared to conventional Fenton catalysts. The ZSM-5 zeolite framework facilitates the synergizes of 3D Lewis acid centers with ultrasound to achieve on-demand generation of H₂O₂ through hydrolysis of calcium peroxide (CaO₂) to enhance ROS generation under hypoxic conditions; and amplification of cavitation effects to achieve deep tissue penetration. The electron-pair catalytic mechanism is oxygen-independent, making Cu/ZM-Ca suitable for hypoxic deep-tissue infections. Density Functional Theory calculations reveal that the Lewis acid site reduces the activation energy of H₂O₂ through enhanced adsorption, allowing direct cleavage of the O─O bond without metal oxidation. This hybrid system reduces MRSA survival by 5-logs in 15 min through synergistic membrane disruption and metabolic blockade. In vivo, ultrasound-activated Cu/ZM-Ca cleared 99.5% of bacteria and resulted in an effective increase in bone regeneration (45.7% vs 24.5% BV/TV). This work establishes a novel class of hypoxia-resistant nanoenzymes based on Lewis acid catalysis, overcoming fundamental constraints of conventional ROS therapies.