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 (H 2 O 2 ) 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 H 2 O 2 through hydrolysis of calcium peroxide (CaO 2 ) 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 H 2 O 2 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.