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Here, we present Lewis acid nanoenzymes (Cu\/ZM\u2010Ca), which avoids valence cycling by through electron\u2010pair\u2010mediated hydrogen peroxide (H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    ) cleavage, exhibiting higher stability compared to compared to conventional Fenton catalysts. The ZSM\u20105 zeolite framework facilitates the synergizes of 3D Lewis acid centers with ultrasound to achieve on\u2010demand generation of H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    through hydrolysis of calcium peroxide (CaO\n                    <jats:sub>2<\/jats:sub>\n                    ) to enhance ROS generation under hypoxic conditions; and amplification of cavitation effects to achieve deep tissue penetration. The electron\u2010pair catalytic mechanism is oxygen\u2010independent, making Cu\/ZM\u2010Ca suitable for hypoxic deep\u2010tissue infections. Density Functional Theory calculations reveal that the Lewis acid site reduces the activation energy of H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    through enhanced adsorption, allowing direct cleavage of the O\u2500O bond without metal oxidation. This hybrid system reduces MRSA survival by 5\u2010logs in 15 min through synergistic membrane disruption and metabolic blockade. In vivo, ultrasound\u2010activated Cu\/ZM\u2010Ca cleared 99.5% of bacteria and resulted in an effective increase in bone regeneration (45.7%\u00a0vs 24.5% BV\/TV). This work establishes a novel class of hypoxia\u2010resistant nanoenzymes based on Lewis acid catalysis, overcoming fundamental constraints of conventional ROS therapies.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202502586","type":"journal-article","created":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T06:19:16Z","timestamp":1758953956000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Hybrid Ultrasound\u2010Enhanced and Self\u2010Cascade\u2010Catalysis\u2010Mediated System with Lewis Acid Active Centers for Treating MRSA\u2010Infected Osteomyelitis"],"prefix":"10.1002","volume":"15","author":[{"given":"Panyue","family":"Liu","sequence":"first","affiliation":[{"name":"Artificial Intelligence Institute Taiyuan University of Technology  Taiyuan 030024 China"},{"name":"Shanxi Key Laboratory of Biomedical Metal Materials Taiyuan University of Technology  Taiyuan 030024 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3186-8067","authenticated-orcid":false,"given":"Xiangyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Artificial Intelligence Institute Taiyuan University of Technology  Taiyuan 030024 China"},{"name":"Shanxi Key Laboratory of Biomedical Metal Materials Taiyuan University of Technology  Taiyuan 030024 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