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As an effective antibacterial technology, sonodynamic therapy (SDT) may be able to break the dilemma. However, indiscriminate reactive oxygen species (ROS) release leads to potential side effects. This study incorporates Staphylococcal Protein A antibody\u2010modified Cu\n                    <jats:sup>2+<\/jats:sup>\n                    \/tetracarboxyphenylporphyrin nanoparticles (Cu(II)NS\u2010SPA) into hydrogel microspheres (HAMA@Cu(II)NS\u2010SPA) to achieve precise eradication of intracellular bacteria. This eradication is under bioorthogonal activation mediated by bacillithiol (BSH) (internally) and ultrasound (US) (externally). To specify, the US responsiveness of Cu(II)NS\u2010SPA is restored when it is reduced to Cu(I)NS\u2010SPA by the BSH secreted characteristically by intracellular MRSA, thus forming a bioorthogonal activation with the external US, which confines ROS production within the infected M\n                    <jats:italic>\u03a6<\/jats:italic>\n                    . Under external US activation at 2\u00a0W\u00a0cm\n                    <jats:sup>\u22122<\/jats:sup>\n                    , over 95% of intracellular MRSA can be cleared. In vivo, a single injection of HAMA@Cu(II)NS\u2010SPA achieves up to two weeks of antibacterial sonodynamic therapy, reducing pro\u2010inflammatory factor expression by 90%, and peri\u2010implant bone trabeculae numbers exceed the control group by five times. In summary, these micro\/nano hydrogel microspheres mediated by internal and external bioorthogonal activation can precisely eliminate intracellular MRSA, effectively treating multi\u2010drug resistant intracellular bacterial infections.\n                  <\/jats:p>","DOI":"10.1002\/advs.202402370","type":"journal-article","created":{"date-parts":[[2024,9,29]],"date-time":"2024-09-29T15:03:42Z","timestamp":1727622222000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Precise Clearance of Intracellular MRSA via Internally and Externally Mediated Bioorthogonal Activation of Micro\/Nano Hydrogel Microspheres"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5172-1068","authenticated-orcid":false,"given":"Jianye","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Orthopaedics The First Affiliated Hospital of Chongqing Medical University Orthopedic Laboratory of Chongqing Medical University  Chongqing 400016 P. 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