Precise Clearance of Intracellular MRSA via Internally and Externally Mediated Bioorthogonal Activation of Micro/Nano Hydrogel Microspheres

Abstract Traditional high‐dose antibiotic treatments of intracellular methicillin‐resistant staphylococcus aureus (MRSA) are highly inefficient and associated with a high rate of infection relapse. 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‐modified Cu2+/tetracarboxyphenylporphyrin nanoparticles (Cu(II)NS‐SPA) into hydrogel microspheres (HAMA@Cu(II)NS‐SPA) 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‐SPA is restored when it is reduced to Cu(I)NS‐SPA by the BSH secreted characteristically by intracellular MRSA, thus forming a bioorthogonal activation with the external US, which confines ROS production within the infected MΦ. Under external US activation at 2 W cm−2, over 95% of intracellular MRSA can be cleared. In vivo, a single injection of HAMA@Cu(II)NS‐SPA achieves up to two weeks of antibacterial sonodynamic therapy, reducing pro‐inflammatory factor expression by 90%, and peri‐implant 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‐drug resistant intracellular bacterial infections.