Antibiotic-resistant bacteria often cause lethal infections in both the surficial and deep organs of humans. Failure of antibiotics in resistant infections leads to more effective alternative therapies, like spatiotemporally controllable piezodynamic therapy (PZDT) with deep penetration. Currently, PZDT demands further investigation for improved treatment outcomes and the corresponding therapeutic mechanisms. Herein, a nanocomposite cloaked is reported with a biomimetic coating of TLR-upregulated macrophage membrane for targeted PZDT against MRSA-induced skin wound infection and osteomyelitis, representing surficial and deep infection models, respectively. To boost the therapeutic efficacy, crystal defect engineering is applied by impregnating Fe