Rapid emergence of multidrug resistant (MDR) "superbugs" poses a severe threat to global health. Notably, undeveloped diagnosis and concomitant treatment failure remain highly challenging. Herein, we report a sonotheranostic strategy to achieve bacteria-specific labeling and visualized sonodynamic therapy (SDT). Using maltohexaose-decorated cholesterol and bacteria-responsive lipid compositions, a smart nanoliposomes platform (MLP18) was developed for precise delivery of purpurin 18, a potent sonosensitizer proved in this study. Taking advantage of the bacteria-specific maltodextrin transport pathway, the prepared MLP18 can specifically target the bacterial infection site and accurately distinguish the foci from sterile inflammation or cancer with a highly selective fluorescence/photoacoustic signal on the bacteria-infected site of mice. Moreover, the bacteria-responsive feature of MLP18 activated an efficient release and internalization of high concentration sonosensitizer into bacterial cells, resulting in effective sonodynamic elimination of MDR bacteria. In situ MRI monitoring visualized such potent sonodynamic activity and indicated that MLP18-mediated SDT could successfully eradicate inflammation and abscess from mice with bacterial myositis. In view of the above advantages, the developed nanoliposomes may serve as a promising sonotheranostic platform against MDR bacteria in the areas of healthcare.

Antibiotic‐free methods hold particular promise for preventing and controlling multidrug‐resistant (MDR) bacterial infection via eradiation of bacteria and their pathogenic virulence. A facile and bioinspired strategy is presented for bridging antibacterial sonodynamic therapy and antivirulence immunotherapy. As a proof‐of‐concept, an antibody which neutralizes alpha‐toxin of methicillin‐resistant Staphylococcus aureus (MRSA) is genetically engineered on to the surface of cell membrane nanovesicles, which then undergo sonosensitizer encapsulation. Compared with conventional passive virulence absorption using natural red blood membrane, the highly active antibody–toxin interaction enables the nanovesicles to capture virulence more potently in vitro. Upon ultrasound activation, the sonosensitizers efficiently generate reactive oxygen species to kill bacteria and accelerate the virulence clearance. In vivo optical imaging shows that the antibody‐piloted nanocapturer can successfully locate MRSA infection and accurately distinguish the foci from sterile inflammation. In situ magnetic resonance imaging and oxyhemoglobin saturation detection visualize the treatment progression, revealing a complete sono‐immunotherapeutic eradication of MRSA myositis in mice. The first combination of antibacterial sonodynamic therapy and antivirulence immunotherapy, which promises a new way for antibiotic‐free nanotheranostics to robustly combat MDR bacterial infections, is presented.

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To address the urgent need for effective sonodynamic therapy (SDT), a facile and efficient strategy is developed for fabricating a new class of sonotheranostics. Herein, a Fe(III)-porphyrin nano-sonosensitizer is prepared by a one-step coordination synthesis, and then anchored with Bis(DPA-Zn)-RGD and manganese superoxide dismutase (SOD2) siRNA. Benefiting from the delicate interactions of the Fe(III)-coordinated nanoformulations, a highly potent sono/gene combinational therapy guided by fluorescence/magnetic resonance imaging is achieved. Importantly, this sonotheranostics significantly enhances the SDT effect of porphyrin through the cancer-targeted delivery capability and enhanced reactive oxygen species production via triple-regulated approaches, including down-regulation of SOD2, depletion of glutathione, and generation of Fenton reaction. This work opens up new perspectives for developing versatile sonotheranostics to overcome the clinical challenges of SDT.