Objective: To make up for the insufficient ultrasound ablation of tumors, the energy output or synergist is increased but faces the big challenge of normal tissue damage. In this study, we report a tumor-homing bacterium, Bifidobacterium bifidum (B. bifidum), adsorbing liposomes that encapsulate perfluorohexane (PFH) and doxorubicin (DOX) to enhance the pulsed-focused ultrasound (PFUS) for tumor therapy, so as to improve the efficacy, safety and controllability of ultrasound treatment. Methods: The PFH and DOX co-loaded cationic liposomal nanoparticles (CL-PFH-DOX-NPs) were prepared for ultrasound (US) imaging, cell-killing, and B. bifidum adsorption for the reactive oxygen species (ROS) testing. The aggregation of B. bifidum and CL-PFH-DOX-NPs is called tumor-homing aggregation (B. bifidum@CL-PFH-DOX-NPs) in this study, and the synergistic effects of B. bifidum@CL-PFH-DOX-NPs were analyzed in vivo. Results: Comprehensive studies validated that CL-PFH-DOX-NPs can enhance US imaging and cell-killing and B. bifidum can promote ROS, and B. bifidum@CL-PFH-DOX-NPs achieve PFUS synergism in vivo. Importantly, active homing of B. bifidum facilitated the delivery and retention of CL-PFH-DOX-NPs in tumors, reducing dispersion in normal tissues, achieving the targeting ability of B. bifidum@CL-PFH-DOX-NPs. The best sonication time was chosen according to the distribution of CL-PFH-DOX-NPs in vivo to achieve efficient therapy. Especially, B. bifidum@CL-PFH-DOX-NPs amplified cavitation and the immune-boosting effects. Conclusion: Multifunctional B. bifidum@CL-PFH-DOX-NPs were successfully constructed with well targeting, which not only realized US imaging monitoring, strong cavitation and complementary killing during PFUS, but also achieved immunity enhancement after PFUS. The combination of PFUS, B. bifidum and CL-PFH-DOX-NPs provides a new idea for the potential application of ultrasound therapy in solid tumors.
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