Modulation of Intratumoral Fusobacterium nucleatum to Enhance Sonodynamic Therapy for Colorectal Cancer with Reduced Phototoxic Skin Injury

[Image: see text] Intratumoral pathogens can contribute to cancer progression and affect therapeutic response. Fusobacterium nucleatum, a core pathogen of colorectal cancer (CRC), is an important cause of low therapeutic efficacy and metastasis. Thus, the modulation of intratumoral pathogens may provide a target for cancer therapy and metastasis inhibition. Herein, we propose an intratumoral F. nucleatum-modulating strategy for enhancing the therapeutic efficacy of CRC and inhibiting lung metastasis by designing an antibacterial nanoplatform (Au@BSA-CuPpIX), which produced reactive oxygen species (ROS) under ultrasound and exhibited strong antibacterial activity. Importantly, Au@BSA-CuPpIX reduced the levels of apoptosis-inhibiting proteins by inhibiting intratumoral F. nucleatum, thereby enhancing ROS-induced apoptosis. In vivo results demonstrated that Au@BSA-CuPpIX effectively eliminated F. nucleatum to enhance the therapeutic efficacy of sonodynamic therapy (SDT) for orthotopic CRC and inhibit lung metastasis. Notably, entrapped gold nanoparticles reduced the phototoxicity of metalloporphyrin accumulated in the skin during tumor treatment, preventing severe inflammation and damage to the skin. Therefore, this study proposes a strategy for the elimination of F. nucleatum in CRC to enhance the therapeutic effect of SDT, thus providing a promising paradigm for improving cancer treatment with fewer toxic side effects and promoting the clinical translational potential of SDT.