Synergistic Interaction between Metal Single-Atoms and Defective WO_3−x Nanosheets for Enhanced Sonodynamic Cancer Therapy

Although metal single-atom (SA)-based nanomaterials are explored as sonosensitizers for sonodynamic therapy (SDT), they normally exhibit poor activities and need to combine with other therapeutic strategies. Herein, the deposition of metal SAs on oxygen vacancy (OV)-rich WO_3−x nanosheets to generate a synergistic effect for efficient SDT is reported. Crystalline WO₃ and OV-rich WO_3−x nanosheets are first prepared by simple calcination of the WO₃·H₂O nanosheets under an air and N₂ atmosphere, respectively. Pt, Cu, Fe, Co, and Ni metal SAs are then deposited on WO_3−x nanosheets to obtain metal SA-decorated WO_3−x nanocomposites (M-WO_3−x). Importantly, the Cu-WO_3−x sonosensitizer exhibits a much higher activity for ultrasound (US)-induced production of reactive oxygen species than that of the WO_3−x and Cu SA-decorated WO₃, which is also higher than other M-WO_3−x nanosheets. Both the experimental and theoretical results suggest that the excellent SDT performance of the Cu-WO_3−x nanosheets should be attributed to the synergistic effect between Cu SAs and WO_3−x OVs. Therefore, after polyethylene glycol modification, the Cu-WO_3−x can quickly kill cancer cells in vitro and effectively eradicate tumors in vivo under US irradiation. Transcriptome sequencing analysis and further molecular validation suggest that the Cu-WO_3−x-mediated SDT-activated apoptosis and TNF signaling pathways are potential drivers of tumor apoptosis induction.