Synergistic Interaction between Metal Single‐Atoms and Defective WO3−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 WO3−x nanosheets to generate a synergistic effect for efficient SDT is reported. Crystalline WO3 and OV‐rich WO3−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 WO3−x nanosheets to obtain metal SA‐decorated WO3−x nanocomposites (M‐WO3−x). Importantly, the Cu‐WO3−x sonosensitizer exhibits a much higher activity for ultrasound (US)‐induced production of reactive oxygen species than that of the WO3−x and Cu SA‐decorated WO3, which is also higher than other M‐WO3−x nanosheets. Both the experimental and theoretical results suggest that the excellent SDT performance of the Cu‐WO3−x nanosheets should be attributed to the synergistic effect between Cu SAs and WO3−x OVs. Therefore, after polyethylene glycol modification, the Cu‐WO3−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‐WO3−x‐mediated SDT‐activated apoptosis and TNF signaling pathways are potential drivers of tumor apoptosis induction. The generation of a strong synergistic effect between metal single‐atoms and oxygen vacancies of WO3−x nanosheets can effectively boost the sonodyanimc therapy performance under ultrasound irradiation, thus realizing highly efficient cancer treatment.