Cu-doped Co ₉ S _{8− <i>x</i>} sonozymes for enhanced sonodynamic and chemodynamic therapy of gallbladder cancer through ion doping and vacancy engineering

Reactive oxygen species (ROS)-mediated tumor therapy modalities, such as sonodynamic and chemodynamic therapy (SDT/CDT), hold great potential for the treatment of gallbladder cancer owing to their non-invasiveness, specificity, and high penetration depth. However, sonosensitizers and nanozymes often suffer from low ROS production efficiency and poor TME susceptibility. Herein, we report for the first time the ROS production amplification strategy through ion doping and vacancy engineering, which can not only improve the sonodynamic activity of sonosensitizers but also enhance the chemodynamic properties of nanozymes. The synergistic modifications enhance the SDT and CDT performances of pristine Co₉S₈ sonozymes through the following aspects: (1) S vacancies narrow the bandgap of Co₉S₈ sonozymes (1.41 eV <i>vs.</i> 1.91 eV) for enhanced SDT; (2) Cu doping improves the Co²⁺/Co³⁺ (0.98 <i>vs.</i> 0.66) of Co₉S₈ sonozymes for augmented CDT; and (3) Cu-doped Co₉S_8-<i>x</i> (Cu-Co₉S_8-<i>x</i>) retains GSH depletion ability for the cascade amplification of ROS production. Overall, significant antitumor effects have been observed to eliminate tumors through Cu-Co₉S_8-<i>x</i>-mediated SDT and CDT. This study provides promising insights into the development of enhanced sonozyme nanoplatforms through ion doping and vacancy engineering.