A Cascade ROS Nanoamplifier for Enhanced Sono‐Chemodynamic Therapy of Osteosarcoma

The cascade amplification of reactive oxygen species (ROS) production plays a vital role in enhancing the effectiveness of sonodynamic/chemodynamic therapy (SDT/CDT) for osteosarcoma. Nevertheless, the currently developed sonosensitizers and nanozymes face challenges such as low ROS production efficiency, poor stability, and limitations imposed by the unfavorable tumor microenvironment (TME). Herein, we report a unique strategy for amplifying ROS yield by combining the augmentation of sonosensitizer/nanozyme activity with the regulation of TME. A heterojunction with bandgap matching is created by combining RuO₂ nanozymes and Zr-based metal-organic frameworks (Zr-MOF) to obtain the enhanced sonodynamic and chemodynamic activities owing to the improved electron-hole separation kinetics. RuO₂ nanozymes serve as an auxiliary semiconductor to sensitize Zr-MOF, suppressing the recombination of US-activated electron-hole pairs and enhancing the multienzyme-mimic activity of Zr-MOF by accelerating electron transfer efficiency. By boosting SDT/CDT performances, depleting GSH, and alleviating tumor hypoxia, RuO₂@Zr-MOF achieves cascade amplification of ROS production. With the combination of intravenous injection of RuO₂@Zr-MOF and US irradiation of tumor tissues, the heterojunction nanoplatforms achieve total elimination of tumor tissues with no chance of recurrence. This work showcases the potential of RuO₂ nanozymes as supplementary semiconductors in the sensitization of sonosensitizers, offering novel insights for heterojunction engineering in combating the refractory osteosarcoma.