Effective treatment of cisplatin-resistant ovarian tumors with a MoS2-based sonosensitizer and nanoenzyme capable of reversing the resistant-microenvironment and enhancing ferroptosis and apoptosis

The complex environment of cisplatin-resistant tumors leads to the failure of currently available treatments. Therefore, a comprehensive and effective strategy is urgently required to overcome cisplatin resistance by targeting multiple pathways. Here, we developed a smart network combining sonodynamic therapy and a nanoenzyme as MoS2/CF3SO2Na nanoparticles ([email protected]3 NPs) to reverse the cisplatin resistance and intensify ovarian cancer treatment. [email protected]3 NPs can catalyze GSH oxidation to inhibit its detoxification to cisplatin. Importantly, under ultrasound irradiation, OH, O2−, CF3, and SO2 are produced via cascade reactions originating from MoS2, all of which can synergistically prevent cisplatin efflux by disturbing ATP production and destroying the efflux protein ATP7B. Notably, CF3 also resulted in effective downregulation of ERCC1 in this process, which could effectively inhibit the repair of cisplatin-damaged DNA. The results of in vitro and in vivo experiments indicated that [email protected]3Pt NPs can effectively induce both the ferroptosis and apoptosis of cisplatin-resistant cells via ultrasound treatment. The smart piezoelectric catalytic network provides a viable framework towards overcoming cisplatin resistance in ovarian cancer in the future.