Boosting Sonodynamic/Gas/Chemo Therapy through Triple Inhibiting Multidrug Resistance Using Responsive Biodegradable Sulfide‐Vacancy‐Rich Nanosheets

Non-targeted chemotherapy remains the primary therapeutic approach for treating triple-negative breast cancer (TNBC), but it frequently results in multidrug resistance and severe side effects. In this study, a responsive biodegradable zinc-doped MoS_2-x nanosheet is developed with rich sulfide vacancies (ZMS) to enhance sono-chemotherapy in TNBC by simultaneously inhibiting multidrug resistance through triple-pathway modulation (reactive oxygen species, H₂S, and Zn²⁺). The introduction of sulfide-vacancies via Zn doping significantly inhibits electron-hole recombination, and eventually boosts the generation of reactive oxygen species under ultrasound (US) activation to enhance sonodynamic therapy (SDT). In addition, the ZMS/DOX can degrade in an acidic tumor microenvironment (TME) to release DOX (doxorubicin hydrochloride), Zn²⁺, and H₂S. Zn²⁺ inhibits intracellular ATP production by disrupting glycolysis in cancer cells, while H₂S synergistically reduces intracellular ATP levels by impairing the mitochondrial electron transport chain. Furthermore, the reduction in ATP levels suppresses the expression of P-glycoprotein, thereby overcoming drug resistance. Additionally, ZMS exhibits catalase-like activity to convert H₂O₂ into O₂ in TME, relieving the tumor's hypoxia as well as enhancing the therapeutic efficacy of SDT and chemotherapy. The proposed biodegradable therapeutic platform holds great promise for strengthening sono-chemotherapy in TNBC treatment and overcoming the limitations associated with traditional chemotherapy.