Boosting Sonodynamic/Gas/Chemo Therapy through Triple Inhibiting Multidrug Resistance Using Responsive Biodegradable Sulfide‐Vacancy‐Rich Nanosheets
Dongmiao Cao, Wei Xia, Kaiyang Wang, Ai−Hong Chen, Ruixin Luo, Lile Dong, Jie Lü, Yicheng Zhu, Xue‐Bo Yin, Yu Luo, Xijian Liu
Abstract
Abstract 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, H 2 S, and Zn 2+ ). 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), Zn 2+ , and H 2 S. Zn 2+ inhibits intracellular ATP production by disrupting glycolysis in cancer cells, while H 2 S 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 H 2 O 2 into O 2 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.