Intracellular Mutual Amplification of Oxidative Stress and Inhibition Multidrug Resistance for Enhanced Sonodynamic/Chemodynamic/Chemo Therapy

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Emerging noninvasive treatments, such as sonodynamic therapy (SDT) and chemodynamic therapy (CDT), have developed as promising alternatives or supplements to traditional chemotherapy. However, their therapeutic effects are limited by the hypoxic environment of tumors. Here, a biodegradable nanocomposite-mesoporous zeolitic-imidazolate-framework@MnO₂ /doxorubicin hydrochloride (mZMD) is developed, which achieves enhanced SDT/CDT/chemotherapy through promoting oxidative stress and overcoming the multidrug resistance. The mZMD decomposes under both ultrasound (US) irradiation and specific reactions in the tumor microenvironment (TME). The mZM composite structure reduces the recombination rate of e⁻ and h⁺ to improve SDT. MnO₂ not only oxidizes glutathione in tumor cells to enhance oxidative stress, but also converts the endogenic H₂ O₂ into O₂ to improve the hypoxic TME, which enhances the effects of chemotherapy/SDT. Meanwhile, the generated Mn²⁺ catalyzes the endogenic H₂ O₂ into ·OH for CDT, and acts as magnetic resonance imaging agent to guide therapy. In addition, dissociated Zn²⁺ further breaks the redox balance of TME, and co-inhibits the expression of P-glycoprotein (P-gp) with generated ROS to overcome drug resistance. Thus, the as-prepared intelligent biodegradable mZMD provides an innovative strategy to enhance SDT/CDT/chemotherapy.