Mutual promotion of oxidative stress amplification and calcium overload by degradable spatially selective self-cascade catalyst for synergistic tumor therapy

The insufficient H2O2, hypoxia and GSH overexpression in tumor microenvironment led to the strong tolerance of cancer cells to various ROS treatments and seriously restrict their therapeutic effect. Hereby, we fabricated a degradable spatially selective multifunctional nanocatalyst-CMFO to synergistically amplify oxidative stress and overload calcium for tumor treatment. The CMFO was constituted by MnFe2O4 nanoparticles as a protective umbrella to coat CaO2, which is stable in normal tissues and leads to specific self-cascade catalytic reaction after accumulation in tumor sites. The nano-CaO2 releases abundant Ca2+ and sufficient H2O2, and Mn/Fe ions released from MnFe2O4 catalyze H2O2 into toxic ·OH. MnFe2O4 and H2O2 can also attenuate tumor hypoxia and deplete intracellular reductant-glutathione (GSH), amplifying the oxidative stress and enhancing ROS-related treatment. More importantly, the generated Ca2+ and ·OH mutually promote their intracellular accumulation by calcium channels and mitochondria, leading enhanced apoptosis of tumor cells. In addition, CMFO can be used as MR agent to identify tumors and monitor the treatment process. Thus, the as-prepared intelligent biodegradable CMFO provides a novel solution for tumor-specific ROS-related treatment and opens a new door for spatially selective self-cascade synergistic therapy.