Pyroptosis-Mediated\nCancer Chemodynamic Therapy Driven\nby Multicascade Responsive Nanocatalyst

The off-target side effects and low catalytic efficiency\nsubstantially\nhindered the biomedical application of chemodynamic therapy (CDT).\nHere, we report a novel pH/GSH cascade activated core–shell\nnanocatalyst (MDC) to enhance cancer targeting and catalytic efficiency\nfor synergistic CDT. The CaCO<sub>3</sub> shell protects the internal\nMnSiO<sub>3</sub> from degradation by GSH during blood transport.\nIn an acidic tumor microenvironment, the rapid biodegradation of CaCO<sub>3</sub> induces CO<sub>2</sub> production, pH increase, and Ca<sup>2+</sup> overload. Subsequently, the exposed MnSiO<sub>3</sub> core\nserves as a drug delivery platform with a GSH responsive Mn<sup>2+</sup> and dihydroartemisinin (DHA) release function. The generated CO<sub>2</sub> optimizes the catalytic conditions, with DHA acting as a\nsubstrate for catalysis, both of which promote Mn<sup>2+</sup>-mediated\nROS generation. In synergy with Ca<sup>2+</sup> overload, they collectively\naccelerate a storm of ROS, activating the Caspase-1/gasdermin D mediated\npyroptosis and achieved remarkable tumor inhibition. Such a multicascade\nresponsive nanoplatform is highly instructive for further metal nanocatalysts\nmediated cancer therapies.