Pyroptosis-Mediated Cancer Chemodynamic Therapy Driven by Multicascade Responsive Nanocatalyst

The off-target side effects and low catalytic efficiency substantially hindered the biomedical application of chemodynamic therapy (CDT). Here, we report a novel pH/GSH cascade activated core–shell nanocatalyst (MDC) to enhance cancer targeting and catalytic efficiency for synergistic CDT. The CaCO₃ shell protects the internal MnSiO₃ from degradation by GSH during blood transport. In an acidic tumor microenvironment, the rapid biodegradation of CaCO₃ induces CO₂ production, pH increase, and Ca²⁺ overload. Subsequently, the exposed MnSiO₃ core serves as a drug delivery platform with a GSH responsive Mn²⁺ and dihydroartemisinin (DHA) release function. The generated CO₂ optimizes the catalytic conditions, with DHA acting as a substrate for catalysis, both of which promote Mn²⁺-mediated ROS generation. In synergy with Ca²⁺ overload, they collectively accelerate a storm of ROS, activating the Caspase-1/gasdermin D mediated pyroptosis and achieved remarkable tumor inhibition. Such a multicascade responsive nanoplatform is highly instructive for further metal nanocatalysts mediated cancer therapies.