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.