Abstract

Abstract Chemodynamic therapy (CDT) utilizes iron‐initiated Fenton chemistry to destroy tumor cells by converting endogenous H 2 O 2 into the highly toxic hydroxyl radical ( . OH). There is a paucity of Fenton‐like metal‐based CDT agents. Intracellular glutathione (GSH) with . OH scavenging ability greatly reduces CDT efficacy. A self‐reinforcing CDT nanoagent based on MnO 2 is reported that has both Fenton‐like Mn 2+ delivery and GSH depletion properties. In the presence of HCO 3 − , which is abundant in the physiological medium, Mn 2+ exerts Fenton‐like activity to generate . OH from H 2 O 2 . Upon uptake of MnO 2 ‐coated mesoporous silica nanoparticles (MS@MnO 2 NPs) by cancer cells, the MnO 2 shell undergoes a redox reaction with GSH to form glutathione disulfide and Mn 2+ , resulting in GSH depletion‐enhanced CDT. This, together with the GSH‐activated MRI contrast effect and dissociation of MnO 2 , allows MS@MnO 2 NPs to achieve MRI‐monitored chemo–chemodynamic combination therapy.