Simultaneous Fenton‐like Ion Delivery and Glutathione Depletion by MnO₂‐Based Nanoagent to Enhance Chemodynamic Therapy

Chemodynamic therapy (CDT) utilizes iron-initiated Fenton chemistry to destroy tumor cells by converting endogenous H₂ O₂ 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 MnO₂ is reported that has both Fenton-like Mn²⁺ delivery and GSH depletion properties. In the presence of HCO₃^- , which is abundant in the physiological medium, Mn²⁺ exerts Fenton-like activity to generate ^. OH from H₂ O₂ . Upon uptake of MnO₂ -coated mesoporous silica nanoparticles (MS@MnO₂ NPs) by cancer cells, the MnO₂ shell undergoes a redox reaction with GSH to form glutathione disulfide and Mn²⁺ , resulting in GSH depletion-enhanced CDT. This, together with the GSH-activated MRI contrast effect and dissociation of MnO₂ , allows MS@MnO₂ NPs to achieve MRI-monitored chemo-chemodynamic combination therapy.