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

Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular H 2 O 2 into hydroxyl radical (•OH), but endogenous H 2 O 2 is insufficient to achieve satisfactory anticancer efficacy. Despite tremendous efforts, engineering CDT agents with specific and efficient H 2 O 2 self-supplying ability remains a great challenge. Here, we report the fabrication of copper peroxide (CP) nanodot, which is the first example of a Fenton-type metal peroxide nanomaterial, and its use as an activatable agent for enhanced CDT by self-supplying H 2 O 2 . The CP nanodots were prepared through coordination of H 2 O 2 to Cu 2+ with the aid of hydroxide ion, which could be reversed by acid treatment. After endocytosis into tumor cells, acidic environment of endo/lysosomes accelerated the dissociation of CP nanodots, allowing simultaneous release of Fenton catalytic Cu 2+ and H 2 O 2 accompanied by a Fenton-type reaction between them. The resulting •OH induced lysosomal membrane permeabilization through lipid peroxidation and thus caused cell death via a lysosome-associated pathway. In addition to pH-dependent •OH generation property, CP nanodots with small particle size showed high tumor accumulation after intravenous administration, which enabled effective tumor growth inhibition with minimal side effects in vivo. Our work not only provides the first paradigm for fabricating Fenton-type metal peroxide nanomaterials, but also presents a new strategy to improve CDT efficacy.