Synthesis of Copper Peroxide Nanodots for H₂O₂ Self-Supplying Chemodynamic Therapy

TLDR

Chemodynamic therapy relies on Fenton catalysts to convert intracellular H₂O₂ into hydroxyl radicals, yet endogenous H₂O₂ levels are often too low, making the design of agents that can self‑supply H₂O₂ a major challenge. This study reports the synthesis of copper peroxide nanodots, the first Fenton‑type metal peroxide nanomaterial, as an activatable agent that enhances CDT by self‑supplying H₂O₂. The nanodots are formed by coordinating H₂O₂ to Cu²⁺ with hydroxide, a complex that dissociates in acidic endo/lysosomes to release Cu²⁺ and H₂O₂, triggering a Fenton reaction that generates hydroxyl radicals, induces lysosomal membrane permeabilization through lipid peroxidation, and initiates lysosome‑associated cell death. In vivo, the small, pH‑responsive nanodots accumulate efficiently in tumors after intravenous injection, producing potent hydroxyl radicals that suppress tumor growth with minimal side effects, establishing a new paradigm for Fenton‑type metal peroxide nanomaterials and improving CDT efficacy.

Abstract

Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular H2O2 into hydroxyl radical (•OH), but endogenous H2O2 is insufficient to achieve satisfactory anticancer efficacy. Despite tremendous efforts, engineering CDT agents with specific and efficient H2O2 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 H2O2. The CP nanodots were prepared through coordination of H2O2 to Cu2+ 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 Cu2+ and H2O2 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.