Sorafenib-Loaded Copper Peroxide Nanoparticles with Redox Balance Disrupting Capacity for Enhanced Chemodynamic Therapy against Tumor Cells

Chemodynamic therapy (CDT) is a promising hydroxyl radical (•OH)-mediated tumor therapeutic method with desirable tumor specificity and minimal side effects. However, the efficiency of CDT is restricted by the pH condition, insufficient H₂O₂ level, and overexpressed reductive glutathione (GSH), making it challenging to solve these problems simultaneously to improve the efficacy of CDT. Herein, a kind of polyvinylpyrrolidone-stabilized, sorafenib-loaded copper peroxide (CuO₂-PVP-SRF) nanoparticle (NPs) was designed and developed for enhanced CDT against tumor cells through the synergetic pH-independent Fenton-like, H₂O₂ self-supplying, and GSH depletion strategy. The prepared CuO₂-PVP-SRF NPs can be uptaken by 4T1 cells to specifically release Cu²⁺, H₂O₂, and SRF under acidic conditions. The intracellular GSH can be depleted by SRF-induced system xc^- dysfunction and Cu²⁺-participated redox reaction, causing the inactivation of GPX4 and generating Cu⁺. A great amount of •OH was produced in this reducing capacity-disrupted condition by the Cu⁺-mediated Fenton-like reaction, causing cell apoptosis and lipid hydroperoxide accumulation-induced ferroptosis. They display an excellent 4T1 cell killing outcome through the improved •OH production capacity. The CuO₂-PVP-SRF NPs display elevated therapeutic efficiency of CDT and show good promise in further tumor treatment applications.