Valence-tailored copper-based nanoparticles for enhanced chemodynamic therapy through prolonged ROS generation and potentiated GSH depletion

Chemodynamic therapy (CDT), an inventive approach to cancer treatment, exploits innate chemical processes to trigger cell death through the generation of reactive oxygen species (ROS). While offering advantages over conventional treatments, the optimization of CDT efficacy presents challenges stemming from suboptimal catalytic efficiency and the counteractive ROS scavenging effect of intracellular glutathione (GSH). In this study, we aim to address this dual challenge by delving into the role of copper valence states in CDT. Leveraging the unique attributes of copper-based nanoparticles, especially zero-valent copper nanoparticles (CuPd NPs), we aim to enhance the therapeutic potential of CDT. Our experiments reveal that zero-valent CuPd NPs outperform divalent copper nanoparticles (Ox-CuPd NPs) by displaying superior catalytic performance and sustaining ROS generation through a dual approach integrating peroxidase-like (POD-like) activity and Cu⁺ release. Notably, zero-valent NPs exhibit enhanced GSH depletion compared to their divalent counterparts, thereby intensifying CDT and inducing ferroptosis, ultimately resulting in high-efficiency tumor growth inhibition. These findings reveal the impact of valences on CDT, providing novel insights for the optimization and design of CDT agents.