Ultrasound Activated Copper-Based Sonosensizer for Dual-Amplified ROS-Mediated Tumor Therapy and Cuproptosis Induction

Sonodynamic therapy (SDT) is a promising noninvasive cancer treatment with deep tissue penetration, but its therapeutic efficacy is limited by insufficient reactive oxygen species (ROS) production. Herein, we developed copper-based sonosensitizer (CCG MPNs) by coordinating copper ions (Cu2+) with chlorin e6 (Ce6) and gallic acid (GA) for dual-amplified ROS-mediated tumor therapy and cuproptosis induction. CCG MPNs dissociate in the high-glutathione (GSH) tumor microenvironment, releasing Cu ions, Ce6, and GA. GA rapidly depletes GSH, enhancing tumor cell sensitivity to ROS and cuproptosis. Additionally, the released Cu+ ions generate cytotoxic hydroxyl radicals via a highly efficient Fenton reaction and ultrasound (US) activation of Ce6 produces singlet oxygen, amplifying ROS-mediated apoptosis by evoke chemodynamic therapy (CDT) and SDT. Moreover, the yielded ROS would cut off the ATP supply, resulting in a decrease in the expression of the copper transporter protein ATP7A. Large accumulations of intracellular Cu+ ions can be more readily induce cuproptosis by promoting lipoylated protein aggregation. In vitro and in vivo anti-tumor studies showed that CCG MPNs group under US treatment exhibited better anti-tumor performance. This multimodal approach overcomes the limitations of the tumor microenvironment, offering a synergistic strategy to enhance tumor therapy efficiency through combined ROS generation and cuproptosis activation.