Piezoelectric-Driven Cu ²⁺ /Cu ⁺ Conversion Strategy for Amplifying Cuproptosis and Oxidative Stress

To overcome the efficiency limitations of cuproptosis in oncology, we engineered a piezoelectric Cu-loaded Bi₄Ti₃O₁₂ nanosheet system for synergistic cuproptosis and ROS-mediated tumor therapy. The incorporation of Cu²⁺ not only enhanced the material's piezoelectric coefficient (<i>d</i>₃₃ = 22.3 pm·V^-1) but also facilitated valence-state modulation under ultrasound (US) stimulation. The resulting piezoelectric field significantly promoted charge separation, accelerating Cu²⁺/Cu⁺ conversion and boosting reactive oxygen species (ROS) generation. This strategy synergistically induces tumor cell death through a dual tumoricidal pathway: on one hand, the accumulation of Cu⁺ under US stimulation further amplifies cuproptosis, and on the other hand, the continuous accumulation of ROS triggers excessive oxidative stress. In a murine breast cancer model, this synergistic approach achieved a 90.6% tumor inhibition rate. This study pioneeringly combines piezoelectric material properties and copper valence transformation, providing insights for breast cancer treatment.