Ultrasound-Activated Copper Matrix Nanosonosensitizer for Cuproptosis-Based Synergy Therapy

Cuproptosis exhibits enormous application prospects in treatment. However, cuproptosis-based therapy is impeded by the limited intracellular copper ions, the nonspecific delivery, uncontrollable release, and chelation of endogenous overproduced glutathione (GSH). In this work, an ultrasound-triggered nanosonosensitizer (p-TiO₂-Cu(I)) was constructed for Cu(I) delivery, on-demand release, GSH consumption, and deeper tissue response. When the nanomedicine was internalized into the tumor cells, ultrasound (US) induced the nanosonosensitizer to produce reactive oxygen species (ROS) to achieve sonodynamic therapy (SDT). GSH, acting as a hole trapping agent, improved the efficiency of SDT. Meanwhile, the downgrade of GSH was beneficial to cuproptosis and oxidative damage-based SDT in return. What is more, the US could regulate the release behavior of Cu(I). Cu(I) bonded to mitochondrial proteins and then aggregated the lipoylated protein, bringing about the turbulence of the tricarboxylic acid cycle. The combination of SDT and cuproptosis showed high matching to induce efficient cuproptosis and may inspire other cuproptosis-based nanosonosensitizer designs.