Ultrasound-activated RuO₂ amplified oxidative stress therapy

Malignant tumors have limited therapeutic options, primarily due to the lack of actionable molecular targets and the redox-adaptive tumor microenvironment. Herein, a RuO₂ sonosensitizer is developed to enable cascade-amplified oxidative stress therapy. Upon US stimulation, RuO₂ generates a measurable sonoelectric response (∼12 nA cm^-2), which promotes charge separation and accelerates catalytic electron transfer, thereby enhancing endogenous H₂O₂ decomposition and oxygen evolution. Notably, this process triggers excessive generation of reactive oxygen species (ROS), including ˙OH and ˙O₂ ^-, while concurrently depleting intracellular glutathione (GSH), resulting in dual disruption of redox homeostasis and the formation of a self-reinforcing "ROS storm". Meanwhile, RuO₂ exhibits efficient cellular internalization and induces pronounced oxidative damage and apoptosis under US activation. In vivo photoacoustic imaging further reveals effective tumor accumulation, with a peak at approximately 9 h post-injection, enabling optimized therapeutic intervention. Moreover, the RuO₂ + US treatment significantly suppresses tumor growth in bearing mice, as evidenced by reduced tumor volume, decreased Ki-67 expression, and enhanced apoptosis (TUNEL staining). Importantly, RuO₂ demonstrates favorable biocompatibility, as indicated by negligible hemolysis, stable hematological parameters, and minimal systemic toxicity in vivo. Collectively, this work establishes a sonoelectric-enhanced platform that integrates ROS overproduction with antioxidant depletion, providing a mechanistically advanced strategy for overcoming redox resistance.