Ultrasound-activated nanoregulator enables Cu2+ directional enrichment and enhances cuproptosis via energy-gated feedback loop

Modulating intratumoral copper homeostasis to trigger cuproptosis is a promising copper‑based anticancer strategy, but its clinical translation is hindered by the absence of precise spatiotemporal control over intracellular copper levels and ATP7A‑mediated active copper efflux. Here we report an ultrasound-activated copper molybdate nanoregulator, HCu 1.5 MoO 5 (HCMO), that releases copper on demand and reprograms copper flux in tumor cells under ultrasound. Once internalized, ultrasound activates HCMO to release copper ions, providing a sustained intracellular copper supply. In parallel, HCMO also generates reactive oxygen species that impair mitochondrial function and depress cellular ATP, thereby attenuating the activity of the ATP-dependent exporter ATP7A and narrowing copper efflux. This dual-axis imbalance, in situ copper supplement, and efflux limitation significantly disrupt cellular copper homeostasis, interrupt the tricarboxylic-acid cycle, induce mitochondrial dysfunction, further enhance copper accumulation, and eventually cause irreversible cuproptosis. Together with apoptosis and necroptosis, the coordinated damage releases damage-associated molecular patterns and induces immunogenic cell death. Overall, this spatiotemporally programmable strategy links materials, physical fields, and immunity in a closed framework to coordinately disrupt copper homeostasis, offering a generalizable route to on-demand cuproptosis therapy.