Ultrasound-Responsive Calcium Copper Phosphate Nanomaterials Induce Tumor Cell Death via the Synergistic Release of Copper and Calcium.

Metastatic breast cancer remains a significant therapeutic challenge due to its high invasiveness and resistance to conventional treatments. In this study, an ultrasound-responsive copper-calcium phosphate (CaCu(PO)) nanomaterial is developed for synergistic ion-mediated tumor therapy. The CaCu(PO) nanomaterials exhibit a uniform morphology and crystalline structure, as well as good colloidal stability. Upon ultrasound irradiation, the release of Cu and Ca is spatiotemporally controlled via mechanical and cavitation effects. In vitro studies using highly metastatic 4T1 cells demonstrate that a combination of CaCu(PO) and ultrasound significantly enhances apoptosis to 37.56%, while inducing 41.37% cell viability at 20 μg/mL of CaCu(PO)+ US. In contrast, CaCu(PO) alone exhibits negligible cytotoxicity. Mechanistic investigations reveal that the combined release of Cu and Ca induces pronounced mitochondrial stress by suppressing the mitochondrial copper/redox regulator FDX1 and the PDH complex E2 subunit DLAT, thereby impairing mitochondrial metabolic homeostasis and promoting mitochondrial dysfunction. Overall, this study presents an ultrasound-triggered CaCu(PO) nanoplatform for the effective ablation of tumor cells.