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 (Ca₁₉Cu₂(PO₄)₁₄) nanomaterial is developed for synergistic ion-mediated tumor therapy. The Ca₁₉Cu₂(PO₄)₁₄ nanomaterials exhibit a uniform morphology and crystalline structure, as well as good colloidal stability. Upon ultrasound irradiation, the release of Cu²⁺ and Ca²⁺ is spatiotemporally controlled via mechanical and cavitation effects. In vitro studies using highly metastatic 4T1 cells demonstrate that a combination of Ca₁₉Cu₂(PO₄)₁₄ and ultrasound significantly enhances apoptosis to 37.56%, while inducing 41.37% cell viability at 20 μg/mL of Ca₁₉Cu₂(PO₄)₁₄+ US. In contrast, Ca₁₉Cu₂(PO₄)₁₄ alone exhibits negligible cytotoxicity. Mechanistic investigations reveal that the combined release of Cu²⁺ and Ca²⁺ 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 Ca₁₉Cu₂(PO₄)₁₄ nanoplatform for the effective ablation of tumor cells.