A Multifunctional Calcium Phosphate Nanoplatform Inducing Synergistic Copper/Calcium Overload and Antiangiogenesis for Enhanced Cancer Therapy

Copper overload-induced cell death (cuproptosis) holds great promise for cancer therapy but remains limited by insufficient intracellular copper accumulation and elevated glutathione (GSH) levels in the tumor microenvironment (TME). Here, we develop a multifunctional nanoplatform (CaP/Cu-F) by incorporating L-buthionine sulfoximine (BSO) into copper-doped calcium phosphate nanoparticles, followed by the loading of fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor. CaP/Cu-F induces dual GSH depletion by inhibiting GSH synthesis and accelerating its consumption during the reduction of Cu²⁺ to Cu⁺. The resulting antioxidant exhaustion synergizes with hydroxyl radical generation through a Cu⁺-mediated Fenton-like reaction to amplify oxidative stress. This redox imbalance, together with Ca²⁺ released from the nanoplatform in response to the acidic TME, facilitates calcium overload. The dysregulation of redox and calcium homeostasis impairs mitochondrial function, leading to adenosine triphosphate (ATP) depletion and downregulation of the copper exporter ATP7A, thereby limiting copper efflux and promoting intracellular copper accumulation. Collectively, these effects trigger cuproptosis, characterized by the aggregation of lipoylated dihydrolipoamide S-acetyltransferase and the suppression of lipoyl synthase. Importantly, CaP/Cu-F facilitates the release of damage-associated molecular patterns and enhances tumor immunogenicity. Meanwhile, fruquintinib-mediated VEGFR inhibition normalizes tumor vasculature, upregulates intercellular adhesion molecules, and improves immune cell infiltration. By integrating redox modulation, calcium overload, cuproptosis, and antiangiogenesis, the CaP/Cu-F nanoplatform exhibits potent antitumor and antimetastatic efficacy. This work thus presents a promising strategy for synergistic cancer therapy.