Breast cancer therapy has always been a hard but urgent issue. Disruption of mitochondrial Ca²⁺ homeostasis has been reported as an effective antitumor strategy, while how to contribute to mitochondrial Ca²⁺ overload effectively is a critical issue. To solve this issue, we designed and engineered a dual enhanced Ca²⁺ nanogenerator (DECaNG), which can induce elevation of intracellular Ca²⁺ through the following three ways: Calcium phosphate (CaP)-doped hollow mesoporous copper sulfide was the basic Ca²⁺ nanogenerator to generate Ca²⁺ directly and persistently in the lysosomes (low pH). Near-infrared light radiation (NIR, such as 808 nm laser) can accelerate Ca²⁺ generation from the basic Ca²⁺ nanogenerator by disturbing the crystal lattice of hollow mesoporous copper sulfide via NIR-induced heat. Curcumin can facilitate Ca²⁺ release from the endoplasmic reticulum to cytoplasm and inhibit expelling of Ca²⁺ in cytoplasm through the cytoplasmic membrane. The in vitro study showed that DECaNG could produce a large amount of Ca²⁺ directly and persistently to flow to mitochondria, leading to upregulation of Caspase-3, cytochrome c, and downregulation of Bcl-2 and ATP followed by cell apoptosis. In addition, DECaNG had an outstanding photothermal effect. Interestingly, it was found that DECaNG exerted a stronger photothermal effect at lower pH due to the super small nanoparticles effect, thus enhancing photothermal therapy. In the in vivo study, the nanoplatform had good tumor targeting and treatment efficacy via a combination of disruption of mitochondrial Ca²⁺ homeostasis and photothermal therapy. The metabolism of CaNG was sped up through disintegration of CaNG into smaller nanoparticles, reducing the retention time of the nanoplatform in vivo. Therefore, DECaNG can be a promising drug delivery system for breast cancer therapy.

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