A Novel pH‐Activatable Nanozyme for Treating Breast Cancer Bone Metastasis by Regulating Cancer Cell Metabolic Reprogramming and the Tumor Microenvironment

Multi‐omics analyses implicate enhanced oxidative phosphorylation (OXPHOS) in breast cancer bone metastasis (BCBM). To target this metabolic vulnerability, we develop SPMMPA, a bone‐targeted nanozyme comprising a Prussian blue core, a disulfide‐bridged mesoporous silica interlayer, and a manganese oxide shell, functionalized with polyethylenimine, alendronate, and the Ser‐Asp‐Ser‐Ser‐Asp peptide. Its acid‐enhanced catalytic activity promotes reactive oxygen species production and glutathione depletion, accompanied by mitochondrial dysfunction, reduced OXPHOS and adenosine triphosphate production, and downregulation of peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha. Alendronate and silicon release contribute to reduced osteoclast activity and preservation of bone structure. Near‐infrared irradiation further enhances treatment efficacy through photothermal heating below 48°C. In mouse models of BCBM, SPMMPA suppresses tumor growth and alleviates osteolysis, without overt toxicity in the assays performed. These findings support a pH‐responsive catalytic strategy that couples disruption of tumor energy metabolism with protection of bone homeostasis.