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.