pH‐Responsive Nanoparticle‐Coated Calcium Phosphate Granules for Bone Cancer Therapy

Osteosarcoma (OS) remains the most prevalent malignant bone tumor, with stagnant survival rates and high recurrence risk due to residual tumor cells, and limited post-resection bone regeneration. Existing bifunctional bone graft substitutes integrating anticancer activity with osteogenesis are hindered by uncontrolled drug release and inefficient intracellular delivery. Here, we report a pH-sensitive nano-microparticle linking strategy, in which imine bonds are used as interfacial linkers between therapeutic nanoparticles and bone scaffolds to enable tumor microenvironment-triggered, on-demand nanotherapeutic release. In this study, we develop β-tricalcium phosphate (β-TCP) granules decorated with selenium (Se)-doped mesoporous silica nanoparticles (SeMIA@TCP), in which nanoparticles are functionalized with imine bonds for acidic pH-responsive detachment and alendronate for strong β-TCP binding. This design ensures stable nanoparticle immobilization under physiological conditions while enabling selective release within the mildly acidic OS microenvironment. In vitro, the SeMIA@TCP showed significant pH-dependent cytotoxicity toward OS cells, while maintaining low toxicity toward human mesenchymal stem cells (hMSCs) under physiological conditions, indicating a OS-targeting profile. Furthermore, the released nanoparticles enhanced alkaline phosphatase (ALP) expression and mineralization in hMSCs, underscoring their osteogenic potential. Collectively, these results demonstrate the potential of tumor microenvironment-responsive Se-doped MSN-assembled TCP granules as a design platform for bifunctional scaffolds in bone cancer treatment.