Black phosphorus (BPs) nanosheets with their inherent and selective chemotherapeutic effects have recently been identified as promising cancer therapeutic agents, but challenges in surface functionalization hinder satisfactory enhancement of their selectivity between tumors and normal cells. To address this issue, we developed a novel biomineralization-inspired strategy to synthesize CaBPs-Na 2 FDP@CaCl 2 nanosheets, aiming to achieve enhanced and selective anticancer bioactivity along with accelerated osteoblast activity. Benefiting from the in situ mineralization and fructose modification, CaBPs-Na 2 FDP@CaCl 2 exhibited improved pH-responsive degradation behavior and targeted therapy for osteosarcoma. The in vitro results indicated that CaBPs-Na 2 FDP@CaCl 2 exhibited efficient uptake and quick degradation by GLUT5-positive 143B osteosarcoma cells, enhancing BPs-driven chemotherapeutic effects through ATP level disturbance-mediated apoptosis of tumor cells. Moreover, CaBPs-Na 2 FDP@CaCl 2 underwent gradual degradation into PO 4 3- , Ca 2+ and fructose in MC3T3-E1 cells, eliminating systemic toxicity. Intracellular Ca 2+ bound to calmodulin (CaM), activating Ca 2+ /CaM-dependent signaling cascades, thereby enhancing osteoblast differentiation and mineralization in pro-osteoblastic cells. In vivo experiments affirmed the anti-tumor capability, inhibition of tumor recurrence and bone repair promotion of CaBPs-Na 2 FDP@CaCl 2 . This study not only broadens the application of BPs in bone tumor therapy but also provides a versatile surface functionalization strategy for nanotherapeutic agents.
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