Calcium‐Polyphenol Functionalized Black Phosphorus Nanosheet System for Osteoporosis Therapy via Macrophage Reprogramming and Bone Microenvironment Remodeling

Osteoporosis poses a significant threat to human health and severely impairs patients' quality of life. Conventional pharmacological interventions are limited by poor patient compliance and suboptimal efficacy. Imbalanced macrophage polarization is a key driver in osteoporosis pathogenesis, and precise regulation toward the anti-inflammatory M2 phenotype represents a critical therapeutic target. A calcium-polyphenol network-functionalized black phosphorus nanosheet system (HCBP) is developed as a bone-targeted cascade-responsive nanoplatform. After intravenous administration, bone-targeting peptides mediate efficient accumulation in bone tissue. The system dissociates in the acidic osteoporotic microenvironment and releases phosphate ions, which combine with calcium ions to form bioactive calcium phosphate. HCBP alleviates inflammation, sustains M2 macrophage polarization, scavenges reactive oxygen species, enhances osteogenesis, and suppresses osteoclast differentiation. Transcriptomic analysis confirms regulation of the TNF-α/NF-κB, IL-17, and osteoclast differentiation pathways, together with inhibited glycolysis. This multifunctional strategy overcomes the limitations of single-target osteoporosis therapies and facilitates the clinical translation of nanomedicines for metabolic bone diseases.