Brake–Drive Osteo System: Sequential Modulation of the Inflammatory Microenvironment and Osteogenesis for Osteoporotic Bone Defect Regeneration

Osteoporotic bone defects, characterized by chronic inflammation and impaired osteogenesis, pose a formidable challenge for functional bone regeneration. Conventional scaffolds lack effective regulation of the inflammatory microenvironment and fail to coordinate anti-inflammatory and osteogenic signals, thereby limiting their ability to couple inflammation resolution with new bone formation. Here, we developed a "Brake-Drive Osteo System", a spatiotemporally programmed biomaterial integrating quercetin-loaded nanovesicles and teriparatide-loaded nucleic acid frameworks within a calcium phosphate scaffold (BCP-T/N@Q/V). This design enables a sequential therapeutic cascade-quercetin first "disengages the inflammatory brake", alleviating microenvironmental resistance to osteogenesis, while teriparatide subsequently "activates the osteogenic drive", promoting bone regeneration. It effectively reprogrammed macrophages toward a pro-regenerative phenotype and mitigated inflammatory stress, establishing an immunologically permissive microenvironment. This osteoimmune modulation significantly enhanced the osteogenic commitment and maturation of osteoporotic bone marrow mesenchymal stem cells. In a rat osteoporotic femoral condyle defect model, the scaffold achieved accelerated, structurally integrated bone regeneration, underscoring its translational potential. Collectively, this "Brake-Drive Osteo System" provides a sequential strategy that couples inflammation resolution with osteogenesis for effective osteoporotic bone regeneration.