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.