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Conventional scaffolds lack effective regulation of the inflammatory microenvironment and fail to coordinate anti\u2010inflammatory and osteogenic signals, thereby limiting their ability to couple inflammation resolution with new bone formation. Here, we developed a \u201cBrake\u2013Drive Osteo System\u201d, a spatiotemporally programmed biomaterial integrating quercetin\u2010loaded nanovesicles and teriparatide\u2010loaded nucleic acid frameworks within a calcium phosphate scaffold (BCP\u2010T\/N@Q\/V). This design enables a sequential therapeutic cascade\u2014quercetin first \u201cdisengages the inflammatory brake\u201d, alleviating microenvironmental resistance to osteogenesis, while teriparatide subsequently \u201cactivates the osteogenic drive\u201d, promoting bone regeneration. It effectively reprogrammed macrophages toward a pro\u2010regenerative 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 \u201cBrake\u2013Drive Osteo System\u201d provides a sequential strategy that couples inflammation resolution with osteogenesis for effective osteoporotic bone regeneration.<\/jats:p>","DOI":"10.1002\/adma.72909","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T07:19:07Z","timestamp":1774423147000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Brake\u2013Drive Osteo System: Sequential Modulation of the Inflammatory Microenvironment and Osteogenesis for Osteoporotic Bone Defect Regeneration"],"prefix":"10.1002","volume":"38","author":[{"given":"Zhuojie","family":"Xiao","sequence":"first","affiliation":[{"name":"National Engineering Research Center for Biomaterials, Department of Orthopedic Surgery and Orthopedic Research Institute West China Hospital Sichuan University  Chengdu 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