Triple-effect strategy with taxifolin-whitlockite nanoparticles embedded hydrogel for osteoporotic bone defect repair and bone homeostasis modulation

• GelMA/MWHNPs@TAX composites possess excellent physical and chemical properties as well as favorable bioadaptability. • GelMA/MWHNPs@TAX composites effectively inhibit osteoclastogenesis by deactivating the NF-κB/MAPK/p38 and NF-κB/MAPK/ERK mediated NFATc1 transcriptional process, while promotes osteogenesis and angiogenesis. • GelMA/MWHNPs@TAX composites can achieve the triple function of osteoclastogenesis inhibition, osteogenic promotion and angiogenesis enhancement to modulate the balance of bone homeostasis and facilitate osteoporotic cranial defect repair. Osteoporosis is a systemic degenerative bone disease caused by bone homeostatic imbalance. Osteoporotic bone defect repair is usually difficult due to overactivated osteoclastogenesis, inhibited osteogenesis, and attenuated angiogenesis under pathological conditions. Herein, a drug delivery system consisting of hollow mesoporous whitlockite nanoparticles (MWHNPs) loaded with osteogenic and anti-osteoclastogenic taxifolin (TAX) is fabricated and encapsulated into gelatin methacryloyl (GelMA) to produce GelMA/MWHNPs@TAX. The triple effects of osteoclastogenesis suppression, osteogenic enhancement, and angiogenesis promotion are exerted by the spatial–temporal sustained release of taxifolin and bioactive ions in the treatment of osteoporotic cranial defects of ovariectomized rats. This novel “one-stone-three-birds” strategy effectively addresses the pathological condition of osteoporosis and achieves a balance between bone resorption and reconstruction, providing tremendous potential for the design and clinical application of other functional biomaterials