Osteoinductive biomaterials are attractive for repairing a variety of bone defects, and biomimetic strategies are useful toward developing bone scaffolds with such capacity. Here, Ding et al. from Soochow University developed a multiple biomimetic design to improve the osteogenesis capacity of composite scaffolds consisting of hydroxyapatite nanoparticles (HA) and silk fibroin (SF). SF nanofibers and water-dispersible HA nanoparticles were blended to prepare the nanoscaled composite scaffolds with a uniform distribution of HA with a high HA content (40%), imitating the extracellular matrix (ECM) of bone. Bone morphogenetic protein-2 (BMP-2) was loaded in the SF scaffolds and HA to tune BMP-2 release. In vitro studies showed the preservation of BMP-2 bioactivity in the composite scaffolds, and programmable sustained release was achieved through adjusting the ratio of BMP-2 loaded on SF and HA. In vitro and in vivo osteogenesis studies demonstrated that the composite scaffolds showed improved osteogenesis capacity under suitable BMP-2 release conditions, significantly better than that of BMP-2 loaded SF−HA composite scaffolds reported previously. Therefore, these biomimetic SF−HA nanoscaled scaffolds with tunable BMP-2 delivery provide preferable microenvironments for bone regeneration.