Composite　materials　incorporating　natural　biopolymers　and　inorganic　minerals　are　attractive　alternatives　to　mimic　the　physicochemical　properties　of　native　bone　tissues　and　have　been　increasingly　applied　in　the　field　of　bone　defect　repair.　However,　the　poor　interfacial　bonding　between　organic　and　inorganic　phases　in　traditional　composite　biomaterials　leads　to　serious　organic-inorganic　phase　separation　and　inevitable　agglomeration　of　inorganic　minerals,　resulting　in　their　insufficient　mechanical　properties　and　weak　bone　remodeling　activity.　Herein,　a　covalent　bond-mediated　interface　engineering　strategy　between　silk　fibroin　macromolecules　and　hydroxyapatite　nanoparticles　is　adopted　to　develop　novel　organic-inorganic　hybrid　composites　(named　mSF/mHA/BP)　with　impressively　high　interfacial　compatibility.　This　method　significantly　enhances　the　interfacial　bonding　between　organic　and　inorganic　phases　and　achieves　uniform　distribution　of　inorganic　nanoparticles,　endowing　mSF/mHA/BP　with　exceptional　load-bearing　capacity,　strengthened　mechanical　performance,　and　superior　anti-crack　propagation.　Besides　ensuring　robust　physicochemical　characteristics,　the　interface-engineered　hybrid　composite　also　provides　a　powerful　platform　for　spatiotemporal　regulation　of　bone　healing　progression.　The　additional　loading　of　nanodrugs　onto　mSF/mHA/BP　effectively　induces　the　osteogenic　differentiation　of　mesenchymal　stem　cells　and　the　angiogenesis　activity　of　vein　endothelial　cells,　regulating　the　osteogenic　metabolism　and　vascular　network　formation.　In　vivo　rat　cranial　bone　defect　studies　verify　that　the　implantation　of　mSF/mHA/BP　effectively　accelerates　the　active　bone　remodeling　process　to　promote　the　regeneration　of　mineralized　bone　tissues　in　the　defect　region,　thus　ensuring　sufficient　osseointegration　and　biomechanical　support.　Overall,　this　interface　engineering　strategy　offers　a　new　design　insight　for　developing　bone　regenerative　organic-inorganic　composite　biomaterials.　©　2025　Elsevier　B.V.