The　effective　repair　of　large　bone　defects　remains　a　major　challenge　due　to　its　limited　self-healing　capacity.　Inspired　by　the　structure　and　function　of　the　natural　periosteum,　an　electrospun　biomimetic　periosteum　is　constructed　to　programmatically　promote　bone　regeneration　using　natural　bone　healing　mechanisms.　The　biomimetic　periosteum　is　composed　of　a　bilayer　with　an　asymmetric　structure　in　which　an　aligned　electrospun　poly(Ε-caprolactone)/gelatin/deferoxamine　(PCL/GEL/DFO)　layer　mimics　the　outer　fibrous　layer　of　the　periosteum,　while　a　random　coaxial　electrospun　PCL/GEL/aspirin　(ASP)　shell　and　PCL/silicon　nanoparticles　(SiNPs)　core　layer　mimics　the　inner　cambial　layer.　The　bilayer　controls　the　release　of　ASP,　DFO,　and　SiNPs　to　precisely　regulate　the　inflammatory,　angiogenic,　and　osteogenic　phases　of　bone　repair.　The　random　coaxial　inner　layer　can　effectively　antioxidize,　promoting　cell　recruitment,　proliferation,　differentiation,　and　mineralization,　while　the　aligned　outer　layer　can　promote　angiogenesis　and　prevent　fibroblast　infiltration.　In　particular,　different　stages　of　bone　repair　are　modulated　in　a　rat　skull　defect　model　to　achieve　faster　and　better　bone　regeneration.　The　proposed　biomimetic　periosteum　is　expected　to　be　a　promising　candidate　for　bone　defect　healing.　©　2024　Wiley-VCH　GmbH.