Engineering　a　proper　immune　response　following　biomaterial　implantation　is　essential　to　bone　tissue　regeneration.　Herein,　a　biomimetically　hierarchical　scaffold　composed　of　deferoxamine@poly(ε-caprolactone)　nanoparticles　(DFO@PCL　NPs),　manganese　carbonyl　(MnCO)　nanosheets,　gelatin　methacryloyl　hydrogel,　and　a　polylactide/hydroxyapatite　(HA)　matrix　is　fabricated　to　augment　bone　repair　by　facilitating　the　balance　of　the　immune　system　and　bone　metabolism.　First,　a　3D　printed　stiff　scaffold　with　a　well-organized　gradient　structure　mimics　the　cortical　and　cancellous　bone　tissues;　meanwhile,　an　inside　infusion　of　a　soft　hydrogel　further　endows　the　scaffold　with　characteristics　of　the　extracellular　matrix.　A　Fenton-like　reaction　between　MnCO　and　endogenous　hydrogen　peroxide　generated　at　the　implant-tissue　site　triggers　continuous　release　of　carbon　monoxide　and　Mn2+,　thus　significantly　lessening　inflammatory　response　by　upregulating　the　M2　phenotype　of　macrophages,　which　also　secretes　vascular　endothelial　growth　factor　to　induce　vascular　formation.　Through　activating　the　hypoxia-inducible　factor-1α　pathway,　Mn2+　and　DFO@PCL　NP　further　promote　angiogenesis.　Moreover,　DFO　inhibits　osteoclast　differentiation　and　synergistically　collaborates　with　the　osteoinductive　activity　of　HA.　Based　on　amounts　of　data　in　vitro　and　in　vivo,　strong　immunomodulatory,　intensive　angiogenic,　weak　osteoclastogenic,　and　superior　osteogenic　abilities　of　such　an　osteoimmunity-regulating　scaffold　present　a　profound　effect　on　improving　bone　regeneration,　which　puts　forward　a　worthy　base　and　positive　enlightenment　for　large-scale　bone　defect　repair.　©　2022　Wiley-VCH　GmbH.