Bioinspired porous core-shell microspheres with spatiotemporal delivery coordinate immunomodulatory-osteogenic...

Critical-sized calvarial defects remain a formidable clinical challenge due to dyssynchronous immunomodulation-osteogenesis coupling and unregulated growth factor release. Here, a bioinspired porous core-shell microsphere system (GCI@HPPS) is developed, integrating hydroxyapatite (HA)-loaded shell, surface-immobilized SDF-1α, and IGF-1-encapsulated cores to immunomodulate osteoimmune microenvironment and osteogenesis promotion. The hierarchical architecture achieved spatiotemporally programmed release: HA degradation-dependent mineralization, SDF-1α-mediated BMSC chemotaxis, and sustained IGF-1 delivery, mimicking natural bone repair cascades. Dual covalent/guest-host crosslinking (GelMA/Ac-β-CD) enhanced compressive strength, while polydopamine functionalization of microspheres conferred electroactivity, hydrophilicity, ROS/RNS scavenging (97.29 % ABTS•+ elimination), antibacterial efficacy (>99.8 %) and hemostasis. In vitro, GCI@HPPS mitigates oxidative stress, induces M2 macrophage polarization, and suppresses inflammatory cascades while concomitantly enhancing endogenous BMSC recruitment, proliferation, and osteogenic differentiation. Proteomics revealed a tetradic anti-inflammatory mechanisms of GCI@HPPS: NF-κB/P-JNK suppression, pro-inflammatory cytokines downregulation, mitochondrial oxidative modulation, and STAT6-driven M2 polarization. In vivo, GCI@HPPS achieved calvarial defect closure at 8 weeks through porous matrix-guided cellular infiltration, and SDF-1α/IGF-1-mediated chemotaxis, Rho/MAPK signaling pathway activation balancing osteoclast-osteoblast dynamics, stage-specific osteogenic induction and AGE-RAGE/VEGF-coupled angiogenesis-osteogenesis. This work pioneers a spatiotemporal delivery paradigm that coordinates inflammation modulation, stem cell recruitment, osteogenic differentiation, and mineralization phases, offering a promising approach for complex cranial reconstruction.