It remains a major challenge to simultaneously achieve bone regeneration and prevent infection in the complex microenvironment of repairing bone defects. Here, we developed a novel ECM-mimicking scaffold by coaxial electrospinning to be endowed with multibiological functions. Lysophosphatidic acid (LPA) and zinc oxide (ZnO) nanoparticles were loaded into the poly-lactic-co-glycolic acid/polycaprolactone (PLGA/PCL, PP) sheath layer of coaxial nanofibers, and deferoxamine (DFO) nanoparticles were loaded into its core layer. The novel scaffold PP-LPA-ZnO/DFO maintained a porous nanofibrous architecture after incorporating three active nanoparticles, showing better physicochemical properties and eximious biocompatibility. In vitro studies showed that the bio-scaffold loaded with LPA nanoparticles had excellent cell adhesion, proliferation, and differentiation for MC3T3-E1 cells and synergistic osteogenesis with the addition of ZnO and DFO nanoparticles. Further, the PP-LPA-ZnO/DFO scaffold promoted tube formation and facilitated the expression of vascular endothelial markers in HUVECs. In vitro antibacterial studies against Escherichia Coli and Staphylococcus aureus demonstrated effective antibacterial activity of the PP-LPA-ZnO/DFO scaffold. In vivo studies showed that the PP-LPA-ZnO/DFO scaffold exhibited excellent biocompatibility after subcutaneous implantation and remarkable osteogenesis at 4 weeks postimplantation in the mouse alveolar bone defects. Importantly, the PP-LPA-ZnO/DFO scaffold showed significant antibacterial activity, prominent neovascularization, and new bone formation in the rat fenestration defect model. Overall, the spatially sustained release of LPA, ZnO, and DFO nanoparticles through the coaxial scaffold synergistically enhanced biocompatibility, osteogenesis, angiogenesis, and effective antibacterial properties, which is ultimately beneficial for bone regeneration. This project provides the optimized design of bone regenerative biomaterials and a new strategy for bone regeneration, especially in the potentially infected microenvironment.

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