An engineered M2 macrophage-derived exosomes-loaded electrospun biomimetic periosteum promotes cell recruitment, immunoregulation, and angiogenesis in bone regeneration

The periosteum, a fibrous tissue membrane covering bone surfaces, is critical to osteogenesis and angiogenesis in bone reconstruction. Artificial periostea have been widely developed for bone defect repair, but most of these are lacking of periosteal bioactivity. Herein, a biomimetic periosteum (termed PEC-Apt-NP-Exo) is prepared based on an electrospun membrane combined with engineered exosomes (Exos). The electrospun membrane is fabricated using poly(ε-caprolactone) (core)-periosteal decellularized extracellular matrix (shell) fibers via coaxial electrospinning, to mimic the fibrous structure, mechanical property, and tissue microenvironment of natural periosteum. The engineered Exos derived from M2 macrophages are functionalized by surface modification of bone marrow mesenchymal stem cell (BMSC)-specific aptamers to further enhance cell recruitment, immunoregulation, and angiogenesis in bone healing. The engineered Exos are covalently bonded to the electrospun membrane, to achieve rich loading and long-term effects of Exos. <i>In vitro</i> experiments demonstrate that the biomimetic periosteum promotes BMSC migration and osteogenic differentiation via Rap1/PI3K/AKT signaling pathway, and enhances vascular endothelial growth factor secretion from BMSCs to facilitate angiogenesis. <i>In vivo</i> studies reveal that the biomimetic periosteum promotes new bone formation in large bone defect repair by inducing M2 macrophage polarization, endogenous BMSC recruitment, osteogenic differentiation, and vascularization. This research provides valuable insights into the development of a multifunctional biomimetic periosteum for bone regeneration.