Mesenchymal stem cell (MSC)-derived exosomes have shown potential as an effective therapeutic tool for repairing bone defects. Researchers from the CHA University School of Medicine demonstrate that silk fibroin (SF) 3D-scaffolds enriched with MSC-derived exosomes successfully enhance bone regeneration in critical-sized rat calvarial defect areas. The exosomes coated on the SF scaffolds were not subjected to any chemical treatments or synthetic procedures to accelerate the osteogenic cellular processes modulated by the exosomes. Specifically, exosomes extracted from human adipose-derived mesenchymal stem cells (hAMSCs) were investigated for their capacity of inducing osteogenic differentiation and bone regeneration in vitro and in vivo. In vitro assay showed beneficial effect of the exosome-coated SF scaffolds on the growth and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). In vivo study confirmed thorough integration and attachment of implanted scaffolds in the bone defect region. These results indicate that SF scaffold coated with exosomes extracted from MSCs can be a suitable bone substitute graft for bone regeneration.