Introduction: Recent advances in the field of nanotechnology have led to the development of platforms for healing or repairing damaged tissues. The present study aimed to provide a bone extracellular matrix (ECM) mimetic platform made of hydroxyapatite and collagen loaded with nanopolymersomes encapsulating dimethyloxalylglycine (DMOG) and decorated with BMP-2 peptide in order to accelerate and increase the differentiation of mesenchymal stem cells to bone tissue. Method: In this study, polymersome nanoparticles carrying DMOG and targeted with BMP-2 peptide were prepared. The physicochemical properties of nanoparticles were evaluated. Thereafter, it was loaded into collagen-nanohydroxyapatite scaffolds and the expression levels of osteogenic genes OCN and OPN and angiogenic genes vcam, vwf, and kdr were checked in mesenchymal stem cells. Results: The surface charge and particle size of the synthesized nanoparticles were reported as -6 mv and 141 nm, respectively. The nanoparticles were able to slowly release 35% of the loaded DMOG within 30 days. The results demonstrated that the expression levels of OCN and OPN genes in cells exposed to polymersomes targeted with BMP-2 peptide were 27 and 2 times more than those of non-targeted polymersomes, respectively. In addition, the expression of angiogenic genes, vwf, kdr, and vcam, displayed a significant increase in targeted polymersomes compared to the non-targeted types (11.7-, 12.8-, and 2.17-fold, respectively). Conclusion: It seems that providing an environment similar to the bone ECM by combining an osteomimetic scaffold made of collagen-nanohydroxyapatite, DMOG as an angiogenic factor, and BMP-2 as the osteogenic factor can be effective in accelerating and increasing the differentiation of mesenchymal stem cells into osteoblasts.