Modification of adipose mesenchymal stem cells-derived small extracellular vesicles with fibrin-targeting peptide CREKA for enhanced bone repair

The process of bone repair is highly regulated by a large number of bioactive factors. Thus, a "cocktail" of bioactive factors supplemented to the defect sites is desirable for bone repair. In this regard, small extracellular vesicles (sEVs) derived from mesenchymal stem cells hold great potential in tissue repair. Nevertheless, the poor homing and retention of sEVs greatly limited their possible clinical application. In the present work, DMPE-PEG-CREKA was inserted into the membrane of sEVs released from adipose-derived mesenchymal stem cells to obtain CREKA functionalized sEVs (CREKA-sEVs), which could target fibrin to accumulate and retain in bone defects. Our results showed that CREKA-sEVs, like sEVs, promoted the osteogenic differentiation of BMSCs, the angiogenic property of HUVECs, and modulated the polarization of macrophages in vitro. Furthermore, due to the improved fibrin-binding and retention capacity of CREKA-sEVs, they enhanced the bone repair substantially in the rat femoral defect model. This study provided a new strategy to improve the therapeutic efficiency of sEVs and showed that CREKA-sEVs had great application value in bone tissue repair.