Genetically engineered extracellular vesicles-based collagen-targeting bioinspired scaffold for tendon regenerative repair

Tendon injuries, particularly massive tendon defects, pose significant clinical challenges due to the limited regenerative capacity of tendons and suboptimal outcomes of current therapies. This study presents a bioinspired scaffold that integrates genetically engineered extracellular vesicles (EVs) with collagen-targeting capabilities into a decellularized bovine tendon sheet (DBTS) for tendon regenerative repair. Tendon-derived stem cells (TDSCs) were genetically modified to overexpress biglycan (Bgn) and fibromodulin (Fmod), producing bioactive EVs that drive tenogenic differentiation via the miR-145-5p/TGFβ2 signaling pathway. The incorporation of a collagen-targeting peptide (CTP) on EVs surfaces ensured efficient attachment and sustained release at the injury site. The resulting bioinspired scaffold (TDSCsBgn/Fmod/CTP EVs-DBTS) provided a supportive microenvironment for tendon regeneration, demonstrated in vitro by improved stem cell proliferation, migration and tenogenic differentiation, and in vivo by enhanced collagen alignment, extracellular matrix remodeling, and biomechanical performance. This scaffold represents a paradigm shift in cell-free regenerative strategies, offering targeted modulation of the tendon niche with translational potential for treating massive tendon injuries.