Bone targeting miR-26a loaded exosome-mimetics for bone regeneration therapy by activating Wnt signaling pathway

Mesenchymal stem cell-derived exosomes (MSC-Exos) have shown great potential in the areas of bone regen-eration and treatment of age-related diseases. Engineered exosomes can integrate multiple functional compo-nents to achieve optimal, targeted therapeutic effects. This study combined large-scale generation, bone-targeting modification, and miR-26a loading for exosome-mimetics (EMs) to construct a cell-free delivery sys-tem that promotes bone regeneration with good biocompatibility. EMs were fabricated through sequential extrusion of MSCs and reached a 15-fold production yield compared to conventional exosome secretion. Systemic injection of Asp8-EM/miR-26a in mouse models accelerated bone-defect healing and prevented osteoporosis. The underlying mechanism involves miR-26a targeting glycogen synthase kinase-38 (GSK-38) to induce 8-catenin accumulation, thus activating Wnt signaling pathway and promoting bone regeneration. This study provides a feasible and effective strategy for modifying EMs to enhance bone regeneration.