Targeted Biomimetic Stem Cell Membrane-Exosome Composite Delivery System for the Treatment of Bone Defects

Exosomes derived from MC3T3-E1 cells (M-Exos) exhibit considerable potential for promoting bone repair and regulating bone metabolism. However, their limited osteogenic efficiency and poor targeting capacity remain major challenges. In this study, we developed a therapeutic system, HAMA + BM-Exo¹³⁸. This platform encapsulates exosomes loaded with the recombinant nucleic acid drug MSA-anti-138 within bone marrow mesenchymal stem cell membranes (BMs), generating a BM-Exo¹³⁸ complex with enhanced bone-targeting ability and therapeutic efficacy. Hyaluronic acid methacrylate (HAMA) hydrogel was employed as a bone-filling material to provide a supportive matrix for the sustained release of BM-Exo¹³⁸, thereby promoting osteogenic differentiation and facilitating bone defect repair both in vitro and in vivo. RNA sequencing analysis indicated that BM-Exo¹³⁸ exerts its therapeutic effects by activating the TGF-β signaling pathway. These findings highlight an integration strategy for exosome-based therapy and offer a promising approach to overcoming current limitations in bone defect treatment, with substantial potential for clinical translation.