Oxidative stress-preconditioned exosomes target BMF to restore mitophagy for alleviating intervertebral disc degeneration

Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) represent a promising cell-free strategy for intervertebral disc degeneration (IDD). Here, we obtained oxidative stress-preconditioned exosomes (O-Exos) from BMSCs exposed to low-concentration hydrogen peroxide. Compared with exosomes from untreated cells (N-Exos), O-Exos more effectively delayed nucleus pulposus (NP) cell senescence and attenuated IDD in vitro and in vivo. The superior effects of O-Exos were associated with restoration of mitophagy and improved mitochondrial homeostasis in TNF/TNF-α-treated NP cells. BMF (Bcl2 modifying factor) was identified as a functionally relevant downstream target suppressed by O-Exos, and Bmf deficiency promoted mitophagy and alleviated IDD. Further analyses showed that O-Exos relieved the inhibitory effect of BMF on BCL2L13-LC3B coupling, thereby restoring mitophagy. In addition, exosomal Mir29a-3p was required for BMF suppression and the superior activity of O-Exos. Together, these findings identify oxidative stress preconditioning as an effective strategy to enhance exosome potency against IDD.