Exosome-deferoxamine loaded bioengineered neural stem cell microfibers inhibited ferroptosis after severe spinal cord injury via H4K12 lactylation

Ferroptosis occurs after spinal cord injury (SCI), leading to neuronal loss and impairment of neural regeneration. Therefore, combining the beneficial effects of existing neural stem cell (NSC) scaffolds with ferroptosis inhibition strategies might lead to better therapeutic outcomes. This study proposes a combinatorial approach integrating NSC microfibers, umbilical cord mesenchymal stem cell-derived exosomes (ucMSC-exos), and deferoxamine (DFO) for SCI repair. In vitro experiments demonstrated that the combined application of ucMSC-exos and DFO successfully inhibited ferroptosis by clearing iron ions and reactive oxygen species (ROS). Furthermore, ucMSC-exos and DFO promoted cellular lactylation by increasing lactate and lactate dehydrogenase (LDH) levels. These changes were found to occur in M2 microglia triggered by ucMSC-exos, suggesting that ucMSC-exo-DFO treatment may suppress ferroptosis by enhancing histone lactylation in M2 microglia. Finally, a 3 mm mouse spinal hemisection model was used to validate the in vivo regenerative effects of the NSC microfibers with ucMSC-exos and DFO. The scaffold successfully inhibited ferroptosis, while additionally suppressed inflammation, promoted neurogenesis and angiogenesis, and ultimately restored motor and sensory functions. In summary, this study elucidated a potential mechanism for ferroptosis inhibition in SCI and provided a promising therapeutic strategy for SCI repair.