Regenerative therapy using MSCs-derived reinforced extracellular vesicles incorporated into ROS-responsive injectable hydrogel for the treatment of spinal cord injury

Severe inflammatory reactions and increased levels of reactive oxygen species (ROS) significantly worsen the degenerative progression of spinal cord injury (SCI). Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) can alleviate inflammation associated with SCI, although their yield is limited. Conversely, MSC-extruded nanovesicles (NVs) possess therapeutic potential and exhibit significantly higher levels than EVs. In this study, an ROS-nanoscaffold (RNS + NVs) was developed for the treatment of SCI. NVs were produced from MSCs via physical extrusion and incorporated into an ROS-nanoscaffold (RNS). RNS + NVs effectively scavenged and degraded ROS, enabling the responsive release of NVs. NVs inhibited pro-inflammatory changes and decreased IL-6 and TNF-α release from lipopolysaccharide-induced BV2 cells, demonstrating anti-inflammatory activity similar to that of EVs. Furthermore, NVs exhibited a more pronounced antioxidative effect than EVs and successfully mitigated oxidative stress-induced damage in H 2 O 2 -induced PC12 cells. Moreover, in SCI models, NV absorption is predominantly mediated by the microglia and neurons. RNS + NVs have shown synergistic benefits in modulating the adverse in vivo microenvironment during the acute stage, consequently creating a favorable setting for tissue healing, long-term locomotion, and alleviation of neuropathic pain. RNS + NVs demonstrated significant potential as antioxidant and anti-inflammatory agents in SCI.