Local delivery of mesenchymal stem cell-extruded nanovesicles through a bio-responsive scaffold for acute spinal cord injury treatment

Intense inflammatory responses and elevated levels of reactive oxygen species (ROS) extremely exacerbate the pathological process of spinal cord injury (SCI). Mesenchymal stem cell (MSC)-derived extracellular vesicles (EV) can mitigate SCI-related inflammation but their production yield remains limited. Alternatively, MSC-extruded nanovesicles (NV) inherit the therapeutic potential from MSCs and have a markedly higher yield than EV. In the present study, a bio-responsive scaffold system (RS + NV) was created for SCI treatment. NV was generated from human MSCs by physical extrusion and encapsulated in a ROS-responsive scaffold (RS). RS + NV efficiently scavenged environmental ROS and underwent degradation, thus facilitating the responsive release of NV. NV inhibited the pro-inflammatory phenotypic transformation, and reduced the secretion of TNF-α and IL-6 from lipopolysaccharide-stimulated BV2 cells, exhibiting comparable anti-inflammatory properties to EV. Additionally, NV posed a superior antioxidative effect than EV and could effectively alleviate the oxidative stress damage of H₂O₂-stimulated PC12 cells. Furthermore, in SCI rats, the uptake of NV was primarily attributed to microglia and neurons. RS + NV exhibited synergistic effects in regulating the hostile microenvironment in vivo during the acute phase, thereby establishing a conducive environment for long-term locomotor, tissue repair, and recovery of neuropathic pain. Overall, RS + NV shows promising potential for use as an anti-inflammatory and antioxidative therapeutic approach for treating SCI.