Multifunctional MXene-Based Hydrogel Remodels Regenerative Microenvironment and Facilitates Neurogenesis of Endogenous Neural Stem Cells for Spinal Cord Injury Recovery

Endogenous neural stem cells (NSCs) hold promise as potential seed cells for spinal cord injury (SCI) repair. However, their migration to the injury site and subsequent neuronal differentiation, essential for rebuilding neural networks, are significantly hindered by an unfavorable lesion microenvironment [characterized by hypoxia, excessive reactive oxygen species (ROS), neuroinflammation, and acidity]. In this study, a conductive hydrogel for SCI treatment was designed by incorporating stromal cell-derived factor-1 alpha (SDF-1 alpha) and MXene nanosheets. This composite hydrogel demonstrated multiple therapeutic functions: first, SDF-1 alpha released from the hydrogel recruited endogenous NSCs to the injury site; second, MXene nanosheets modified the microenvironment, enhancing NSC activation and differentiation by scavenging ROS and reprogramming macrophages to the M2 phenotype; third, the hydrogel's electroconductivity, imparted by MXene nanosheets, further promoted NSC differentiation. Moreover, transcriptome analysis revealed that MXene nanosheets facilitated SCI recovery via the PI3K-Akt and calcium signaling pathways. This work represents the first development of an MXene-based multifunctional hydrogel for stimulating endogenous NSCs in SCI repair. The strategy of targeting endogenous NSCs while reshaping the hostile microenvironment for migration and neuronal differentiation introduces a treatment approach for SCI treatment with a significant potential for clinical applications.