Hydrogel-based delivery of solanesol enhances Treg-astrocyte crosstalk and reduces scar formation following spinal cord injury.

Spinal cord injury (SCI) is a severe neurological condition that often leads to permanent disability, with glial scar formation serving as a key obstacle to functional recovery. In this study, we use transcriptomic profiling and molecular analyses to delineate the pathological signaling cascade involved in SCI. The TGFβ-integrin αvβ3-PTK2-PTEN axis promotes A1 astrocyte polarization and CS56 deposition, thereby contributing to glial scar formation. Treatment with solanesol (SOL) promoted Treg cell infiltration and elevated CCN3 secretion, which, in turn, induced the "integrin switch" from αvβ3 to αvβ5 in astrocytes. This receptor remodeling activated the integrin αvβ5-AMPK-NEDD4 pathway, leading to PTEN degradation, decreasing A1 astrocyte polarization, maintaining A2 astrocytes, reducing scar formation, and improving motor recovery. SOL delivered through a gelatin methacrylate hydrogel (GMH) provided localized sustained release with favorable safety, highlighting its translational potential. The findings of this study uncover a mechanistic link between immune regulation and astrocytic signaling, and propose hydrogel-based SOL delivery as a promising therapeutic strategy for SCI.