ROS-Responsive Trifluoperazine Prodrug Nanoparticles and Mesenchymal Stem Cell Exosomes Synergistically Modulate Astrocyte Phenotype for Spinal Cord Injury Repair

Spinal cord injury (SCI) often triggers pronounced astrocytic edema, which worsens neurological deficits. To counteract the key role of Aquaporin-4 (AQP4) delocalization in this process, we developed a reactive oxygen species (ROS)-responsive nanodrug delivery system to restore AQP4 polarity and reduce edema. We synthesized a trifluoperazine (TFP) prodrug linked by a ROS-cleavable thioketal bond that self-assembled into TFP-ROS nanoparticles (TFP-ROS Nano). In parallel, we isolated exosomes from human umbilical cord mesenchymal stem cells (hUCMSC-Exos) to harness their regenerative potential. Under hypoxic conditions in vitro, TFP-ROS Nano protected astrocytes from apoptosis and modulated AQP4 expression, promoting a shift from the neurotoxic A1 phenotype to the neuroprotective A2 phenotype. In a murine SCI model, combined treatment with hUCMSC-Exos and TFP-ROS Nano outperformed each monotherapy: treated animals showed greater motor recovery by Basso Mouse Scale scores and better preservation of spinal cord architecture, with reduced tissue necrosis and maintained structural integrity. Together, these results suggest that the TFP-ROS Nano, especially when used synergistically with hUCMSC-Exos, provides a promising strategy to alleviate astrocytic edema and promote neuro-regeneration after SCI.