GDNF-Enriched Small Extracellular Vesicle-Loaded ROS-Scavenging Hydrogel Promotes Neural Regeneration After Spinal Cord Injury.

Spinal cord injury (SCI) is a severe traumatic disorder of the central nervous system that results in substantial motor and sensory dysfunction. The hostile post-injury microenvironment, marked by excessive oxidative stress, inflammatory responses, and progressive neuronal degeneration, greatly limits neural repair. In this study, we developed a multifunctional reactive oxygen species (ROS)-scavenging hydrogel composed of N-acryloylglycylamide (NAGA), xanthan gum (XG), carbomer 940 (CBP940), and tannic acid (TA) (termed NXCT) to locally deliver glial cell line-derived neurotrophic factor (GDNF)-enriched small extracellular vesicles (sEVs). GDNF, as a key neurotrophic protein, was incorporated into engineered sEVs to enhance their neuroregenerative activity. The resulting GDNF-sEVs@NXCT hydrogel exhibited favorable antioxidant and anti-inflammatory properties in vitro and effectively supported neuronal survival and axonal regeneration. After in situ implantation into the injured spinal cord, GDNF-sEVs@NXCT reduced ROS accumulation, alleviated inflammatory responses, promoted neural and myelin regeneration, and enhanced motor functional recovery in SCI rats. RNA-sequencing further uncovered that these therapeutic effects of GDNF-sEVs@NXCT were associated with PI3K/AKT pathway activation. Overall, these results demonstrate that the GDNF-sEVs@NXCT hydrogel provides a bioactive macromolecule-based therapeutic strategy for SCI repair via microenvironment modulation and neuroregeneration, highlighting its translational potential for spinal cord repair.