Abstract
ABSTRACT
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.