Dual-function Injectable Hydrogel with Exosome-Cerium Oxide Nanocomposite Mediates Brain Infarction Therapy

Abstract Stroke is a leading global cause of disability and death, with ischemic stroke posing a particularly severe threat. Despite reperfusion therapy, poor outcomes often persist due to oxidative stress, neuroinflammation, and nerve impairment. This study developed an injectable hydrogel based on dual-modified hyaluronic acid for sustained delivery of exosome-cerium oxide nanocomposite (EXO@CeO2), targeting the pathological brain microenvironment after ischemic stroke. In an oxygen-glucose deprivation model, EXO@CeO2 effectively scavenged reactive oxygen species (ROS), reduced ROS-mediated apoptosis, stabilized mitochondrial membrane potential, and modulated inflammation by downregulating pro-inflammatory cytokines (IL-1β, IL-6) and upregulating anti-inflammatory IL-10. It also exhibited pro-angiogenic effects while preserving neuronal structure and function. In a murine photothrombotic stroke model, the hydrogel alleviated cerebral oxidative stress in the acute phase and promoted microglial polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. During recovery, it improved local cerebral blood flow and led to sustained improvements in neurobehavioral function. In summary, this injectable hydrogel enables sustained codelivery of exosomes and cerium oxide, offering a combined therapy integrating antioxidant and exosome-mediated reparative effects for ischemic stroke. Collectively, this dual strategy simultaneously mitigates acute oxidative damage and promotes long-term neurovascular repair.