Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Cognitive impairment is a common sequela in glioblastoma survivors, yet the underlying mechanisms remain poorly understood. Extracellular vesicles (EVs) derived from glioblastoma are established mediators of intercellular signaling within the tumor microenvironment. Here, we investigated whether GBM-derived EVs released after radiation treatment (RT-EVs) regulate cognitive function. Treatment with RT-EVs was associated with cognitive deficits and neuroinflammatory responses in vivo. In vitro, RT-EVs activated the NF{kappa}B pathway and induced the release of neurotoxic H2O2. Importantly, NF{kappa}B p50 knockdown abolished the H2O2 release previously triggered by RT-EVs, demonstrating mechanistic dependence on NF{kappa}B signaling. Collectively, these findings identify GBM-derived RT-EVs as critical mediators of cognitive impairment through NF{kappa}B-dependent redox imbalance. EV-driven redox dysregulation may therefore represent a therapeutic target to mitigate GBM-associated cognitive dysfunction.