Human neural stem cell-derived extracellular vesicles remediate glioblastoma therapy-induced brain fog

Cranial radiation therapy (RT) with concomitant and adjuvant temozolomide (TMZ; Stupp protocol) prolongs survival in glioma but frequently results in persistent cognitive impairment. Human neural stem cell (hNSC)-derived extracellular vesicles (EVs) are a promising acellular therapy whose bioactive cargo can modulate neuroinflammation and synaptic integrity. We evaluated two GMP-grade hNSC-derived EVs (Shef6 and UCI-191) in syngeneic glioma-bearing and non-tumor adult male and female mice treated with fractionated cranial RT (3 × 9 Gy) plus concomitant low-dose (25 mg/kg) and adjuvant high-dose (66.7 mg/kg, intraperitoneal) TMZ. EV administration improved memory performance in RT-TMZ–exposed mice and, notably, Shef6-EVs also extended survival in glioma-bearing mice in the absence of chemoradiotherapy. Immunofluorescence analyses demonstrated attenuated gliosis and preservation of synaptic integrity in EV-treated RT-TMZ–exposed brains, while transcriptomic profiling identified distinct neuroprotective gene expression pathways in vivo associated with each EV line. Critically, neither Shef6 nor UCI-191 EVs diminished the anti-tumor efficacy of RT-TMZ and did not lead to peripheral organ toxicity following intra venous injections. These data support hNSC-derived EVs as a translational strategy to mitigate treatment-related neurotoxicity while preserving oncologic benefit in a clinically relevant glioma model.