Casey Hudson, Robert P. Krattli, Sanad M. El-Khatib, Arya R. Vagadia, An H. Do, Shreya Madan, Manal T. Usmani, Tracy Nguyen, Devyani Swami, Katja Piltti, Leslie M. Thompson, Brian J. Cummings, Aileen J. Anderson, Munjal M. Acharya
Cranial radiation therapy (RT) with concomitant and adjuvant temozolomide (TMZ; Stupp protocol) prolongs glioma survival 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 EVs derived from GMP-grade hNSCs (Shef6 and UCI-191) in syngeneic glioma-bearing and non-tumor adult mice treated with fractionated cranial RT (3 × 8.67 Gy) together with 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 associated with each EV source. Critically, neither Shef6 nor UCI-191 EVs diminished or interfered with the anti-tumor efficacy of RT-TMZ. 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.