Despite significant therapeutic advances with chemotherapy and immunotherapy in some solid tumors, clinical outcomes for glioblastoma multiform (GBM) remain suboptimal. Owing to their high yield, easy accessibility and cost-effectiveness, plant-derived extracellular vehicles (EVs) have become attractive platforms for biomedical uses. Our study shows that fully natural ginger-derived exosomes (GEXO) effectively inhibited GBM progression through dual mechanisms: (a) direct activation of apoptotic pathways in GBM cells, and (b) induction of immunogenic cell death (ICD) that transforms dead tumor cells into endogenous vaccines. Mechanistically, GEXO demonstrated superior blood-brain barrier (BBB) penetration through clathrin-, caveolin- and macropinocytosis-mediated transcytosis, followed by tumor-specific accumulation via exocytosis. Transcriptomic analysis revealed that GEXO promoted an immunogenic shift in dying GBM cells, enhancing dendritic cell maturation and cytotoxic T-cell responses. In orthotopic GL261 and CT2A models, GEXO significantly prolonged survival without observable toxicity. The natural GEXO platform represents a promising, biosafe strategy with clinical potential for refractory GBM.
Keywords: apoptosis; blood-brain barrier; glioblastoma; immunotherapy; plant-derived exosomes.