Natural Ginger-Derived Exosomes as Effective Therapeutics for Glioblastoma.

Abstract

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.