Extracellular vesicles as nanocarriers in glioblastoma: implications for chemoresistance and immune evasion

Glioblastoma (GBM), the most aggressive primary brain tumor, remains highly resistant to conventional therapies because of its pronounced intratumoral heterogeneity, adaptive plasticity, and complex tumor microenvironment. Increasing evidence indicates that extracellular vesicles (EVs) play central roles in mediating intercellular communication within GBM and contribute to multiple mechanisms associated with therapeutic resistance. This review critically examines the biogenesis, molecular cargo composition, and functional heterogeneity of GBM-derived EVs, with particular emphasis on their involvement in chemoresistance-related processes, including apoptosis evasion, DNA repair modulation, stemness maintenance, immune reprogramming, metabolic adaptation, and remodeling of the tumor microenvironment. EV-associated cargos, including microRNAs, long non-coding RNAs, circular RNAs, proteins, and lipids, appear to coordinately regulate interconnected resistance networks under therapeutic pressure rather than functioning through isolated pathways. Importantly, this review distinguishes between findings derived from in vitro systems, preclinical in vivo models, and patient-derived clinical evidence in order to better contextualize the current translational relevance of EV-based mechanisms. Emerging evidence further suggests that EV-mediated effects may be context-dependent and, in certain settings, may exert non-canonical or antiproliferative functions. In addition to their pathological roles, EVs are increasingly being investigated as potential biomarkers and therapeutic platforms for GBM management. However, substantial translational barriers remain, including EV heterogeneity, lack of isolation standardization, scalability limitations, cargo-loading inefficiency, regulatory challenges, and incomplete understanding of off-target and physiological effects. By integrating mechanistic insights with translational considerations, this review provides a balanced framework for understanding the dual and context-dependent roles of EVs in GBM progression and therapeutic resistance while highlighting critical knowledge gaps that must be addressed before clinical implementation.