Gut Microbiota-Derived Extracellular Vesicles as Emerging Nanocarriers for Glioma Therapy: Opportunities and Translational Challenges

Abstract

Glioblastoma is a highly malignant primary brain tumor characterized by extensive infiltration, resistance to treatment, and extremely low survival rates even with the most aggressive multimodal therapy, including surgical resection, radiotherapy, and temozolomide-based chemotherapy. The blood-brain barrier (BBB), the strongly immunosuppressive glioma microenvironment, and the systemic toxicity of conventional therapies collectively restrict therapeutic efficacy. Significant advances in microbiome research have identified the gut-brain axis and microbiota-derived extracellular vesicles (EVs) as important modulators of neuroinflammation, BBB integrity, and central nervous system (CNS) homeostasis, thereby opening new avenues for brain-targeted drug delivery. This narrative review synthesizes current evidence on gut microbiota-derived EVs most notably bacterial extracellular vesicles (BEVs), such as outer membrane vesicles (OMVs) from Gram-negative bacteria as candidate vehicles for glioma-targeted drug delivery. The review first describes the bidirectional gut-brain axis and identifies microbiota-derived metabolites relevant to glioma genesis and treatment response. Second, a comprehensive overview of the biogenesis, physicochemical properties, and barrier-crossing capacity of BEVs is provided, with emphasis on in vivo evidence supporting their ability to cross the intestinal epithelium, vascular endothelium, and BBB to transport cargoes toward the CNS. Third, established approaches to isolate, characterize, and load therapeutic cargo into EVs are reviewed, alongside surface engineering and hybrid vesicle design strategies, drawing on the broader mammalian EV drug-delivery literature in glioblastoma. Importantly, although preclinical evidence demonstrates that mammalian cell-derived EVs can be loaded with chemotherapeutics or nucleic acids to augment brain delivery and modulate glioma immunity, no direct in vivo demonstration that gut microbiota-derived EVs can deliver therapeutic cargo to glioma tissue currently exists. This review therefore critically evaluates the translational disconnect between BEV biology and EV-based glioma therapies, and addresses issues of nomenclature (MISEV2023), standardization, scalability, safety, and regulatory pathways. Gut microbiota-derived EVs represent a promising but still investigational modality whose utility in glioma will depend upon rigorous mechanistic studies, robust manufacturing protocols, and careful toxicological evaluation.