Engineered Extracellular Vesicles in Glioma Therapy: Recent Advances and Applications

Abstract: Gliomas are a highly heterogeneous group of primary tumors of the central nervous system. The blood-brain barrier and the complex tumor microenvironment restrict drug penetration and reduce the effectiveness of standard chemotherapy. Extracellular vesicles (EVs) have gained attention as potential delivery vehicles because they can move across biological barriers, are generally well tolerated, and naturally shuttle signals between cells. However, unmodified EVs face practical hurdles for clinical use, including limited tissue targeting, modest drug payload capacity, low manufacturing yield, and imperfect control over what they carry. To overcome these constraints, growing efforts have focused on engineering EVs to improve delivery performance and therapeutic precision. This review outlines key EV characteristics and commonly used isolation methods, with an emphasis on engineering approaches for glioma therapy. We also summarize recent progress in engineered EV-based treatments for glioma and discuss the main barriers to clinical translation. The infographic illustrates therapeutic cargo loading and surface functionalization processes for various applications. The top section shows different therapeutic cargos such as messenger RNA, microRNA, photosensitizer, small interfering RNA, circular RNA, photothermal agents, drugs (e.g., TMZ, DOX), plasmid, synthetic nanoparticles and sonosensitizer. Methods for loading these cargos include electroporation, sonication and freeze-thaw cycles. The central section depicts an extracellular vesicle with various cargos and functional molecules. The bottom section details surface functionalization techniques like chemical conjugation, lipid insertion, genetic engineering and membrane fusion. The right side lists therapeutic applications: chemotherapy delivery, nucleic acid therapeutics, physical energy therapy involving reactive oxygen species, immunotherapy and multimodal synergistic therapy.Infographic on therapeutic cargo loading and surface functionalization for various applications. Keywords: glioma, extracellular vesicles, engineering, glioma therapy, multimodal therapy