In recent years, research on exosomes for GBM treatment has yielded promising results as scientists gain a deeper understanding of their components’ roles. This research can be broadly categorized into two main directions:

Exosomes exhibit characteristics influenced by the organ and tissue of their origin, granting them distinct properties, including tropism to specific organs and uptake by particular cell types [24]. Notably, exosomes derived from human-umbilical-cord-derived mesenchymal stem cells (hUC-MSCs) have shown promise in partially inhibiting tumor growth by modulating the miR-10a-5p/PTEN pathway. Research conducted by Hao et al. suggests that hUC-MSCs-derived exosomes may offer alternative strategies for treating glioma [126]. Furthermore, exosomes derived from rat bone marrow mesenchymal stem cells (rBMMSCs) have demonstrated their potential as a standalone treatment for glioblastoma (GBM), independent of additional therapies or as a drug delivery system, as revealed in recent investigations [127]. Another study highlighted that exosomes derived from LPS/INFγ-triggered microglial cells have the ability to induce phenotypic shifts in tumor-associated myeloid cells. This shift is characterized by the upregulation of genes related to inflammation and leads to the inhibition of glioma growth [128]. Additionally, the incorporation of focused ultrasound has been shown to enhance the efficacy of exosome accumulation in gliomas, thereby improving the effectiveness of the treatment course [129].

Exosomes produced by cancer cells play a crucial role in driving overall tumor progression [82]. Consequently, there is ongoing research into methods for eliminating or suppressing their production, often considered as supplementary therapies. One noteworthy target in this effort is Munc 13-4, a Ca²⁺-dependent soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor and Rab-binding protein. Studies have demonstrated that Munc 13-4 serves as the key regulator for the Ca²⁺ ion-mediated exosome release pathway in various cancer cell lines (although not specifically in glioma cells). Thus, targeted depletion of Munc 13-4 offers the potential to suppress oncogenic exosome secretion and hinder tumor progression [130]. Furthermore, the secretion of exosome-related PTRF can be controlled through the ubiquitination of PTRF by UBE2O, leading to a downregulation of exosome release [131]. Boosting UBE2O expression in cells holds promise as a novel approach for glioma treatment. In a similar vein, proton pump inhibitors (PPIs) and neutral sphingomyelinase 2 (nSMase2) are potential targets for reducing exosome secretion [132,133].

Exosome-mediated immunotherapy holds promise as an effective treatment approach, leveraging the unique properties of exosome donor cells [134]. Dendritic cells (DCs) stand out as highly efficient antigen-presenting cells, capable of eliciting potent immune responses. In preclinical studies, DC-derived exosomes have demonstrated superior anticancer efficacy compared to traditional DC vaccinations. This superiority arises from their enhanced immunogenicity and increased resistance against immunosuppressive factors [135,136]. Ning et al. made a significant discovery by demonstrating that DC-derived exosomes, loaded with chaperone-rich cell lysates and modulating Cbl-b and c-Cbl signaling, can trigger more robust antitumor T-cell immune responses [137]. Additionally, Liu et al. found that tumor-derived exosomes containing α-Galcer are effective for DC-based vaccinations. They employed α-Galcer-activated invariant NK-T cells as a cellular adjuvant, breaking immunological tolerance and generating antigen-specific cytotoxic T-cell (CTL) responses against GBM cells [138]. Furthermore, a MUC1 glycopeptide antigen was recently linked to dendritic-cell-derived exosomes to create a promising anticancer vaccine candidate. This construct not only increased cytokine production in vivo but also induced high MUC1-specific IgG antibody titers with strong binding affinity for MUC1-positive tumor cells [139]. Exosome-mediated immunotherapy has gained significant attention recently and exhibits remarkable potential as a treatment option for gliomas [140].

Exosomes, owing to their biocompatibility, stability, and diminutive nano-scale dimensions, have been engineered to serve as effective carriers for therapeutic compounds, demonstrating promising initial success.

Exosomes can serve as efficient carriers for delivering chemotherapy medications into the brain and glioma site, overcoming the restrictions of the blood–brain barrier. Studies have utilized brain-endothelial-cell-isolated exosomes loaded with paclitaxel and doxorubicin, demonstrating their potential to inhibit GBM growth [141]. Similarly, coating doxorubicin-loaded nanoparticles with brain-endothelial-cell-derived exosomes allows for effective drug delivery to GBM cells, extending the survival of GBM-bearing animals [142]. Neutrophil exosomes, due to their inflammation-driven nature and BBB-crossing ability, have also been employed for transporting doxorubicin, effectively targeting infiltrating GBM cells [143].

Combining modified exosomes with other drugs, such as temozolomide, further enhances the efficacy of GBM therapy. Modified exosomes loaded with paclitaxel, created from embryonic stem cells and conjugated with a tumor-targeting peptide, have shown improved targeting and therapeutic effectiveness against GBM cells [55]. In addition, exosomes were loaded with superparamagnetic iron oxide nanoparticles (SPIONs) and curcumin (Cur), and click chemistry was employed to attach a neuropilin-1-targeted peptide to the exosome membrane, thus creating glioma-targeting exosomes with combined imaging and therapeutic capabilities [144]. Drawing inspiration from brain-targeting exosomes, Wang and colleagues reported the exploration of biomimetic nanovesicles [145]. These were engineered through membrane fusion between blood exosomes and tLyp-1 peptide-modified liposomes, demonstrating potential for brain-targeted drug delivery. These examples underscore the potential of exosomes in drug delivery against brain tumors. More research and details are shown in Table A2.

Nucleotide-based gene therapy holds great promise in clinical applications. Exosomes can potentially deliver mRNA, noncoding RNA, and antisense oligonucleotides (AON) to inhibit glioma. Studies have shown that exosomes loaded with miR-124a or miR29a-3p can significantly reduce the vitality and clonogenicity of GSCs [146,147]. Targeted modification of exosomes further enhances their delivery efficiency [51]. These results demonstrate the potential of exosomes as delivery systems for anti-tumor nucleotide drugs, indicating their potential for therapeutic use. Before these treatment approaches can be implemented in clinical settings, further extensive research is needed.