A detailed evaluation of the advantages among extracellular vesicles from three cell origins for targeting delivery of celastrol and treatment of glioblastoma.

As one of the most common brain tumors, glioblastoma (GBM) lacks efficient therapeutic treatment and remains lethal. Extracellular vesicles (EVs) have emerged as a promising platform for GBM therapies. Nevertheless, the properties of EVs are significantly influenced by their cell origins. This study aimed to evaluate the advantages of EVs derived from bone marrow mesenchymal stem cells (BMSCs), human glioblastoma cells (U-87 MG) and macrophage cells (RAW264.7) to develop a more effective strategy for the delivery of anti-GBM drug celastrol (Cel). Three kinds of EVs exhibited spherical- or oval-shapes with an average size ranging from 90 to 140 nm. Western blot analysis confirmed the presence of specific EV markers (ALIX, CD63 or TSG101). Notably, the yield of BMSCs-derived EVs (BMSC-EVs) significantly surpassed that of U-87 MG and RAW264.7 cells. Furthermore, BMSC-EVs demonstrated the highest entrapment efficiency for Cel (72 %) and enhanced internalization into the target cells U-87 MG. The increased cytotoxicity and cell apoptosis further confirmed that Cel-loaded BMSC-EVs (BMSC-EVs-Cel) were more potent for killing U-87 MG cells compared with free Cel. In vivo studies utilizing both orthotopic and subcutaneous GBM models revealed facilitated blood-brain barrier penetration and transportation of cargo into tumor tissue by BMSC-EVs. Importantly, BMSC-EVs-Cel could effectively inhibit GBM growth, induce tumor tissue apoptosis and suppress intratumoral microvessel density in comparison with free Cel and temozolomide, while successfully decrease systemic toxicity. Overall, this study elucidates the properties of EVs derived from distinct cell origins and highlights the great potential of BMSC-EVs for brain tumor treatment.