Exosomal delivery of rapamycin modulates blood-brain barrier penetration and VEGF axis in glioblastoma.

Exosomes (Exos), nanosized membranous vesicles (30-160 nm), have been validated as an effective drug delivery system capable of traversing biological barriers. Mesenchymal stem cells (MSCs), due to their near-limitless self-renewal capabilities, provide a plentiful source of exosomes for clinical applications. In this study, we utilized an exosome-encapsulated rapamycin (Exo-Rapa) delivery strategy, which permits the use of smaller drug dosages to achieve effects typically seen with higher dosages, thus enhancing drug efficacy. Moreover, Exos can transport pharmaceuticals across the blood-brain barrier (BBB) to the brain, and further penetrate GL261 cells to exert their effects. Within the tumor microenvironment, Exo-Rapa is released more rapidly and efficiently at the tumor site. The acidic conditions in tumors accelerate the release of Exo-Rapa, a characteristic that may make it a promising targeted therapeutic in future cancer research. Additionally, a series of in vivo experiments have further demonstrated the permeability of Exo-Rapa across the BBB, enabling it to accumulate at tumor sites; it also ameliorates inflammatory responses in Glioblastoma multiforme (GBM) mouse models and enhances anti-tumor activity through the regulation of angiogenesis via the VEGF/VEGFRs axis. Our results indicate that MSC-derived exosomes are a potent therapeutic carrier for GBM, offering an effective strategy for enhancing drug delivery across the BBB and providing a scientific foundation for the use of exosomes in the treatment of GBM and other diseases.