Exosome-based Cannabidiol Formulation Demonstrates Superior Anti-glioma Activity by Boosting Cellular Uptake and Cytotoxicity

Background: Cannabidiol (CBD) exhibits potential anti-tumor properties, but its clinical application against aggressive brain tumors such as glioma is severely limited by poor bioavailability and low cellular uptake. Therefore, developing advanced drug delivery systems to unlock its therapeutic potential is urgently needed. Methods: In this study, we developed and characterized an exosome-based CBD formulation (CBD-exos) derived from human umbilical cord mesenchymal stem cells (hUC-MSCs). We systematically evaluated its drug-loading capacity, cellular uptake efficiency, and compared its anti-glioma effects directly with those of free CBD in the U87MG and U251 human glioma cell lines. Results: CBD-exos presented as typical ~140 nm vesicles and were efficiently loaded with CBD (25 μg per mg of exosomal protein). Critically, fluorescence tracing confirmed that CBD-exos were rapidly internalized by glioma cells. Consequently, CBD-exos demonstrated dramatically enhanced cytotoxicity, with IC50 values of 0.9 μM in U87MG and 0.5453 μM in U251 cells—representing a 7.8-fold and 4.4-fold increase in potency compared to free CBD, respectively. This superior activity was further validated by a more potent inhibition of cell migration (P<0.001) and a more pronounced induction of S-phase cell cycle arrest. Conclusion: Our findings indicate that utilizing exosomes as a nanocarrier is a highly effective strategy for overcoming the limitations of CBD. The resulting CBD-exos formulation significantly enhances anti-glioma activity by greatly boosting cytotoxicity, highlighting its potential as a highly promising novel therapeutic agent for glioma.