Abstract: This study explores the potential of hybrid exosome vesicles (RU-exos) prepared by fusion of U87 and RAW264.7 cell-derived exosomes as a delivery system for cannabidiol (CBD) to cross the blood-brain barrier (BBB) and target glioblastoma (GBM). thereby exerting antitumor effects through the modulation of mitophagy pathways. RU-exos@CBD were characterized using transmission electron microscopy (TEM), dynamic light scattering, and Zeta potential measurements. Intracellular reactive oxygen species (ROS) levels were detected using the DCFH-DA probe, changes in mitochondrial membrane potential (MMP) were assessed with the JC-1 probe, and the expression of mitophagy-related proteins was analyzed by Western blot. Additionally, an orthotopic GBM model in nude mice was established to evaluate the in vivo targeting ability, therapeutic efficacy, and biosafety of RU-exos@CBD. Immunohistochemistry (IHC) and immunofluorescence (IF) were used to examine tumor cell proliferation. Experimental results showed that RU-exos@CBD treatment led to intracellular ROS accumulation and a decrease in MMP, preliminarily confirming the induction of mitophagy. Further mechanistic studies revealed that RU-exos@CBD activates mitophagy by inhibiting the PI3K/AKT/mTOR pathway. In vivo experiments demonstrated that RU-exos@CBD effectively crosses the BBB and accumulates in tumor regions, significantly enhancing the inhibition of GBM proliferation compared with free CBD. Hematoxylin and eosin (H&E) staining of major organs revealed no significant pathological damage, indicating that RU-exos@CBD possesses favorable biosafety and tissue compatibility.