Glioma is the most common malignant primary brain tumor with aggressiveness and poor prognosis. Although extracellular vesicles (EVs)-based cell-to-cell communication mediates glioma progression, the key molecular mediators of this process are still not fully understood. Herein, we elucidated an EVs-mediated transfer of suprabasin (SBSN), leading to the aggressiveness and progression of glioma. High levels of SBSN were positively correlated with clinical grade, predicting poor clinical prognosis of patients. Upregulation of SBSN promoted, while silencing of SBSN suppressed tumorigenesis and aggressiveness of glioma cells in vivo. EVs-mediated transfer of SBSN resulted in an increase in SBSN levels, which promoted the aggressiveness of glioma cells by enhancing migration, invasion, and angiogenesis of recipient glioma cells. Mechanistically, SBSN activated NF-kappa B signaling by interacting with annexin A1, which further induced Lys63-linked and Met1-linear polyubiquitination of NF-kappa B essential modulator (NEMO). In conclusion, the communication of SBSN-containing EVs within glioma cells drives the formation and development of tumors by activating NF-kappa B pathway, which may provide potential therapeutic target for clinical intervention in glioma.