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Immunotherapies have shifted the paradigm for cancer treatment in the past decade, but none of the existing immunotherapies have been approved for treating glioblastoma. Therapeutic cancer vaccines, consisting of tumor antigens and adjuvants for modulating dendritic cells (DCs), have shown the promise to elicit persistent humoral and cytotoxic T lymphocyte (CTL) response. Tumor-derived exosomes, the nano-sized extracellular vesicles secreted by tumor cells, are a good source of tumor antigens and have been widely explored as cancer vaccines. However, the resulting CTL response and antitumor efficacy is still limited, likely due to the sub-optimal modulation of DCs and ineffective processing and presentation of exosome-cased tumor antigens. The primary goal of this project is to develop a new-generation exosome vaccine for treating glioblastoma, by achieving seamless integration of exosome-encased glioblastoma antigens and immunomodulators. We will utilize our recently developed metabolic labeling technology to generate chemically tagged glioblastoma exosomes for subsequent conjugation of a controllable and sufficient amount of TLR3/7/8/9 agonists and DC-targeting ligands (e.g., anti-DEC205), which we anticipate to dramatically improve the CTL response and antitumor efficacy against glioblastoma. Exosome vaccines will be fabricated from both mouse glioblastoma and surgically resected human glioblastoma, and assessed for CTL response and antitumor efficacy in immunocompetent mice and CD34+ humanized mice, respectively. Successful completion of this project will yield potent glioblastoma exosome vaccines with great potential for clinical translation.