Tumor cell-derived engineered exosome enhances effective immunotherapy for orthotopic glioblastoma and its recurrences

Glioblastoma multiforme (GBM) is considered as one of the most lethal malignancies in the central neuron system (CNS). Despite significant advances in immunotherapy approaches for multiple tumors, the highly immunosuppressive tumor microenvironment (TME) of GBM presents critical challenges. Inspired by tumor-derived exosomes, which carry a range of tumor-associated antigens and possess improved blood-brain barrier (BBB) transcytosis, we have developed CpG adjuvant-functionalized GBM tumor-derived exosomes (Exo-CpG) to inhibit GBM proliferation and elicit long-lasting protective immunity via potent stimulation of the body's innate immunity. Our exosomal nanoplatform efficiently activates the antigen-presenting dendritic cells (DCs) in lymph nodes, promoting their maturation, and generating a strong T cell response. In combination with the anti-programmed cell death ligand-1 antibody (aPD-L1), these exosomes effectively restrain the growth of GBM in orthotopic primary GL261 and phosphatase and tensin homologue (PTEN)-deficient immunosuppressive CT2A models in immune-competent mice, significantly prolonging survival by effectively suppressing GBM recurrence. This fully natural exosomal nanoplatform offers a promising strategy for targeting the immunosuppressive TME of orthotopic primary GBM and its recurrences. We have developed natural tumor cell-derived exosomes (Exo-CPG) as immunotherapy tool to fight homologous GBM and GBM recurrences for the first time, demonstrating effective tumor inhibition with improved survival in multiple mouse models. • The exosomes realize effective tumor inhibition towards orthotopic GBM and its recurrences. • The exosomes leverage enhanced BBB permeability via multiple pathways mediated transcytosis. • The antigens combine with the adjuvant CPG, promoting the induction of immunogenicity and overcoming the heterogeneity of GBM. • The natural and readily fabrication of these exosomes render the possibility of clinical translation for treating GBM.