Abstract

Glioblastoma (GBM) is an aggressive brain cancer with limited treatment options largely due to its immunosuppressive tumor microenvironment and the restrictive blood-brain barrier. While immunotherapy shows significant promise, its efficacy is limited by the immune privilege of the central nervous system and glioma's immune evasion mechanisms. In this study, we developed an intranasally delivered lipid nanodisc-based vaccine integrated with immune-stimulating outer membrane vesicles (AC-LND@OMV). This nanohybrids is specifically designed to optimize antigen presentation and immune activation, enhancing dendritic cell uptake, maturation, and antigen cross-presentation. Intranasal delivery significantly reduces M2 macrophage polarization, decreases the prevalence of myeloid-derived suppressor cells, and inhibits T cell exhaustion. It also induces higher IgG levels and stronger mucosal immune response compared to intramuscular route. These findings underscore the potential of AC-LND@OMV to reprogram the immune landscape in GBM, offering a promising strategy for personalized immunotherapy.