Intranasal and Intravenous Sequential Administration of Survivin Peptide‐CpG Nanovaccines Elicits Potent Immunity Toward Glioblastoma

Abstract Peptide vaccines hold great promise for treatment of glioblastoma (GBM), though their efficacy remains suboptimal due to factors such as immunosuppressive tumor microenvironment, poor accessibility to tumor site and inadequate activation of antigen‐presenting cells. Here, this work reports on survivin peptide‐CpG oligodeoxynucleotide (ODN) nanovaccines (SPOD‐NV), which feature antigen peptides strategically displayed on polymersomes with CpG ODN encapsulated as an immunostimulatory adjuvant. Sequential administration via intranasal and intravenous routes elicits robust immune response against murine GBM. These results demonstrate that SPOD‐NV significantly enhances mucosa penetration and markedly improves dendritic cell uptake and activation. Notably, the intranasal administration of SPOD‐NV to orthotopic murine GL261 tumor models reveals marked accumulation in cervical lymph nodes and tumors, likely facilitated by lymphatic transport from nasal mucosa and pathways via olfactory bulb and trigeminal nerve, bypassing the blood‐brain barrier. Interestingly, the therapeutic strategy, comprising three intranasal and two intravenous administrations of SPOD‐NV in combination with anti‐CTLA‐4 antibody, results in substantial tumor inhibition, achieving a 43% complete regression rate, in line with the stimulation of robust and long‐lasting local and systemic anti‐GBM immune responses. These intranasal‐intravenous administration strategy of peptide‐CpG nanovaccines provides a potential curative therapy for brain tumors, paving the way for further developments in GBM immunotherapy.