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Here, this work reports on survivin peptide\u2010CpG oligodeoxynucleotide (ODN) nanovaccines (SPOD\u2010NV), 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\u2010NV significantly enhances mucosa penetration and markedly improves dendritic cell uptake and activation. Notably, the intranasal administration of SPOD\u2010NV 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\u2010brain barrier. Interestingly, the therapeutic strategy, comprising three intranasal and two intravenous administrations of SPOD\u2010NV in combination with anti\u2010CTLA\u20104 antibody, results in substantial tumor inhibition, achieving a 43% complete regression rate, in line with the stimulation of robust and long\u2010lasting local and systemic anti\u2010GBM immune responses. These intranasal\u2010intravenous administration strategy of peptide\u2010CpG nanovaccines provides a potential curative therapy for brain tumors, paving the way for further developments in GBM immunotherapy.<\/jats:p>","DOI":"10.1002\/adma.202420630","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T11:14:24Z","timestamp":1749467664000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Intranasal and Intravenous Sequential Administration of Survivin Peptide\u2010CpG Nanovaccines Elicits Potent Immunity Toward Glioblastoma"],"prefix":"10.1002","volume":"37","author":[{"given":"Yan","family":"Shi","sequence":"first","affiliation":[{"name":"Biomedical Polymers Laboratory College of Chemistry Chemical Engineering and Materials Science and State Key Laboratory of Radiation Medicine and Protection Soochow University  Suzhou 215123 P. R. 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