Nanohydrogel Composite Vaccine Capable of Bypassing the Blood–Brain Barrier and Targeting Tumors for Glioblastoma Immunotherapy via Intranasal Immunization

Background: Glioblastoma (GBM) is a primary malignant tumor of the central nervous system and has a high lethal rate despite therapeutic advances. Although immunotherapies have achieved great success in solid tumors, the highly immunosuppressive tumor microenvironment and the blood–brain barrier (BBB) obstruction hinder the development of immunotherapies for GBM. In this study, we innovatively developed a nanohydrogel composite vaccine (nanoCOM-GEL) for GBM immunotherapy via intranasal immunization. Methods: The nanoCOM-GEL used GelMA as the hydrogel matrix and was co-formulated with antigenic peptides, the BBB-penetrating peptide (peptide 22), as well as immune cell stimulants and chemokines. The efficiency of this vaccine in bypassing the BBB and its capacity to induce anti-GBM immune responses were evaluated in vitro and in vivo. Results: The nanoCOM-GEL vaccine demonstrated superior BBB-bypassing and BBTB-penetrating capabilities, potent immunostimulatory activity, and effective GBM-targeting efficacy, as validated in both cellular and animal models. In an orthotopic GBM mouse model (n = 8 per group), intranasal immunization with nanoCOM-GEL significantly extended median survival from 21 days (control group) to more than 60 days (nanoCOM-GEL group), representing a 2.8-fold increase (p < 0.001). The vaccine markedly inhibited tumor growth, as evidenced by an 82.5% reduction in tumor tissue at day 21 compared to controls (p < 0.01). Mechanistically, nanoCOM-GEL increased intratumoral CD8+ T cell infiltration by 9.5-fold and upregulated DCs by 6.4-fold, while simultaneously reducing intratumoral M2-type tumor-associated macrophages by 79.3% (p < 0.001), effectively reshaping the immunosuppressive tumor microenvironment. Conclusions: This innovative nanoCOM-GEL vaccine achieved potent anti-GBM therapeutic efficacy and provided a promising strategy for effective GBM immunotherapies.