{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T10:12:22Z","timestamp":1789035142999,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012905","name":"Key R&D Program of Shandong Province, China","doi-asserted-by":"publisher","award":["2022CXPT056"],"award-info":[{"award-number":["2022CXPT056"]}],"id":[{"id":"10.13039\/100012905","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>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\u2013brain 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 &lt; 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 &lt; 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 &lt; 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.<\/jats:p>","DOI":"10.3390\/vaccines14090797","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:13:03Z","timestamp":1789031583000},"page":"797","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nanohydrogel Composite Vaccine Capable of Bypassing the Blood\u2013Brain Barrier and Targeting Tumors for Glioblastoma Immunotherapy via Intranasal Immunization"],"prefix":"10.3390","volume":"14","author":[{"given":"Dawei","family":"Dai","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Shuo","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Changzheng Hospital, Naval University School of Medicine, Shanghai 201209, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Guangming","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Shanghai Geriatric Medical Center, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Yongming","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5867-2243","authenticated-orcid":false,"given":"Ang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Tongji University, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41572-024-00516-y","article-title":"Glioma","volume":"10","author":"Weller","year":"2024","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1038\/s41423-024-01226-x","article-title":"Immunotherapy for glioblastoma: Current state, challenges, and future perspectives","volume":"21","author":"Liu","year":"2024","journal-title":"Cell. Mol. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kiel, K., Piranlioglu, R., Godlewski, J., and Bronisz, A. (2025). Harnessing immunotherapy: Cancer vaccines as novel therapeutic strategies for brain tumor. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1588081"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/978-3-031-97242-3_6","article-title":"Immunotherapy in Glioblastoma","volume":"129","author":"Williams","year":"2025","journal-title":"Cancer Treat Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"676301","DOI":"10.3389\/fimmu.2021.676301","article-title":"Immunotherapy for Glioblastoma: Current Progress and Challenges","volume":"12","author":"Yu","year":"2021","journal-title":"Front Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s00262-026-04372-5","article-title":"Targeting the COX-2\/PGE2 axis to enhance NK and T cell immunotherapy in brain tumors","volume":"75","author":"Shen","year":"2026","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s10143-025-04103-x","article-title":"Elucidating the causal relationships between cerebrospinal fluid metabolites and glioblastoma insights from mendelian randomization study","volume":"49","author":"Yan","year":"2026","journal-title":"Neurosurg. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s11064-025-04659-6","article-title":"Centratherin Exhibits Antitumor Activity Against Glioblastoma Cells","volume":"51","author":"Pinheiro","year":"2026","journal-title":"Neurochem. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"104765","DOI":"10.1016\/j.drudis.2026.104765","article-title":"Current Clinical Evidence on Nose-to-Brain Drug Delivery","volume":"31","author":"Silva","year":"2026","journal-title":"Drug Discov. Today"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/s41573-021-00139-y","article-title":"Strategies for delivering therapeutics across the blood\u2013brain barrier","volume":"20","author":"Terstappen","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"21154","DOI":"10.1021\/acsnano.5c06051","article-title":"Enhanced Nano-Vaccine Utilizing Biomineralized Virus-like Particles for Efficient Glioblastoma Immunotherapy via the Nose-To-Brain Delivery Pathway","volume":"19","author":"Wang","year":"2025","journal-title":"ACS Nano"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2420630","DOI":"10.1002\/adma.202420630","article-title":"Intranasal and Intravenous Sequential Administration of Survivin Peptide-CpG Nanovaccines Elicits Potent Immunity Toward Glioblastoma","volume":"37","author":"Shi","year":"2025","journal-title":"Adv. Mater."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7965","DOI":"10.1039\/D4AY01409J","article-title":"Micro-fluidic covalent immobilization of multi-gradient RGD peptides on a gelatin surface for studying endothelial cell migration","volume":"16","author":"Yang","year":"2024","journal-title":"Anal. Methods"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.biomaterials.2015.08.045","article-title":"Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels","volume":"73","author":"Yue","year":"2015","journal-title":"Biomaterials"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"100281","DOI":"10.1016\/j.nxmate.2024.100281","article-title":"Dual-hydrogel thermoresponsive system with bioinspired pore control for drug delivery","volume":"6","author":"Lee","year":"2024","journal-title":"Next Mater."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9171","DOI":"10.1016\/j.biomaterials.2013.08.039","article-title":"LDLR-mediated peptide-22-conjugated nanoparticles for dual-targeting therapy of brain glioma","volume":"34","author":"Zhang","year":"2013","journal-title":"Biomaterials"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5864","DOI":"10.1021\/acsami.6b15831","article-title":"Peptide-22 and Cyclic RGD Functionalized Liposomes for Glioma Targeting Drug Delivery Overcoming BBB and BBTB","volume":"9","author":"Chen","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1186\/s12951-026-04358-6","article-title":"Enhanced mRNA vaccine combined with immune checkpoint blockade efficiently suppresses tumor growth and metastasis","volume":"24","author":"Zhang","year":"2026","journal-title":"J. Nanobiotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"eadz8466","DOI":"10.1126\/sciimmunol.adz8466","article-title":"CXCL16-mediated recruitment of gammadelta T cells to the brain reduces sociability in mice","volume":"11","author":"Takayama","year":"2026","journal-title":"Sci. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.jconrel.2021.07.040","article-title":"\u201cCytokine-microfactories\u201d recruit DCs and deliver tumor antigens via gap junctions for immunotherapy","volume":"337","author":"Guo","year":"2021","journal-title":"J. Control. Release"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11389","DOI":"10.2147\/IJN.S526305","article-title":"Hydrogel-Based Vaccines: A Promising Approach for Cancer Immunotherapy","volume":"20","author":"Zhang","year":"2025","journal-title":"Int. J. Nanomed."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e2210452","DOI":"10.1002\/adma.202210452","article-title":"Biomaterial-Based In Situ Cancer Vaccines","volume":"36","author":"Bo","year":"2023","journal-title":"Adv. Mater."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12724","DOI":"10.1021\/acsnano.6c03253","article-title":"InjectableTrojan Horse Hydrogel Unleashing Penetrable and Immunostimulatory Nanomicelles for Postoperative Treatment of Glioblastoma","volume":"20","author":"Zhang","year":"2026","journal-title":"ACS Nano"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/s41586-019-1914-8","article-title":"Tertiary lymphoid structures improve immunotherapy and survival in melanoma","volume":"577","author":"Cabrita","year":"2020","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101848","DOI":"10.1016\/j.smim.2023.101848","article-title":"Antigen cross-presentation by dendritic cells: A critical axis in cancer immunotherapy","volume":"71","author":"Moussion","year":"2023","journal-title":"Semin. Immunol."},{"key":"ref_26","first-page":"1","article-title":"Targeting tumor-associated macrophages to synergize tumor immunotherapy","volume":"6","author":"Xiang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/s12943-024-02064-1","article-title":"Decoding the spatiotemporal heterogeneity of tumor-associated macrophages","volume":"23","author":"Chu","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12943-022-01513-z","article-title":"Glioma targeted therapy: Insight into future of molecular approaches","volume":"21","author":"Yang","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3774","DOI":"10.1021\/acsbiomaterials.0c01571","article-title":"RGD-Modified Alginate\u2013GelMA Hydrogel Sheet Containing Gingival Mesenchymal Stem Cells: A Unique Platform for Wound Healing and Soft Tissue Regeneration","volume":"7","author":"Ansari","year":"2021","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.actbio.2023.07.037","article-title":"Constructing epidermal rete ridges using a composite hydrogel to enhance multiple signaling pathways for the maintenance of epidermal stem cell niche","volume":"169","author":"Shen","year":"2023","journal-title":"Acta Biomater."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.addr.2020.10.004","article-title":"Lymphatic immunomodulation using engineered drug delivery systems for cancer immunotherapy","volume":"160","author":"Manspeaker","year":"2020","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1016\/j.ccell.2023.09.013","article-title":"Tumor-reactive T helper cells in the context of vaccination against glioma","volume":"41","author":"Zhao","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"iv41","DOI":"10.1093\/noajnl\/vdaf028","article-title":"Immunologic specificity in glioblastoma: Antigen discovery and translational implications","volume":"7","author":"Hill","year":"2025","journal-title":"Neuro-Oncol. Adv."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s12943-025-02305-x","article-title":"Advances in cancer immunotherapy: Historical perspectives, current developments, and future directions","volume":"24","author":"Zhang","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"24650","DOI":"10.1021\/acsnano.3c10797","article-title":"Nanoplatform Based Intranasal Vaccines: Current Progress and Clinical Challenges","volume":"18","author":"Bai","year":"2024","journal-title":"ACS Nano"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Tay, B.Q., Wright, Q., Ladwa, R., Perry, C., Leggatt, G., Simpson, F., Wells, J.W., Panizza, B.J., Frazer, I.H., and Cruz, J.L.G. (2021). Evolution of Cancer Vaccines\u2014Challenges, Achievements, and Future Directions. Vaccines, 9.","DOI":"10.3390\/vaccines9050535"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e2400323","DOI":"10.1002\/adhm.202400323","article-title":"Mesoporous Silica Nanoparticles as an Ideal Platform for Cancer Immunotherapy: Recent Advances and Future Directions","volume":"13","author":"Godakhindi","year":"2024","journal-title":"Adv. Healthc. Mater."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1186\/s12951-022-01605-4","article-title":"Engineering nano-drug biointerface to overcome biological barriers toward precision drug delivery","volume":"20","author":"Waheed","year":"2022","journal-title":"J. Nanobiotechnol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1038\/s41578-021-00315-x","article-title":"Multifunctional biomolecule nanostructures for cancer therapy","volume":"6","author":"Wang","year":"2021","journal-title":"Nat. Rev. Mater."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"12343","DOI":"10.2147\/IJN.S497480","article-title":"Nose to Brain: Exploring the Progress of Intranasal Delivery of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers","volume":"19","author":"Zheng","year":"2024","journal-title":"Int. J. Nanomed."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"123331","DOI":"10.1016\/j.biomaterials.2025.123331","article-title":"Bioengineered metastatic cancer nanovaccine with a TLR7\/8 agonist for needle-free intranasal immunization","volume":"321","author":"Jung","year":"2025","journal-title":"Biomaterials."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1093\/carcin\/bgac063","article-title":"Intratumoral microbiota: New frontiers in tumor immunity","volume":"43","author":"Zhang","year":"2022","journal-title":"Carcinogenesis"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Gao, J., Liang, Y., and Wang, L. (2022). Shaping Polarization Of Tumor-Associated Macrophages In Cancer Immunotherapy. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.888713"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"41571","DOI":"10.1021\/acsami.5c05498","article-title":"Cantharidin-Loaded Nanomedicine Modified with Amphiphilic Peptides Induce Immunogenic Cell Death to Enhance PD-1 Blockade","volume":"17","author":"Tang","year":"2025","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"13428","DOI":"10.1073\/pnas.2001569117","article-title":"Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics","volume":"117","author":"Buss","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/9\/797\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:37:52Z","timestamp":1789033072000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/9\/797"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":45,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["vaccines14090797"],"URL":"https:\/\/doi.org\/10.3390\/vaccines14090797","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]}}}