Enhanced Nano-Vaccine Utilizing Biomineralized Virus-like Particles for Efficient Glioblastoma Immunotherapy via the Nose-To-Brain Delivery Pathway

Glioma, a primary malignant tumor of the central nervous system, remains a formidable challenge despite advancements in treatment. Immunotherapies hold promise, but their efficacy is hindered by the blood–brain barrier (BBB) and immunosuppressive tumor microenvironment (TME). The nose-to-brain transport pathway offers a potential solution for bypassing the BBB and avoiding systemic absorption issues. In this study, we developed a calcium phosphate (CaP)-covered nanovaccine (NV) based on hepatitis B core antigen derived virus-like particles (HBc VLPs), optimized for mucosal delivery applications. After biomineralization, this NVs exhibited enhanced mucosal adhesion and significantly higher accumulation in glioma tissue. Furthermore, by leveraging the immunogenicity of HBc VLPs and displaying a glioma-associated antigen EphA2 671–679 on its surface, this NVs served as both immunogen and adjuvant. They promoted significant antiglioma therapeutic efficacy and elicited robust, durable tumor suppression by increasing effective T cell infiltration, reducing regulatory T cells and M2-type tumor-associated macrophages. This innovative NV construction strategy highlights the potential of CaP-coated VLPs for enhancing nose-to-brain delivery and immunological enhancement, offering a promising avenue for the development of effective immunotherapies for glioma.