Advancing brain immunotherapy through functional nanomaterials

Glioblastoma (GBM), a highly aggressive brain tumor, poses significant treatment challenges due to its highly immunosuppressive microenvironment and the brain immune privilege. Immunotherapy activating the immune system and T lymphocyte infiltration holds great promise against GBM. However, the brain's low immunogenicity and the difficulty of crossing the blood-brain barrier (BBB) hinder therapeutic efficacy. Recent advancements in immune-actuated particles for targeted drug delivery have shown the potential to overcome these obstacles. These particles interact with the BBB by rapidly and reversibly disrupting its structure, thereby significantly enhancing targeting and penetrating delivery. The BBB targeting also minimizes potential long-term damage. At GBM, the particles demonstrated effective chemotherapy, chemodynamic therapy, photothermal therapy (PTT), photodynamic therapy (PDT), radiotherapy, or magnetotherapy, facilitating tumor disruption and promoting antigen release. Additionally, components of the delivery system retained autologous tumor-associated antigens and presented them to dendritic cells (DCs), ensuring prolonged immune activation. This review explores the immunosuppressive mechanisms of GBM, existing therapeutic strategies, and the role of nanomaterials in enhancing immunotherapy. We also discuss innovative particle-based approaches designed to traverse the BBB by mimicking innate immune functions to improve treatment outcomes for brain tumors.