Abstract

Glioblastoma (GBM), the most aggressive primary brain tumor, remains a challenge for immunotherapies, like immune checkpoint blockade (ICB), due to the blood-brain barrier (BBB) and immunosuppressive tumor microenvironment (TME) deficient in cytotoxic T-cells and effective T-cell-dendritic cell (DC) interactions. Herein, we engineer a biomimetic nanoplatform comprising paclitaxel (PTX) nanoparticles (NPs) encapsulated in a tumor-associated antigen-loaded DC membrane modified with ICB antibodies. The DC membrane not only facilitates BBB penetration and GBM targeting but also directly engages with T-cells reminiscent of T-cell-antigen-presenting cell (APC) clusters. Simultaneously, PTX NPs induce immunogenic cell death, eliciting persistent stimulatory signals for DC maturation and subsequent T-cell priming, thus synergistically "starting the engine" of T-cell immune responses. Meanwhile, ICB antibodies further "release the brakes" by mitigating T-cell exhaustion and dysfunction. In GBM-bearing mice, this nanoplatform outperformed ICB monotherapy, significantly inhibiting tumor growth and prolonging survival by reshaping the TME. We observed increased number of cytotoxic T-cells proximal to DCs that form T-cell-APC clusters, accompanied by enhanced T-cell proliferation and effector function. This study provides a promising paradigm for overcoming immunotherapy resistance in GBM.