Hierarchical Targeting Nanoplatform for NIR-II Photoacoustic Imaging and Photo-Activated Synergistic Immunotherapy of Glioblastoma

Glioblastoma (GBM) stands as the most aggressive malignant brain tumor, characterized by poor prognosis, high recurrence rate, and resistance to multiple therapies, posing a significant clinical challenge. Here, a hierarchical targeting platform is presented for NIR-II photoacoustic (PA) imaging-guided photo-chemo synergistic immunotherapy of GBM. A new molecular probe is developed with exceptional NIR-II light-harvesting capabilities and enhanced molecular motion, boosting both photothermal conversion and PA signal. This probe, combined with a thermo-responsive prodrug, is assembled into nanoparticles that are further camouflaged with tumor cell membranes and bioorthogonally modified with a transferrin-mimicking peptide, facilitating blood-brain barrier penetration and GBM targeting. High-contrast NIR-II PA imaging allows for precise detection and delineation of GBM, providing accurate guidance for subsequent treatment. The NIR-II light-triggered photothermal effect, coupled with the hyperthermia-activated prodrug, significantly induces immunogenic cell death, enhancing tumor-killing efficiency and amplifying the anti-tumor immune response. This self-synergistic immunotherapy not only stimulates robust anti-tumor immunity and inhibits primary tumor growth but also prevents post-surgical tumor recurrence, significantly prolonging survival time. This work exemplifies a novel paradigm for tackling the diagnostic and therapeutic challenges posed by deeply seated and poorly immunogenic brain tumors.