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

Abstract 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.