PB@Ag2S Nanoagent with Enhanced Blood–Brain Barrier Penetration and Synergistic Chemodynamic‐Immune Therapy via Light‐Induced Iron Valence Transition

Abstract Gliomas, characterized by high mortality rates, present significant therapeutic challenges due to their invasive growth, chemoresistance, and the blood–brain barrier (BBB). To address these limitations, a multifunctional Prussian blue/Ag 2 S nanoplatform (PB@Ag 2 S) is developed, integrating chemodynamic therapy, BBB modulation, and enhanced immunotherapy. Under near‐infrared (NIR) irradiation, Fe 2+ in Prussian blue is oxidized to Fe 3+ , amplifying chemodynamic therapy through hydroxyl radical generation and glutathione depletion (GSH reduced by 1.9‐fold). Concurrently, Fe 3+ oxidizes thiol groups in Vascular Endothelial cadherin (VE‐cadherin), reducing its expression by 40.6% and transiently disrupting the BBB, thereby enhancing intracranial accumulation of the nanoplatform by 3.0‐fold. Integrated Ag 2 S nanoparticles enable real‐time treatment monitoring via NIR‐II fluorescence imaging. Unlike conventional immunotherapies, which exhibit limited efficacy in glioma due to its immunosuppressive microenvironment, the PB@Ag 2 S platform uniquely promotes dendritic cell maturation and reprograms tumor‐associated macrophages toward the anti‐tumor M1 phenotype. This dual immunomodulatory action effectively converts the immunosuppressive “cold” tumor microenvironment into an immunologically active state. In glioma models, this multifunctional platform achieved tumor eradication within 14 days. By integrating photo‐controlled multimodal actions, this theranostic platform effectively addresses critical clinical challenges in glioma therapy.