Dysfunctional T Cell Reprogramming via Cascade‐Responsive Catalytic Nanosponges‐Mediated Tumor‐Specific Antigen Capture for Remote Glioblastoma Immunotherapy
Thi My Hue Huynh, Ngoc‐Tri Tran, Yu‐Sheng Lee, Yun‐Hsuan Chang, Hoi Man Iao, Wan‐Chi Pan, Hui‐Wen Lien, Tsu‐Chin Chou, Wen‐Hsuan Chiang, Ssu‐Ju Li, Y. L. Chen, Shang‐Hsiu Hu
Abstract
ABSTRACT Immunotherapy holds promise for treating aggressive glioblastoma (GBM) by enhancing T cell infiltration. However, the immune‐privileged environment of the brain and the low immunogenicity of vaccines often limit the effective recruitment of lymphocytes within GBM tumors. In this study, a cascade‐responsive catalytic nanosponge that doubles as a brain tumor penetrant and T cell reprogramming inducer was developed for GBM immunotherapy. The nanosponge (AG@cTNS) consists of graphene/tin oxide nanosheets (TNS) coated with covalent‐organic framework (COF, c), on which 2,2′‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS, A) and glucose oxidase (GO x , G) were coloaded. Through convection‐enhanced delivery, tumor‐responsive ABTS/GOx and low‐power second near‐infrared light (NIR‐II) exposure (0.8 W/cm 2 ) enhance tumor permeability and reside in deep brain tumors. Subsequently, under high‐frequency magnetic field (HFMF) irradiation, oxidative stress therapy accelerates the generation of H 2 O 2 and subsequent oxidized ABTS •+ , which is known as the Kelvin force law, thereby promoting the glutathione depletion cycle and promoting wireless charging mitochondrial depolarization in extensive tumor areas. By leveraging HFMF, the catalytic nanosponge stimulates the release of tumor‐associated antigens, notably neoantigens and damage‐associated molecular patterns. Porous cTNS then functions as an antigen carrier, programming dendritic cells for sustained immune activation. In combination with anti‐PD‐1, this approach suppresses brain metastasis and extends survival beyond 60 days.