Engineered Microglia‐Exosomes Coated Highly Twisting AIE Photothermal Agents to Efficiently Cross Blood‐Brain‐Barrier for Mild Photothermal‐Immune Checkpoint Blockade Therapy in Glioblastoma

Abstract Immune checkpoint blockade (ICB) therapy has achieved remarkable therapeutic effects in cancer, but it is not effective in glioblastoma (GBM). The main reason is that it is difficult for drugs to penetrate blood‐brain‐barrier (BBB) to GBM and lacks enough pre‐existing cytotoxic CD8 + T cells in GBM microenvironment. Here, two AIE photothermal agents (Fs and Fo) are synthesized with NIR‐II fluorescence emission and increase molecular twisting of AIE photothermal agents by simply changing one O atom into S atom, improving Fs photothermal conversion efficiency to 48%. Subsequently, engineered microglia‐exosomes AIE nanoparticles (EE@Fs‐NPs) are prepared by encapsulating Fs with microglia‐exosomes which express immune checkpoint LAG3 inhibitory antibody (anti‐LAG3) via genetic engineering technology. Engineered microglia‐exosomes endow that EE@Fs‐NPs cross BBB and target GBM, which successfully deliver anti‐LAG3 to GBM. Anti‐LAG3 highly reverses T cells exhaustion and generates TNF‐α for inhibiting the expression of heat shock proteins to enhance tumor cells thermosensitivity. Moreover, AIE photothermal agents of EE@Fs‐NPs generate mild photothermal therapy to destroy tumor cells and improve the infiltration of cytotoxic CD8 + T cells in GBM, which increases the responsiveness of ICB therapy. EE@Fs‐NPs produce powerful mild photothermal‐immune synergistic therapeutic effect, which will provide a therapeutic platform for the efficient treatment of GBM.