Engineered Microglia‐Exosomes Coated Highly Twisting AIE Photothermal Agents to Efficiently Cross Blood‐Brain‐Barrier for Mild Photothermal‐Immune Checkpoint Blockade Therapy in Glioblastoma
Engineered Microglia‐Exosomes Coated Highly Twisting AIE Photothermal Agents to Efficiently Cross Blood‐Brain‐Barrier for Mild Photothermal‐Immune Checkpoint Blockade Therapy in Glioblastoma
复制标题
DOI：
10.1002/adfm.202310237
复制
发表时间：
2023-12
影响因子：
19
通讯作者：
Xun Lin;Zhihong Sun;Shiyun Huang;Chuyao Liu;Jin Peng;Yueying Li;Yue Xiong;Hong Gao;Jianwei Chen;Junyang Qi;Chengming Sun;Lintao Cai;Guanjun Deng;Wenbin Deng
中科院分区：
文献类型：
--
作者：
Xun Lin;Zhihong Sun;Shiyun Huang;Chuyao Liu;Jin Peng;Yueying Li;Yue Xiong;Hong Gao;Jianwei Chen;Junyang Qi;Chengming Sun;Lintao Cai;Guanjun Deng;Wenbin Deng
免疫检查点阻断(ICB)治疗癌症取得了显著疗效，但对胶质母细胞瘤(GBM)疗效不佳。主要原因是药物难以穿透血脑屏障(BBB)进入GBM，GBM微环境中缺乏足够的细胞毒性CD8+T细胞。在这里，合成了两种具有近红外-II荧光发射的AIE光热剂(FS和FO)，通过简单地将一个O原子转变为S原子来增加AIE光热剂的分子扭曲，使FS的光热转换效率提高到48%。随后，通过基因工程技术，将表达免疫检查点LAG3抑制抗体(抗LAG3)的小胶质细胞外切体包被FS，制备了工程化小胶质细胞外切体AIE纳米粒(Ee@Fs-NPs)。工程化的小胶质细胞外切体赋予Ee@Fs-NPs跨BBB和靶向GBM的能力，成功地将抗LAG3基因转移到GBM。抗LAG3能显著逆转T细胞耗竭，产生肿瘤坏死因子α，抑制热休克蛋白的表达，增强肿瘤细胞的热敏感性。此外，Ee@Fs-NPs的AIE光热剂产生温和的光热治疗，以破坏肿瘤细胞，并改善细胞毒性CD8+T细胞在GBM中的渗透，从而增加ICB治疗的反应性。Ee@Fs-NPs具有强大的温和光热-免疫协同治疗作用，将为GBM的高效治疗提供治疗平台。
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.