Wang Yang, Li Guangzhe, Su Jianlong, Liu Yiming, Zhang Xiaomai, Zhang Guanyi, Wu Zhihao, Li Jinrong, Wang Xu, Zhang Yuxuan, Bai Mingrui, Yao Yuanhang, Wang Ruimin, Shao Kun
Cancer Hospital of Dalian University of Technology, Dalian University of Technology, Shenyang, 110042, China.
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian, 116024, China.
Small. 2025 Feb;21(6):e2406839. doi: 10.1002/smll.202406839. Epub 2025 Jan 10.
Glioblastoma (GBM), the most malignant brain tumor with high prevalence, remains highly resistant to the existing immunotherapies due to the significant immunosuppression within tumor microenvironment (TME), predominantly manipulated by M2-phenotypic tumor-associated macrophages (M2-TAMs). Here in this work, an M2-TAMs targeted nano-reprogrammers, MG5-S-IMDQ, is established by decorating the mannose molecule as the targeting moiety as well as the toll-like receptor (TLR) 7/8 agonist, imidazoquinoline (IMDQ) on the dendrimeric nanoscaffold. MG5-S-IMDQ demonstrated an excellent capacity of penetrating the blood-brain barrier (BBB) as well as selectively targeting M2-TAMs in the GBM microenvironment, leading to a phenotype transformation and function restoration of TAMs shown as heightened phagocytic activity toward tumor cells, enhanced cytotoxic effects, and improved tumor antigen cross-presentation capability. In the meantime, by induction of a function-oriented "gear effect", MG5-S-IMDQ treatment extended its impact systemically by enhancing the infiltration of type I conventional dendritic cells (cDC1s) into the tumor sites and bolstering adaptive immune responses. In sum, by precisely working on M2-TAMs as a unique target in tumor situ, the nano-reprogrammers successfully established a robust immune network that worked synergistically to combat tumors. This facile nanoplatform-based immunomodulatory strategy, serving as a powerful and convenient immune monotherapy or as a complementary treatment alongside other therapies like surgery, provided deep insights for advancing translational study in GBM.
胶质母细胞瘤（GBM）是最常见的恶性脑肿瘤，由于肿瘤微环境（TME）中存在显著的免疫抑制，主要由M2表型的肿瘤相关巨噬细胞（M2-TAMs）操纵，因此对现有的免疫疗法仍具有高度抗性。在这项工作中，通过在树枝状纳米支架上修饰甘露糖分子作为靶向部分以及 toll 样受体（TLR）7/8 激动剂咪唑喹啉（IMDQ），建立了一种靶向 M2-TAMs 的纳米重编程剂 MG5-S-IMDQ。MG5-S-IMDQ 表现出优异的穿透血脑屏障（BBB）的能力以及在 GBM 微环境中选择性靶向 M2-TAMs 的能力，导致 TAMs 的表型转化和功能恢复，表现为对肿瘤细胞的吞噬活性增强、细胞毒性作用增强以及肿瘤抗原交叉呈递能力提高。同时，通过诱导功能导向的“齿轮效应”，MG5-S-IMDQ 治疗通过增强 I 型常规树突状细胞（cDC1s）向肿瘤部位的浸润和增强适应性免疫反应，系统性地扩大了其影响。总之，通过精确作用于肿瘤原位的独特靶点 M2-TAMs，纳米重编程剂成功建立了一个强大的免疫网络，协同对抗肿瘤。这种基于纳米平台的简便免疫调节策略，作为一种强大而便捷的免疫单一疗法或作为与手术等其他疗法联合的辅助治疗，为推进 GBM 的转化研究提供了深刻见解。
