Wang Ruonan, Li Huixin, He Shasha, Feng Yuanji, Liu Cong, Hao Kai, Zhou Danhua, Chen Xiaoyuan, Tian Huayu
State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China.
Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM), Xiamen, 361005, China.
Adv Mater. 2025 Feb;37(5):e2412141. doi: 10.1002/adma.202412141. Epub 2024 Dec 11.
Lymph nodes are crucial immune foci as the primary target for cancer immunotherapy. However, the anti-tumor functions of tumor-draining lymph nodes (TDLNs) are critically suppressed by tumors. Here, a novel spatiotemporal nano-regulator is presented, designed to modulate the dendritic cells (DCs) in TDLNs, establishing a supportive niche for immune surveillance. The DC-mediated nano-regulator (DNR) is established by the self-assembly of an imidazoquinoline (IMDQ) prodrug, inhibitory immune checkpoint (ICP) siRNA, and mannan (a TLR4 agonist). This unique design leverages the spatiotemporal activation of TLR4 and TLR7/8, thereby optimizing DC maturation and cytokine production. This further promotes efficient T cell priming. Simultaneously, the ICP-targeting siRNA mitigates the tolerogenic effects induced by tumor-derived factors and TLR activation, preventing T cell exhaustion. In essence, DNR facilitates potent remodeling of TDLNs and the tumor microenvironment, activating the anti-tumor immunity cascade. When combined with vaccines, DNR greatly promotes tumor regression and the establishment of long-term immunological memory.
淋巴结作为癌症免疫治疗的主要靶点，是至关重要的免疫病灶。然而，肿瘤引流淋巴结（TDLN）的抗肿瘤功能受到肿瘤的严重抑制。在此，我们提出了一种新型的时空纳米调节剂，旨在调节TDLN中的树突状细胞（DC），为免疫监视建立一个支持性微环境。DC介导的纳米调节剂（DNR）是由咪唑喹啉（IMDQ）前药、抑制性免疫检查点（ICP）siRNA和甘露聚糖（一种TLR4激动剂）自组装而成。这种独特的设计利用了TLR4和TLR7/8的时空激活，从而优化DC成熟和细胞因子产生。这进一步促进了有效的T细胞启动。同时，靶向ICP的siRNA减轻了肿瘤衍生因子和TLR激活诱导的耐受性效应，防止T细胞耗竭。本质上，DNR促进了TDLN和肿瘤微环境的有效重塑，激活了抗肿瘤免疫级联反应。当与疫苗联合使用时，DNR极大地促进了肿瘤消退和长期免疫记忆的建立。
