Mitochondria-targeting polymer cLipG/CuET activates the cGAS/STING pathway to enhance cholangiocarcinoma immunotherapy.

IF 12.6 1区生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Nanobiotechnology Pub Date : 2025-10-09 DOI:10.1186/s12951-025-03689-0

Ge Bai, Hongwen Liu, Wei Li, Sijia Chen, Lishan Wang, Zhangding Wang, Yue Zhou, Yani Pan, Yu Liu, Qi Chen, Nannan Zhang, Jingjing Wei, Xueni Fu, Yaru Zhou, Yun Zhu, Lei Xu, Lei Wang

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引用次数: 0

Abstract

Background: The remodeling of extracellular matrix often fails chemotherapeutic agents to fight intrahepatic cholangiocarcinoma (ICC). The cGAS/STING pathway can trigger the innate immune response to obtain better immunotherapeutic outcomes.

Results: A cLipG/CuET nanocomposite was designed and synthesized based on glycyrrhizic acid (GA) and copper diethyldithiocarbamate (CuET). GA can open mitochondrial permeability transition pores (MPTPs), allowing Cu (II) to interrupt mitochondrial function through copper toxicity. By activating the cGAS-STING signaling pathway in macrophages, this mitochondrial-targeting polymer (cLipG/CuET) significantly boosted the production of mitochondrial reactive oxygen species (mtROS), and promoted the escape of damaged mitochondrial DNA (mtDNA) from ICC cells. Consequently, M1 polarization of cancer-associated macrophages enhanced the immune response against ICC. In the mouse model, the intravenous administration of cLipG/CuET transformed the ICC from "cold" into "hot".

Conclusions: With a high biosafety, cLipG/CuET exerted a synergistic effect on the immune checkpoint inhibitor αCTLA-4 against ICC, and their combination provided a new therapeutic strategy.

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线粒体靶向聚合物cLipG/CuET激活cGAS/STING通路，增强胆管癌免疫治疗。

背景：细胞外基质的重塑常常导致化疗药物治疗肝内胆管癌（ICC）失败。cGAS/STING通路可触发先天免疫反应，获得较好的免疫治疗效果。结果：设计并合成了以甘草酸（GA）和二乙基二硫代氨基甲酸铜（CuET）为原料的cLipG/CuET纳米复合材料。GA可以打开线粒体通透性过渡孔（MPTPs），允许Cu （II）通过铜毒性中断线粒体功能。这种线粒体靶向聚合物（cLipG/CuET）通过激活巨噬细胞中的cGAS-STING信号通路，显著促进线粒体活性氧（mtROS）的产生，并促进受损线粒体DNA （mtDNA）从ICC细胞中逃逸。因此，癌症相关巨噬细胞的M1极化增强了对ICC的免疫应答。在小鼠模型中，静脉给药cLipG/CuET使ICC从“冷”变为“热”。结论：cLipG/CuET与免疫检查点抑制剂αCTLA-4具有协同作用，具有较高的生物安全性，两者联合治疗ICC提供了一种新的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Nanobiotechnology BIOTECHNOLOGY & APPLIED MICROBIOLOGY-NANOSCIENCE & NANOTECHNOLOGY

CiteScore

13.90

自引率

4.90%

发文量

493

审稿时长

16 weeks

期刊介绍： Journal of Nanobiotechnology is an open access peer-reviewed journal communicating scientific and technological advances in the fields of medicine and biology, with an emphasis in their interface with nanoscale sciences. The journal provides biomedical scientists and the international biotechnology business community with the latest developments in the growing field of Nanobiotechnology.