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
{"title":"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。","authors":"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","doi":"10.1186/s12951-025-03689-0","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Results: </strong>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\".</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":"23 1","pages":"631"},"PeriodicalIF":12.6000,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mitochondria-targeting polymer cLipG/CuET activates the cGAS/STING pathway to enhance cholangiocarcinoma immunotherapy.\",\"authors\":\"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\",\"doi\":\"10.1186/s12951-025-03689-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Results: </strong>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\\\".</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":16383,\"journal\":{\"name\":\"Journal of Nanobiotechnology\",\"volume\":\"23 1\",\"pages\":\"631\"},\"PeriodicalIF\":12.6000,\"publicationDate\":\"2025-10-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Nanobiotechnology\",\"FirstCategoryId\":\"5\",\"ListUrlMain\":\"https://doi.org/10.1186/s12951-025-03689-0\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Nanobiotechnology","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.1186/s12951-025-03689-0","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
Mitochondria-targeting polymer cLipG/CuET activates the cGAS/STING pathway to enhance cholangiocarcinoma immunotherapy.
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.
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.
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