<br>ATP 响应性锰基细菌材料协同激活 cGAS-STING 通路用于肿瘤免疫治疗,Advanced Materials

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ATP 响应性锰基细菌材料协同激活 cGAS-STING 通路用于肿瘤免疫治疗
Advanced Materials ( IF 27.4 ) Pub Date : 2024-02-27 , DOI: 10.1002/adma.202310189
Huang Yang _{1,

2} , Sisi Yang ₃ , Quanshi Guo ₂ , Jifang Sheng ₃ , Zhengwei Mao _{1,

2}

Affiliation

刺激环磷酸鸟苷（GMP）-磷酸腺苷（AMP）合酶（cGAS）-干扰素基因刺激剂（STING）途径是细菌激活肿瘤免疫系统的重要策略。然而，有限的刺激能力对推进细菌免疫疗法提出了重大挑战。在这里，成功设计了一种腺苷 5′-三磷酸 (ATP) 响应性锰 (Mn) 基细菌材料（大肠杆菌@PDMC-PEG（聚乙二醇）），它表现出协同激活 cGAS-STING 的卓越能力途径。在以 ATP 水平升高为特征的肿瘤微环境中，这种生物混合材料会降解，导致二价锰离子 (Mn ²⁺ ) 的释放以及随后的细菌暴露。这种组合协同激活 cGAS-STING 途径，因为 Mn ²⁺增强了 cGAS 对细菌分泌的细胞外 DNA (eDNA) 的敏感性。体内实验结果表明，生物杂化材料大肠杆菌@PDMC-PEG和VNP20009@PDMC-PEG可有效抑制小鼠皮下黑色素瘤和兔原位肝癌的生长。这里为基于细菌的肿瘤免疫疗法的发展提供了宝贵的见解。

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ATP-Responsive Manganese-Based Bacterial Materials Synergistically Activate the cGAS-STING Pathway for Tumor Immunotherapy

Stimulating the cyclic guanosine monophophate(GMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial strategy by which bacteria activate the tumor immune system. However, the limited stimulation capability poses significant challenges in advancing bacterial immunotherapy. Here, an adenosine 5′-triphosphate (ATP)-responsive manganese (Mn)-based bacterial material (E. coli@PDMC-PEG (polyethylene glycol)) is engineered successfully, which exhibits an exceptional ability to synergistically activate the cGAS-STING pathway. In the tumor microenvironment, which is characterized by elevated ATP levels, this biohybrid material degrades, resulting in the release of divalent manganese ions (Mn²⁺) and subsequent bacteria exposure. This combination synergistically activates the cGAS-STING pathway, as Mn²⁺ enhances the sensitivity of cGAS to the extracellular DNA (eDNA) secreted by the bacteria. The results of the in vivo experiments demonstrate that the biohybrid materials E. coli@PDMC-PEG and VNP20009@PDMC-PEG effectively inhibit the growth of subcutaneous melanoma in mice and in situ liver cancer in rabbits. Valuable insights for the development of bacteria-based tumor immunotherapy are provided here.

更新日期：2024-02-27

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