通过杯突和铁突激活协同肿瘤免疫疗法的功能性纳米酶系统。

IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Lina Gu, Ying Sun, Tingjie Bai, Sijie Shao, Shumin Tang, Panpan Xue, Wanlin Cai, Xian Qin, Xuemei Zeng, Shuangqian Yan
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引用次数: 0

摘要

升高的铜水平诱导肿瘤铜下垂和铁下垂,导致免疫原性细胞死亡和随后的抗肿瘤免疫反应。然而,肿瘤细胞中铜代谢失调维持了稳态铜平衡,而缺氧微环境阻碍了治疗效果。在这项研究中,我们提出了一种名为CussOMEp的纳米酶系统,该系统由聚醚化的铜基纳米载体(CussNV)组成,并加载了奥美拉唑(一种铜转运蛋白抑制剂),通过促进铜沉降和铁沉降来增强肿瘤协同免疫治疗。CussNV由二硫代二乙醇酸和铜离子组装而成,表现出过氧化物酶、谷胱甘肽氧化酶和过氧化氢酶样活性,并具有响应降解性。这种纳米酶通过产生氧来缓解肿瘤缺氧,通过产生致命的羟基自由基诱导铁下垂,并消耗谷胱甘肽。此外,奥美拉唑通过抑制细胞内铜转运atp酶1 (ATP7A),促进脂化蛋白寡聚化和铜还原,增加细胞内铜浓度和氧化应激。在乳腺肿瘤小鼠模型中,CussOMEp引发了强大的抗肿瘤免疫反应,包括树突状细胞成熟和T细胞增殖。当与PD-1抗体(αPD-1)联合使用时,CussOMEp在双侧和肺转移模型中显著抑制肿瘤转移。这项工作提出了一个功能纳米酶系统作为一个有前途的策略协同肿瘤免疫治疗利用铁下垂和铜下垂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Functional nanozyme system for synergistic tumor immunotherapy via cuproptosis and ferroptosis activation.

Elevated copper levels induce tumor cuproptosis and ferroptosis, leading to immunogenic cell death and subsequent antitumor immune responses. However, dysregulated copper metabolism in tumor cells maintains homeostatic copper balance, while hypoxic microenvironments hinder therapeutic efficacy. In this study, we present a nanozyme system, termed CussOMEp, comprising a copper-based nanovector (CussNV) that is PEGylated and loaded with omeprazole, a copper transporter inhibitor, to enhance tumor synergistic immunotherapy by promoting cuproptosis and ferroptosis. CussNV is assembled from dithiodiglycolic acid and copper ions, exhibiting peroxidase, glutathione oxidase, and catalase-like activities, along with responsive degradability. This nanozyme alleviates tumor hypoxia by producing oxygen, induces ferroptosis through the generation of lethal hydroxyl radicals, and depletes glutathione. Additionally, omeprazole increases cellular copper concentration and oxidative stress by inhibiting the intracellular copper-transporting ATPase 1 (ATP7A), enhancing lipoylated protein oligomerization and cuproptosis. In a breast tumor mouse model, CussOMEp elicits robust antitumor immune responses, including dendritic cell maturation and T cell proliferation. When combined with PD-1 antibodies (αPD-1), CussOMEp significantly inhibits tumor metastasis in bilateral and lung metastatic models. This work presents a functional nanozyme system as a promising strategy for synergistic tumor immunotherapy leveraging ferroptosis and cuproptosis.

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来源期刊
Journal of Nanobiotechnology
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.
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