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用于级联类酶催化以及同步增强铁死亡/铜死亡免疫疗法的单个铜(I)位点的空间隔离

Spatial Isolation of Single Copper(I) Sites for Cascade Enzyme-Like Catalysis and Simultaneous Ferroptosis/Cuproptosis Boosted Immunotherapy.

作者信息

Zhang Yuanyuan, Ya Shengnan, Huang Jingnan, Ju Yangyang, Fang Xueyang, Ouyang Xinteng, Zeng Qingdong, Zhou Xinyao, Yan Xiyun, Nie Guohui, Fan Kelong, Zhang Bin

机构信息

Department of Otolaryngology Shenzhen Key Laboratory of Nanozymes and Translational Cancer Research Shenzhen Institute of Translational Medicine The First Affiliated Hospital of Shenzhen University Shenzhen Second People's Hospital Shenzhen University Medical School Shenzhen China.

School of Medical Imageology Wannan Medical College Wuhu China.

出版信息

Exploration (Beijing). 2025 Mar 6;5(3):20240275. doi: 10.1002/EXP.20240275. eCollection 2025 Jun.


DOI:10.1002/EXP.20240275
PMID:40585770
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12199402/
Abstract

Nanozyme-based immunogenic cell death (ICD) inducers that effectively induce a strong immune response via enzyme-like process have attracted great attention, but how to ensure controllable active sites and maximize site utilization remains a problem. Here, we report a structurally well-defined and highly functional single-site copper(I) nanomodulators termed CuNTD, constructed by precisely anchoring atomically dispersed self-assembly S-Cu(I)-S sites onto a two-dimensional TiC surface. Leveraging Cu with a higher catalytic efficiency than Cu, CuNTD generates reactive oxygen species (ROS) storms through photothermal-enhanced cascade catalysis, further inducing mitochondrial dysfunction, ferroptosis and cuproptosis. Multifunctional CuNTD triggers strong ICD through cascade-regulatory pathways of photothermal-amplified ROS storms, cuproptosis and ferroptosis, effectively promoting dendritic cell maturation while reducing monotherapies side effects and resistance. In vivo, CuNTD combined with FDA-approved immunoadjuvants significantly prolong the survival of mice. With its demonstrated biosafety and high efficiency as an ICD inducer, this study provides a promising framework for advancing augmented tumor immunotherapy with significant clinical potential.

摘要

基于纳米酶的免疫原性细胞死亡(ICD)诱导剂通过类似酶的过程有效诱导强烈的免疫反应,已引起广泛关注,但如何确保可控的活性位点并最大限度地提高位点利用率仍是一个问题。在此,我们报道了一种结构明确且功能高度强大的单位点铜(I)纳米调节剂,称为CuNTD,它是通过将原子分散的自组装S-Cu(I)-S位点精确锚定在二维TiC表面构建而成。利用催化效率高于铜的铜,CuNTD通过光热增强级联催化产生活性氧(ROS)风暴,进一步诱导线粒体功能障碍、铁死亡和铜死亡。多功能CuNTD通过光热放大的ROS风暴、铜死亡和铁死亡的级联调节途径触发强烈的ICD,有效促进树突状细胞成熟,同时减少单一疗法的副作用和耐药性。在体内,CuNTD与FDA批准的免疫佐剂联合使用可显著延长小鼠的生存期。鉴于其作为ICD诱导剂所展示的生物安全性和高效性,本研究为推进具有重大临床潜力的增强型肿瘤免疫治疗提供了一个有前景的框架。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/eadb376d5256/EXP2-5-20240275-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/bec305b690d1/EXP2-5-20240275-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/b3297d39c0e9/EXP2-5-20240275-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/c1a9cfd2e021/EXP2-5-20240275-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/b1778adc478a/EXP2-5-20240275-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/c8e3db170b2d/EXP2-5-20240275-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/f806043f9fda/EXP2-5-20240275-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/017a6041f96a/EXP2-5-20240275-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/eadb376d5256/EXP2-5-20240275-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/bec305b690d1/EXP2-5-20240275-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/b3297d39c0e9/EXP2-5-20240275-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/c1a9cfd2e021/EXP2-5-20240275-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/b1778adc478a/EXP2-5-20240275-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/c8e3db170b2d/EXP2-5-20240275-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/f806043f9fda/EXP2-5-20240275-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/017a6041f96a/EXP2-5-20240275-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d43a/12199402/eadb376d5256/EXP2-5-20240275-g007.jpg

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引用本文的文献

[1]
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Theranostics. 2025-7-28

[2]
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[3]
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J Phys Chem B. 2025-7-10

本文引用的文献

[1]
Precise modulation and use of reactive oxygen species for immunotherapy.

Sci Adv. 2024-5-17

[2]
Bioorthogonal Cu Single-Atom Nanozyme for Synergistic Nanocatalytic Therapy, Photothermal Therapy, Cuproptosis and Immunotherapy.

Angew Chem Int Ed Engl. 2024-7-1

[3]
Cellular Trojan Horse initiates bimetallic Fe-Cu MOF-mediated synergistic cuproptosis and ferroptosis against malignancies.

Sci Adv. 2024-4-12

[4]
A Comprehensive Strategy Based on High Clinical Translational Nanosystem for Programmable Immunotherapy of Triple Negative Breast Cancer.

Adv Mater. 2024-7

[5]
Single Atom Catalysts Remodel Tumor Microenvironment for Augmented Sonodynamic Immunotherapy.

Adv Mater. 2024-6

[6]
Spatial engineering of single-atom Fe adjacent to Cu-assisted nanozymes for biomimetic O activation.

Nat Commun. 2024-3-12

[7]
Rational design of ICD-inducing nanoparticles for cancer immunotherapy.

Sci Adv. 2024-2-9

[8]
Single-Site Nanozymes with a Highly Conjugated Coordination Structure for Antitumor Immunotherapy via Cuproptosis and Cascade-Enhanced T Lymphocyte Activity.

J Am Chem Soc. 2024-2-14

[9]
Embedding Atomically Dispersed Manganese/Gadolinium Dual Sites in Oxygen Vacancy-Enriched Biodegradable Bimetallic Silicate Nanoplatform for Potentiating Catalytic Therapy.

Adv Sci (Weinh). 2024-1

[10]
Ultrathin Clay Nanoparticles-Mediated Mutual Reinforcement of Ferroptosis and Cancer Immunotherapy.

Adv Mater. 2024-3

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