Materials Today
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2023
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IF 24.2
Xiao-Kang Jin,Jun-Long Liang,Shi-Man Zhang,Qian-Xiao Huang,Shun-Kang Zhang,Chuan-Jun Liu,Xian-Zheng Zhang
Owing to the deficiency of infiltrating immune cells and the accumulation of immunosuppressive cells in tumor microenvironment (TME), immunotherapy remains enormous challenges in colorectal cancer (CRC). Here, CRC was found to be sensitive to cuproptosis which could further evoke immune responses and mediate immune resistance. Thus, a cuproptosis-mediated immunotherapy nanoreactor (CCJD-FA) was constructed by encapsulating copper-based shell-coated CaO 2 and bromodomain-containing protein 4 inhibitor JQ-1 with DSPE-PEG-FA. Within tumor cells, CCJD-FA was disassembled under GSH environment, and the exposed CaO 2 could generate H 2 O 2 under the acidic condition, which reacted with the released Cu 2+ via Fenton-like reaction to produce O 2 for relieving hypoxia and Cu + for inducing cuproptosis. Furthermore, CCJD-FA could also inhibit intracellular glycolysis and ATP generation, then blocking the Cu + efflux protein ATP7B. Meanwhile, the IFN-γ-induced PD-L1 expression could be exactly reduced by the BRD4 suppression and oxygen supply. These effects sensitized cancer cells to cuproptosis, further evoking systemic immune responses and reshaping immunosuppressive TME to inhibit tumor growth.
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高影响因子
ADVANCED FUNCTIONAL MATERIALS
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2023
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IF 19
Fan Zhao,Liying Liang,Heng Wang,Chen Wang,Dan Su,Yao Ying,Wangchang Li,Juan Li,Jingwu Zheng,Liang Qiao,Xiaozhou Mou,Shenglei Che,Jing Yu
Copper overload is a novel way to achieve copper-ion-interference therapy by disrupting copper homeostasis and treating diseases through multiple cell death pathways. However, it is difficult to reach copper overload since excess intracellular copper ions will be pumped out. Herein, copper overload is achieved by both raising cellular uptake and reducing the efflux of copper ions using hydrogen sulfide (H 2 S)-responsive copper hydroxyphosphate nanoparticles (Cu 2 (PO 4 )(OH) NPs). After immersion in an H 2 S-enriched colon cancer microenvironment, Cu 2 (PO 4 )(OH) NPs can transform into copper sulfide NPs with reduced size for higher cell entering, resulting in improved Fenton activity as well as copper ion dissociation. Reactive oxygen species generated by the Fenton reaction not only activate inflammasomes and Caspase-1 proteins, cause the cleavage of gasdermin D to induce pyroptosis, but also affect mitochondrial function and down-regulate copper exporter ATP7A to further reduce the copper excretion. The combination of higher endocytosis and lower exportation leads to maximized copper overload. Together with the efficient copper ions release, mitochondrial tricarboxylic acid cycle can be disrupted and iron-sulfur cluster proteins are downregulated, ultimately triggering cuproptosis. As both pyroptosis and cuproptosis are efficient ways to induce cell death, this study provides a novel way to realize effective tumor-targeted therapy based on H 2 S-activated copper overload with simple Cu 2 (PO 4 )(OH) NPs.
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高影响因子
Biomaterials Advances
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2025
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IF 6
Rongxiang Zhang,Xuelei Yin,Zenghui Xu,Qikang Yan
Purpose Development of Ce/Cu-modified black ceramics and investigation of the mechanism of anti-osteosarcoma activity. Methods Black ceramics doped with 0.3–0.7 wt% CeO 2 and CuO were prepared and analyzed using energy-dispersive X-ray spectroscopy (EDS), compression stress-strain tests, weight change, and antibacterial assays. MNNG/HOS and MG63 cells were seeded on ceramic substrates, and their adhesion and morphology were analyzed using scanning electron microscopy (SEM) and phalloidin staining. In vitro, we first assessed the anti-tumor effects of ceramic materials, then validated their impact on cuproptosis by measuring Cu 2+ levels and the expression of related proteins, including SLC31A1, HSP70, and ATP7A. Mitochondrial dysfunction and TCA abnormalities were assessed by measuring mitochondrial membrane potential, reactive oxygen species, mitochondrial structure, TCA cycle metabolites (citric acid and lactic acid), ATP levels, and DLAT and LIAS protein levels. The cuproptosis inhibitor TTM, PI3K activator 740Y P, and AKT activator SC79 were used to explore the relationship between cuproptosis and the PI3K/AKT pathway in osteosarcoma cells treated with Ce/Cu-doped black ceramics. Results Our research confirmed the superior anti-tumor properties of the Ce/Cu-modified black ceramic and its potential mechanisms against osteosarcoma. The Ce/Cu-doped black ceramic caused mitochondrial dysfunction and disrupted TCA cycle metabolism, resulting in cuproptosis in MNNG/HOS and MG63 cells. The PI3K/AKT pathway was involved in cuproptosis in osteosarcoma cells treated with Ce/Cu-modified ceramics. Conclusion Our research confirmed that Ce/Cu-modified black ceramics have superior anti-tumor effects and potential mechanisms, confirming the clinical potential of Ce/Cu-modified black ceramics in cancer treatment and providing theoretical basis for the clinical translation.
研究领域:
材料科学
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肿瘤学
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纳米医学
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细胞生物学
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生物医学工程
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PubMed
高影响因子
PeerJ
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2024
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IF 2.3
Bingyu Wang,Jianqing Zhou,Ning An
Cuproptosis-related key genes play a significant role in the pathological processes of acute myocardial infarction (AMI). However, a complete understanding of the molecular mechanisms behind this participation remains elusive. This study was designed to identify genes and immune cells critical to AMI pathogenesis. Based on the GSE48060 dataset (31 AMI patients and 21 healthy persons, GPL570-55999), we identified genes associated with dysregulated cuproptosis and the activation of immune responses between normal subjects and patients with a first myocardial attack. Two molecular clusters associated with cuproptosis were defined in patients with AMI. Immune infiltration analysis showed that there was significant immunity heterogeneity among different clusters. Multiple immune responses were closely associated with Cluster2-specific differentially expressed genes (DEGs). The generalized linear model machine model presented the best discriminative performance with relatively lower residual and root mean square error, and a higher area under the curve (AUC = 0.870). A final two-gene-based generalized linear model was constructed, exhibiting satisfactory performance in two external validation datasets (AUC = 0.719, GSE66360 and AUC = 0.856, GSE123342). Column graph, calibration curve, and decision curve analyses also proved the accuracy of AMI prediction. We also constructed a mouse C57BL/6 model of AMI (3 h, 48 h, and 1 week) and used qRT-PCR and immunofluorescence to detect the expression changes of CBLB and ZNF302. In this study, we present a systematic analysis of the complex relationship between cuproptosis and a first AMI attack, and provide new insights into the diagnosis and treatment of AMI.
研究领域:
生物信息学
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医学
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心血管疾病
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DOI
PubMed
高影响因子
Acta Biomaterialia
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2026
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IF 10.4
Chunyuan Hou,Yu Zhang,Jun Gu,Jun Wan,Ziyao Zhao,Peicheng Wang,Shujun Feng,Jun Luo
Piezocatalytic therapy (PCT) has garnered increasing interest in the field of cancer treatment. However, its therapeutic efficacy is hampered by the limitations of current piezoelectric materials and the intrinsic therapeutic resistance of tumors. Here, leveraging elaborately designed copper-coordinated covalent organic frameworks (CuCOF-2N) as piezocatalysts, a smart ultrasound-controlled nanoreactor (Cu2N@D-FA) is constructed by co-encapsulating with doxorubicin prodrug into folic acid-modified liposomes, to enhance the antitumor efficacy of PCT through the combination of cuproptosis and bioorthogonal catalysis. The structure-property comparison with related COFs underscores the important role of highly polar triazine rings and symmetry-disrupting bidentate ligands in enhancing piezoelectric performance of CuCOF-2N. Upon ultrasound irradiation, CuCOF-2N not only produces hydroxyl radicals independently of oxygen but also enables a self-sustained oxygen supply for generating superoxide anions and singlet oxygen, which surmount constraints of traditional piezoelectric materials to trigger strong PCT. Moreover, the mediated-copper valence switching in CuCOF-2N permits spatiotemporally precise bioorthogonal catalysis and triggers cuproptosis, overcoming therapeutic limitations and amplifying the PCT effect. In vivo studies demonstrate that Cu2N@D-FA selectively accumulates in the tumor and effectively eliminates the tumor without side-effects under US stimulation. Therefore, this study highlights the great promise of COFs in piezocatalysis and offers a paradigm for enhancing PCT. Statement of Significance A sonopiezoresponsive copper-coordinated covalent organic framework is designed and co-encapsulated with a doxorubicin prodrug in folic acid-modified liposomes to enable synergistic piezocatalytic therapy. The CuCOF enables oxygen-independent hydroxyl radical generation while providing a self-sustained oxygen supply for the production of superoxide anions and singlet oxygen. Ultrasound triggers reversible valence state switching of copper within the framework, enabling in situ bioorthogonal catalysis, and the concomitant mitochondrial accumulation of copper induces cuproptosis. The CuCOF-based nanoreactor demonstrates good biocompatibility and achieves potent tumor suppression under mild ultrasound irradiation. Download: Download high-res image (340KB) Download: Download full-size image
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DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2026
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IF 9.6
Wei Wang,Zheng Niu,Longyue He,Yuze Liu,Zhou Shen,Lining Zhao,Xiaoping Yin,Leyong Zeng
Disrupting redox homeostasis is a feasible strategy for reversing immunosuppressive tumor microenvironment. Herein, by coating copper selenide (Cu 2-x Se) on the surface of gold/molybdenum (AuMo), a AuMo@Cu 2-x Se nanozyme with triple-enzyme activities of glucose oxidase/glutathione peroxidase/peroxidase was reported for inducing immunogenic cell death (ICD) and cuproptosis, thereby enhancing antitumor immunotherapy. Benefiting from the reversible valence transition of Mo 6+ /Mo 4+ and Cu 2+ /Cu + , and the multi-enzyme activities, the reactive oxygen species (ROS) generation was enhanced, and the near-infrared II photothermal performance further promoted ROS generation, ultimately disrupting redox homeostasis. Moreover, by combining ROS storm and Cu 2+ transportion, the mitochondrial dysfunction was triggered, which activated ICD and cuproptosis, releasing damage related molecular patterns and regulating cuproptosis-related proteins. Under a 1064 nm laser irradiation, the AuMo@Cu 2-x Se nanozyme facilitated dendritic cells maturation, T cells infiltration, M1 macrophages polarization, and memory and regulatory T cells production. The developed AuMo@Cu 2-x Se nanozyme provided a feasible strategy of integrating cuproptosis and photo/catalytic/immunotherapy, significantly suppressing primary and metastatic tumors for breast cancer. A multifunctional dual-site co-valence cycling AuMo@Cu 2-x Se nanozyme for boosting cuproptosis and triple-modal photo-catalytic-immunotherapy via redox homeostasis imbalance. Download: Download high-res image (110KB) Download: Download full-size image
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2026
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IF 8.7
Xiaobing Yao,Yuan Ruan,Ting Rao,Fangyou Lin,Wenbin Zhang
Prostate cancer is a prevalent immune-cold malignancy in which hypoxia and glutathione (GSH) enrichment hinder redox-dependent therapies and cuproptosis. A hyaluronic-acid–coated copper–manganese Prussian blue nanomedicine (Cu/Mn-PB@HA) was developed to remodel the tumor microenvironment (TME) and enhance mitochondria-associated cuproptosis. The multivalent Cu/Mn centers enable catalase-like O 2 generation, GSH-oxidase–like depletion of GSH, and Fenton-like ·OH production, which together enhance chemodynamic therapy (CDT) and create a favorable window for cuproptosis. In acidic and GSH-rich conditions, copper valence cycling initiates cuproptosis, whereas released Mn 2+ enhances CDT and activates the cGAS–STING pathway, thereby promoting dendritic-cell maturation and cytotoxic T-cell responses. The HA shell enables CD44-mediated enrichment, improving tumor accumulation without compromising biosafety. In vitro , the platform elevates ROS, induces mitochondrial depolarization, downregulates HIF-1α, and modulates cuproptosis-related proteins. Concurrently, immunogenic cell-death markers are elevated together with cGAS–STING signaling. In vivo , preferential tumor accumulation and significant tumor inhibition are achieved with favorable serum biochemistry and hepatic/renal histology. By integrating “oxygenation–desensitization–ROS” chemistry with Mn 2+ - enhanced immune activation, Cu/Mn-PB@HA provides a comprehensive strategy for treating immune-cold solid tumors and serves as a versatile platform for theranostic development.
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PubMed
高影响因子
ACS Nano
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2025
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IF 16
Yechun Jiang,Weinan Zhang,Litao Liu,Yayun Wu,Weiqi Li,Jun Liang,Hui Shen,Shu Fang,Xianyu Huang,Zhaoyou Chu,Lingling Xu,Haisheng Qian
The immunosuppressive niche of the breast cancer microenvironment and the vascular basement membrane significantly hinder the efficacy of nanoparticle-based antitumor immunotherapy delivered via the vascular system. This study describes the design of a puncture-delivered tumor implant, utilizing a photo-cross-linked gelatin methacryloyl hydrogel as the matrix, loaded with Cu0.5Mn2.5O4 nanoparticles (CMO NPs) and monomethyl fumarate (MMF), enabling the sustained release of nanoparticles through matrix metalloproteinase-responsive degradation. Mechanistically, CMO NPs induce cuproptosis and immunogenic cell death (ICD) in tumor cells, while synergizing with MMF to trigger substantial mtDNA release into the cytosol. Subsequently, the liberated mtDNA synergizes with Mn2+ to activate the cGAS-STING signaling pathway, which cooperates with ICD to enhance CD8+ T cell infiltration and increase the levels of related inflammatory factors in the breast tumor microenvironment. Notably, the implant significantly enhances the efficacy of αPD-1 therapy by modulating PD-L1/PD-1 expression. In summary, the implant designed in this study provides a practical strategy for nanoparticle delivery and immunotherapy of breast cancer.
研究领域:
生物材料
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纳米医学
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免疫学
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肿瘤学
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药物递送
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生物工程
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DOI
PubMed
高影响因子
Materials Horizons
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2025
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IF 10.7
Chen Peng,Jiaxin Li,Nan Wang,Xinyue Zhang,Wen Zhang,Zhirui Li,Keyi Zhang,Yangchaowei Ji,Wei He,Yan Li
We develop pyruvate with good biocompatibility and mitochondria-targeting ability as a copper ionophore (pyruvate-Cu). To further overcome its drawbacks, traceable nanoparticles are constructed to deliver pyruvate-Cu for triple negative breast cancer (TNBC) treatment. In vitro and in vivo results demonstrate that this work provides an efficient platform for enhanced TNBC therapy.
研究领域:
纳米医学
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癌症生物学
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药理学
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生物化学
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材料科学
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DOI
PubMed
高影响因子
Small
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2024
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IF 13
Jiao Chang,Weimin Yin,Hui Zhi,Shiyu Chen,Jiuyuan Sun,Yuge Zhao,Li Huang,Liangyi Xue,Xiaoyou Zhang,Tingting Zhang,Haiqing Dong,Yongyong Li
Cuproptosis is an emerging programmed cell death, displaying great potential in cancer treatment. However, intracellular copper content to induce cuproptosis is unmet, which mainly ascribes to the intracellular pumping out equilibrium mechanism by copper exporter ATP7A and ATP7B. Therefore, it is necessary to break such export balance mechanisms for desired cuproptosis. Mediated by diethyldithiocarbamate (DTC) coordination, herein a strategy to efficiently assemble copper ions into polydopamine nanostructure (PDA-DTC/Cu) for reprogramming copper metabolism of tumor is developed. The deposited Cu 2+ can effectively trigger the aggregation of lipoylated proteins to induce cuproptosis of tumor cells. Beyond elevating intracellular copper accumulation, PDA-DTC/Cu enables to break the balance of copper metabolism by disrupting mitochondrial function and restricting the adenosine triphosphate (ATP) energy supply, thus catalytically inhibiting the expressions of ATP7A and ATP7B of tumor cells to enhance cuproptosis. Meanwhile, the killed tumor cells can induce immunogenic cell death (ICD) to stimulate the immune response. Besides, PDA-DTC/Cu NPs can promote the repolarization of tumor-associated macrophages (TAMs ) to relieve the tumor immunosuppressive microenvironment (TIME). Collectively, PDA-DTC/Cu presented a promising “one stone two birds” strategy to realize copper accumulation and inhibit copper export simultaneously to enhance cuproptosis for 4T1 murine breast cancer immunotherapy.
研究领域:
癌症生物学
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纳米技术
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免疫治疗
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细胞生物学
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材料科学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2025
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IF 8.2
Meiru Zhang,Hui Xu,Xiaozan Wu,Botao Chen,Xiyu Gong,Yongju He
Cuproptosis is a new copper-dependent form of regulated cell death and shows enormous promise in cancer therapy. However, its therapeutic performance is compromised by the strictly regulated copper metabolism and highly expressed intracellular glutathione (GSH). Herein, an intelligent nanoplatform (NSeMON-P@CuT/LipD) is rationally developed as a copper metabolic disrupter, GSH consumer, and Fenton-like reaction trigger for cancer cuproptosis/ferroptosis/apoptosis therapy. NSeMON-P@CuT/LipD is constructed from the preparation of diselenide-bridged mesoporous organosilica nanoparticles, and then pemetrexed (Pem) is loaded followed by surface deposition with a Cu2+-3,3′-dithiobis(propionohydrazide) (TPH) coordinated network and coating with a diclofenac (DC)-encapsulated liposome. In response to the specific tumor microenvironment, the obtained NSeMON-P@CuT/LipD can release DC, Cu2+, and Pem and simultaneously amplify cellular oxidative stress by consuming GSH and catalyzing endogenous H2O2 into hydroxyl radicals (•OH). Both liberated DC and augmented oxidative stress can inhibit glycolysis, reduce ATP level, and then block copper transporter ATP7B, resulting in metabolic disorders and the high retention of copper in cells for •OH generation. Moreover, the overloaded copper can promote dihydrolipoamide S-acetyltransferase oligomerization and Fe–S cluster protein loss, thus evoking cuproptosis. Collectively, the augmented oxidative stress activates prominent ferroptosis, which cooperates with cuproptosis and Pem-mediated apoptosis to significantly inhibit the tumor growth of 4T1 tumor-bearing mice. This study demonstrates feasible strategies to enhance tumor cuproptosis using a single nanoplatform and may also inspire the design of advanced cuproptosis-related therapies.
研究领域:
纳米医学
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肿瘤学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
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2024
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IF 18.5
Jiahe Hu,Jiuxin Zhu,Kuan Wang,Xiuwei Yan,Lei Xu,Xiaoling Zhang,He Ding,Piaoping Yang,Shaoshan Hu,Rui Xie
Ferroptosis and cuproptosis are emerging modes of programmed cell death and have been increasingly used to eliminate tumor cells. However, converting ferroptosis/cuproptosis into effective treatments is challenging because of the inherent antioxidant and plasma membrane repair systems and inefficient copper ion delivery. Herein, an engineered doping method is developed to encapsulate ZnO 2 with Cu 2+ -doped ZIF-8 and modify the surface by transferrin (Tf). In the resulting ZnO 2 @Cu/ZIF-8-Tf nanosystem, Tf specifically binds to transferrin receptors for targeting and aggregation. In the tumor microenvironment, Cu 2+ /Fe 3+ is released from the nanosystem and reacted with glutathione (GSH) to produce Cu + /Fe 2+ . Excessive accumulation of Cu + interfered with the tricarboxylic acid cycle and induced coproptosis. Furthermore, the additional Fe 2+ caused iron overload and enhanced ferroptosis. ZnO 2 supplied hydrogen peroxide to mediate the overproduction of reactive oxygen species (ROS). Moreover, the depletion of GSH deactivated glutathione peroxidase 4 (GPX4) and inhibited the system X c − -GSH-GPX4 pathway, and the amplified ROS triggered lipid peroxidation and reprogrammed lipid metabolism, causing malfunctioning of both antioxidant and membrane repair systems. In summary, the ferroptosis/cuproptosis pathways are activated at multiple levels in the ZnO 2 @Cu/ZIF-8-Tf nanosystem, which ensures its outstanding antitumor effect.
研究领域:
癌症生物学
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纳米技术
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药学
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细胞生物学
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DOI
高影响因子
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