ACS Applied Materials & Interfaces
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2026
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IF 7.8
Ding Tan,Yan Sun,Xudong Li,Ya Wang,Xianbin Sun,Haijun Chen,Yuxiang Lin,Yu Gao
Copper-based nanotherapeutics have emerged as a promising anticancer platform by simultaneously inducing cuproptosis and enabling multimodal therapy. However, their clinical application remains constrained by uncontrolled copper ion release, a complex tumor microenvironment (TME), and insufficient therapeutic penetration. To address these challenges, we developed a multifunctional nanoplatform (BCB) through the integration of baicalein–copper coordinated nanoparticles with a boron-dipyrromethene-derived photosensitizer. BCB exhibited a uniform spherical morphology with an average size of approximately 150 nm, excellent stability, TME-responsive release, and multiple catalytic functions, including peroxidase-like and photodynamic activities. Through synergistic chemodynamic and phototherapeutic actions, BCB effectively depleted glutathione, generated abundant reactive oxygen species, disrupted mitochondrial membrane potential, and triggered cuproptosis. In murine melanoma models, BCB plus light irradiation achieved a 75% cure rate, even at low doses. Moreover, BCB exhibited antimigratory properties and bone-penetrating capability, with selective accumulation in intramedullary tumor sites, highlighting its potential for treating bone-metastatic cancers. This multimodal nanoplatform represents a promising synergistic strategy for overcoming current therapeutic limitations in both primary and metastatic tumors.
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高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Xujian Yang,Gao He,Jiarui Wang,Jilin Zhong,Yu Luo,Feng Jiang,Lile Dong,Xiang Li
To overcome the efficiency limitations of cuproptosis in oncology, we engineered a piezoelectric Cu-loaded Bi4Ti3O12 nanosheet system for synergistic cuproptosis and ROS-mediated tumor therapy. The incorporation of Cu2+ not only enhanced the material’s piezoelectric coefficient (d33 = 22.3 pm·V–1) but also facilitated valence-state modulation under ultrasound (US) stimulation. The resulting piezoelectric field significantly promoted charge separation, accelerating Cu2+/Cu+ conversion and boosting reactive oxygen species (ROS) generation. This strategy synergistically induces tumor cell death through a dual tumoricidal pathway: on one hand, the accumulation of Cu+ under US stimulation further amplifies cuproptosis, and on the other hand, the continuous accumulation of ROS triggers excessive oxidative stress. In a murine breast cancer model, this synergistic approach achieved a 90.6% tumor inhibition rate. This study pioneeringly combines piezoelectric material properties and copper valence transformation, providing insights for breast cancer treatment.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
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IF 9.7
Lele Ma,Huiying Zheng,Wanlin Xie,Weidi Sun,Qunying Yuan,Kun Song,Peiyu Xi,Fengli Qu,Hui Zhang
Cuproptosis, a copper-dependent form of regulated cell death driven by mitochondrial metabolism, holds promise as a therapeutic strategy for cancer. However, its efficacy is hampered by tumor metabolic heterogeneity and mutant p53 (mut-p53)-driven metabolic rewiring that blunts cuproptosis sensitivity. Here, we report the rational design of CuF16@246, an acid-responsive, dual-functional copper-based nanocoordination polymer that integrates Cu 2+ and the p53 reactivator eprenetapopt (APR-246) within a single perfluorosebacic acid (PFSEA)-coordinated framework to synergistically induce cuproptosis and reverse tumor metabolic reprogramming. CuF16@246 comprises a PFSEA-coordinated copper framework with good colloidal stability and pH-dependent co-release of Cu 2+ and APR-246, enabling controlled Cu 2+ release and in situ APR-246 loading. Mechanistically, CuF16@246 triggers hallmarks of cuproptosis, including dihydrolipoamide S -acetyltransferase (DLAT) oligomerization and the depletion of the iron‑sulfur (Fe-S) cluster proteins ferredoxin 1 (FDX1) and lipoic acid synthase (LIAS), while APR-246 converts mut-p53 toward a wild-type-like, DNA-binding-competent state, upregulates metabolic targets such as TP53-induced glycolysis and apoptosis regulator (TIGAR) and glutaminase 2 (GLS2), suppresses glycolysis, and enhances tricarboxylic acid (TCA) cycle flux, thereby sensitizing tumor cells to cuproptosis. In vitro and in vivo studies demonstrate that CuF16@246 exhibits more efficient cellular uptake, more potent cytotoxicity, and more significant tumor growth inhibition than individual treatments, without inducing hemolysis or major organ toxicity. This work establishes a dual-functional strategy that combines metabolic reprogramming with sensitized cuproptosis, providing a promising framework for developing advanced copper-based nanomedicines for the treatment of mut-p53-positive cancers.
研究领域:
癌症生物学
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纳米医学
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分子治疗
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细胞死亡机制
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代谢工程
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高影响因子
Small
·
2025
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IF 12.1
You Zou,Yi Xie,Minghui Ou,Qian Lin,Yulian Li,Lizhi Wu,Wenjing Wang,Yiming Chen,Xing Jiang,Shengqiu Chen,Shiming Chen,Changsheng Zhao
Cuproptosis, a newly discovered cell death mechanism driven by cuprous ions (Cu(I)), faces challenges in achieving efficient pathway activation due to limitations in tumor cell targeting and intracellular copper accumulation. To address these, a NIR-triggered nanoplatform (Cu(I)-TA@HG) is developed for precise Cu(I) delivery to metastatic nasopharyngeal carcinoma (NPC) cells, thereby inducing potent cuproptosis. Drawing inspiration from the critical role of membrane proteins in cancer metastasis, tumor-homing nanovesicles derived from GAS6-overexpressing cell membranes (HG-CMs) are engineered. These membranes exhibit enhanced affinity for the AXL receptor, which is frequently overexpressed in metastatic NPC. The HG-CMs encapsulated cuprous-loaded nanoparticles (Cu(I)-TA), facilitating specific recognition via the GAS6-AXL axis and promoting highly targeted NPC delivery while minimizing off-target effects. Upon reaching the tumor, the Cu(I)-TA@HG can effectively trigger cuproptosis through the synergistic effect originating from the GAS6-AXL axis-directed cell targeting and TA-interfering copper ion excretion. Crucially, in vivo experiments demonstrate that this nanoplatform not only eradicates primary tumor sites but also effectively eliminates early metastatic lesions, leading to significant suppression of lung metastasis in an NPC model. This work establishes a strategic foundation for the rational design of nanotherapeutics that exploit cuproptosis for the treatment of aggressive and metastatic cancers.
研究领域:
肿瘤学
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纳米医学
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细胞死亡机制
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癌症转移
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药物递送系统
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高影响因子
IUBMB LIFE
·
2026
·Vol. 78
·期 1
·e70088
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IF 3.2
Yuan-yuan Fang,Si-yi Zhang,Chuan-yu Leng,Jing-Lv,Shu-fen Zhao,Xue-ying Sun,Xin-Li,Yang-yang Lu,Bing-Wang,Wei-wei Qi
Gastric cancer represents the fifth most common malignancy globally and the third leading cause of cancer-related deaths. Due to its insidious early symptoms and frequent metastasis at diagnosis, the survival rate remains dismal. There is thus an urgent clinical need for novel therapeutic agents. Innovative strategies combining traditional chemotherapy with interventions that induce novel cell death pathways represent a promising translational direction for improving patient outcomes. Punicalagin (PUN), a natural polyphenol derived from pomegranate, exhibits potent antioxidant and broad-spectrum antitumor activities, yet its role in gastric cancer remains understudied. Three gastric cancer cell lines (AGS, HGC27, MFC) and one normal gastric mucosal epithelial cell line (GES-1) were initially selected for in vitro experiments. The effects of PUN on gastric cancer cells and normal gastric mucosal epithelial cells were assessed through MTT assay, propidium iodide (PI) staining, and cell colony formation assays, while cell migration ability was evaluated using a scratch wound healing assay. The inhibitory effect of PUN on gastric cancer was tested in a subcutaneous tumor model in nude mice, with pathological changes in vital tissues and organs observed via hematoxylin and eosin (H&E) staining. Subsequently, transcriptome sequencing was performed, and JC-1, H2DCFDA, and DHE staining methods were employed to measure mitochondrial function and reactive oxygen species (ROS) levels in PUN-treated cells. Western blotting was used to detect the expression of apoptosis- and cell cycle-related proteins. Next, two gastric cancer cell lines (AGS, HGC27) were selected for in vitro experiments to assess the combined effects of PUN and the copper ionophore elesclomol (ES) (hereafter referred to as ES-Cu, representing the combination of ES and Cu 2+ ). Cell viability was assessed using the MTT assay, and morphological changes were observed under a microscope. Cell proliferation and migration abilities were assessed via colony formation and scratch wound healing assays, respectively. Fluorescence staining was used to examine mitochondrial function and ROS levels in cells co-treated with PUN and ES-Cu. Laser confocal microscopy and Western blotting were employed to determine the oligomerization level of DLAT protein by quantifying soluble and insoluble protein expression, along with the expression of ACO2, ETFDH, FDX1, and LIAS proteins. Molecular docking, molecular dynamics simulations, immunofluorescence staining, and transfection techniques were utilized to confirm the critical role of FDX1 in copper-induced cell death following co-treatment with PUN and ES-Cu. We found that PUN could suppress the viability, proliferation, and migration of gastric cancer cells in a concentration- and time-dependent manner. Subsequent in vivo experiments demonstrated that PUN inhibited tumor growth in nude mice at a safe dosage. Besides, transcriptome sequencing and Western blot analysis revealed that PUN induced cell cycle arrest and apoptosis. Secondly, the cell death mechanism triggered by PUN was closely associated with mitochondrial stress. PUN increased intracellular ROS levels and reduced mitochondrial membrane potential. Transcriptome sequencing and proteomic analysis further revealed molecular changes at both the mRNA and protein levels, with differential gene analysis identifying potential targets and pathways. Moreover, when PUN was combined with ES-Cu, cell viability, proliferation, and migration were all suppressed, while exacerbating mitochondrial dysfunction and elevated oxidative stress. Laser confocal microscopy and Western blotting were used to assess the expression of soluble and insoluble proteins, confirming the oligomerization of the DLAT protein. Western blot also showed that PUN could regulate the expression levels of ACO2, ETFDH, FDX1, and LIAS proteins. Molecular docking, molecular dynamics simulations, and siRNA transfection were performed to confirm the critical role of ferredoxin 1 (FDX1) in copper-induced cell death. Furthermore, when used in combination with chemotherapy drugs, PUN exhibited synergistic inhibitory effects on gastric cancer growth. PUN demonstrates significant antitumor activity both in vivo and in vitro by inducing mitochondrial dysfunction, which subsequently triggers apoptosis. In combination therapy strategies, PUN can work synergistically with chemotherapy drugs to suppress gastric cancer growth. Furthermore, PUN enhances its inhibitory effect on gastric cancer by working synergistically with cuproptosis through targeting FDX1.
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高影响因子
Materials Today Bio
·
2026
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IF 11
Xinyu Gu,Shen Shen,Yuting He,Chen Xue,Minghang Zhang,Yitao Fan,Ziyi Xu,Lifan Zhang,Yingda Xie,Ziming Wang,Li Li,Juan Lu,Qingmiao Shi
Cancer immunotherapy has revolutionized the landscape of cancer treatment, particularly through the development of immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis. However, the therapeutic efficacy of these interventions is frequently hindered by the immunosuppressive tumor microenvironment (TME), which is characterized by hypoxia, poor immune cell infiltration, and impaired antigen presentation. To overcome these barriers, MP-GCZ has been developed as a self-oxygenating biomimetic nanomotor to synergistically reprogram the TME and enhance antitumor immune responses through integrated multimodal mechanisms. This nanosystem combines photothermal therapy (PTT), cuproptosis-induced immunogenic cell death (ICD), and localized immune checkpoint modulation to address the complex immunosuppressive network of the TME. By leveraging a metal-organic framework scaffold, MP-GCZ enables controlled delivery of therapeutic components that alleviate hypoxia, trigger immunogenic tumor cell death, and enhance adaptive immune responses. When activated by near-infrared irradiation, MP-GCZ enhances dendritic cell maturation, increases infiltration of cytotoxic T lymphocytes, thereby transforming immunologically "cold" tumors into inflamed, immunogenic environments. Preclinical studies demonstrate that this strategy effectively suppresses both primary tumor growth and distant metastases, driven by systemic antitumor immunity. MP-GCZ represents a promising comprehensive approach to overcoming TME-mediated resistance and may offer a valuable solution to enhance the clinical efficacy of cancer immunotherapy.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Jieqi Chen,Mingxuan Xie,Zhen Yu,Lei Cao,Yue Shen,Xiangping Li,Yueqin Li
Immunotherapy has improved the treatment of non-small cell lung cancer (NSCLC), but its efficacy remains limited by the immunosuppressive tumor microenvironment. Although copper has recently emerged as a potential anticancer target, its role in tumor immunity remains unclear. In this study, we investigated the effects of Cu 2+ on tumor immunity and its impact on PD-L1 blockade therapy. Cu 2+ significantly inhibited NSCLC growth in vitro and in vivo without causing obvious systemic toxicity. Mechanistically, Cu 2+ induced cuproptosis, accompanied by metabolic alterations and cuproptosis-associated molecular changes. Importantly, Cu 2+ treatment triggered immunogenic cell death (ICD), as evidenced by increased calreticulin exposure and enhanced ATP and HMGB1 release. Pharmacological inhibition of cuproptosis attenuated these ICD-associated responses, supporting a mechanistic link between cuproptosis and ICD. In vivo, Cu 2+ treatment promoted dendritic cell maturation, increased CD4 + and CD8 + T-cell infiltration, reduced myeloid-derived suppressor cell accumulation, and facilitated macrophage polarization toward a pro-inflammatory phenotype. Furthermore, Cu 2+ significantly enhanced the antitumor efficacy of PD-L1 blockade. These findings demonstrate that Cu 2+ promotes antitumor immunity through a cuproptosis-associated ICD pathway and improves responsiveness to PD-L1 blockade. Targeting copper homeostasis may represent a potential strategy for enhancing immunotherapy efficacy in NSCLC. Download: Download high-res image (470KB) Download: Download full-size image
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Pengjun Yuan,Yujing Wang,Ao Wang,Jinhui Lin,Xingzhu Chen,Xiyu Liu,Yingrui Zhang,Wenjuan Gao,Peiyuan Wang,Guilong Zhang,Lu Liu
The X-ray-induced photodynamic therapy (X-PDT) has brought significant promise for treating deeply seated cancers in clinical settings. However, the clinical application of X-PDT remains limited, primarily due to the issues related to cancer cells' intrinsic antioxidant mechanisms and radiotherapy's low efficacy. To address these issues, this study presents a nanocatalyst-based radiosensitizer PCuLu, which is meticulously designed and constructed to enhance the effectiveness of X-PDT combined with copper-induced cell death (Cuproptosis) for tumor treatment. Leveraging the unique properties of the rare-earth element lutetium, PCuLu effectively absorbs X-rays and deposits the radiation energy, causing irreversible damage to the deoxyribonucleic acid (DNA) of cancer cells. The PCuLu nanocatalyst also promotes enhanced cuproptosis, further amplifying the therapeutic effects of X-PDT. Our findings reveal the beneficial role of enhancing copper toxicity in radiotherapy (RT), offering a new strategy for the synergistic integration of cuproptosis with radiation therapy. This work broadens the scope of copper-mediated cancer treatment. It provides a promising approach to overcoming the current limitations in X-PDT, potentially leading to more effective clinical outcomes in tumor treatment.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Tao Bai,Luhao Wang,Zhentao Qiao,Zhiwei Wang
Diabetic patients are considered as the high risk population to develop critical limb ischemia (CLI), a peripheral vascular disease (PVD) resulted from atherosclerosis. Cuproptosis is a novel copper-dependent cell death that has shown the regulatory role in diabetes, while its effect on diabetic CLI has not been explored yet. In this study, Diabetic CLI mice was induced by femoral artery ligation (FAL) on diabetic mice. Endothelial injury in diabetic CLI was mimicked in human microvascular endothelial cells (HMEC-1) via the induction with high glucose (HG) and nutrient deprivation (ND). Besides, copper chelator Ammonium Tetrathiomolybdate (TM), which has shown the anti-cuproptosis property, was administrated to explore its potential effects on diabetic CLI mice and HG/ND-induced HMEC-1 cells. Strikingly, obvious cuproptosis was found in the gastrocnemius muscles of diabetic CLI mice and HG/ND-induced HMEC-1 cells, as evidenced by the copper overload and dysregulated cuproptosis-related proteins (such as Fe-S cluster proteins, copper exporter ATP7A, and copper importer SLC31A1). More importantly, TM protected against the hindlimb ischemic damages in diabetic CLI mice and alleviated cuproptosis-associated cell deaths in HG/ND-induced HMEC-1 cells. In summary, this study indicates the involvements of cuproptosis in diabetic CLI, and provides novel insights into copper chelator TM on diabetic CLI therapy.
研究领域:
医学
·
分子生物学
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高影响因子
Journal of Inflammation Research
·
2025
·
IF 4.1
Qiaohui Ren,Xinyue Zhu,Nannan Wang,Kang Yu,Wei Lv,Lianzi Wang,Yan Zang,Dongyue Ma,Xinyi Zhou,Junxiao Yao,Mengjiao Shen,Li Yu,Tao Li
Purpose We explored the effects of miR-133a-5p and ATP7B on cuproptosis in hepatocellular carcinoma.Methods Initially, we assessed the impact of miR-133a-5p on hepatocellular carcinoma (HCC) using CCK-8 assays, cell scratch assays, and flow cytometry. Subsequently, we utilized elesclomol in combination with copper ions to induce cuproptosis in the HCC cell lines PLC/PRF/5 and Huh-7. We evaluated the influence of miR-133a-5p on cuproptosis using CCK-8 assays, cell scratch assays, flow cytometry, and Western blotting. To elucidate the underlying mechanisms, we employed bioinformatics to identify potential downstream target genes of miR-133a-5p and conducted dual-luciferase reporter assays to confirm the binding sites. Finally, we validated the regulatory effect of miR-133a-5p on ATP7B by modulating miR-133a-5p expression through cell transfection experiments.Results The results from the CCK-8 assay, cell scratch assay, and flow cytometry demonstrated that miR-133a-5p significantly inhibits the proliferation and migration of HCC cells while promoting their apoptosis. Furthermore, Elesclomol in combination with copper ions induces cuproptosis in HCC cells. Compared to the cuproptosis observed in HCC as a control, miR-133a-5p further suppresses the proliferation and migration of HCC cells, enhances their death, and increases the expression of cuproptosis-related proteins more prominently. Bioinformatics analysis suggested that ATP7B might be a downstream target gene of miR-133a-5p. This was confirmed by dual luciferase assays, which identified a binding site between miR-133a-5p and ATP7B. Additionally, the expression levels of ATP7B were found to decrease or increase in response to the regulation by miR-133a-5p.Conclusion MiR-133a-5p facilitates cuproptosis in hepatocellular carcinoma through targeting of ATP7B.
研究领域:
肿瘤学
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分子生物学
·
遗传学
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高影响因子
PHARMACOLOGICAL RESEARCH
·
2025
·
IF 10.5
Binghui Kong,Xuehui Zheng,Yang Hu,Yuan Zhao,Jinghan Hai,Yun Ti,Peili Bu
Pathological myocardial remodelling is the initiation of pressure overload-induced heart failure, and its involvement in the associated molecular mechanisms remains to be fully elucidated. The aim of this study was to investigate whether Sirtuin3 (SIRT3) can affect pathological myocardial remodeling by regulating cellular cuproptosis and its potential mechanisms. In this study, we found that pressure overload induced pathologic myocardial remodeling in which cardiomyocytes showed a distinct cuproptosis signature accompanied by downregulation of SIRT3 expression. In vitro experiments demonstrated that copper ions reduced SIRT3 expression by 40% (p<0.01) via lysosomal degradation. In vivo validation showed that pressure overload reduced SIRT3 expression by 35% (p<0.01) in myocardial tissue. And SIRT3 knockdown increased pressure overload-induced pathological myocardial remodeling and cardiomyocyte apoptosis. In contrast, cardiomyocytes-specific overexpression of SIRT3 by adeno-associated virus vectors attenuated pressure overload-induced pathologic myocardial remodeling and was unaffected by circulating levels of copper ions and hepatic and renal impairment. Mechanistically, the reduction of SIRT3 induced cardiomyocytes to become copper ion-sensitive state cells by affecting the binding of copper ion transporter proteins to microtubule-associated protein 1a/1b-Light chain 3 (LC3) in cardiomyocytes. Disturbance of copper ion homeostasis in cardiomyocytes leads to accumulation of copper ions in cardiomyocytes and the development of cuproptosis. These findings elucidate a novel mechanism by which SIRT3 affects cardiomyocyte death in pressure overload-induced pathologic myocardial remodeling and suggest the great potential of SIRT3-regulated cuproptosis of cardiomyocytes in the prevention or treatment of pathologic myocardial remodeling.
研究领域:
心血管病学
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分子生物学
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病理生理学
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高影响因子
Nanoscale Horizons
·
2025
·
IF 6.6
Xiao Wan Han,Xu Chen,Tianle Yang,Ying Yi Luo,Rui Xue Liang,San Qi An,Xinli Liu
Cuproptosis has recently received much attention in cancer treatment. However, copper ionophores don’t show the obvious clinical efficacy. Although some Cu-based and copper ionophores-loaded nanomaterials have been applied to induce cuproptosis, it is difficult to achieve the clinical translation limited by the complicated composition, harsh synthesis condition, external stimulus, and potential biotoxicity. Phytic acid, a naturally occurring organic phosphorus carbohydrate, possesses distinct antineoplastic effect on multiply types of cancer and high biocompatibility. Based on metal-phosphonate coordination, a novel Cu-phytic acid nanozyme (denoted as CP) with pH/GSH dual-response was fabricated by a “one-spot” method. CP with three enzyme-mimicking activities enhanced cuproptosis therapy through GSH depletion, reactive oxygen species augment, hypoxia relief and the attenuation of glycolysis. As a proof of concept, Elesclomol (a copper ionophore)-resistant A549 cells were used to investigate CP- induced cuproptosis for inhibition of tumor growth in vitro and in vivo.
研究领域:
生物医学
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纳米技术
·
肿瘤学
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高影响因子
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