International Journal of Nanomedicine
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2026
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IF 6.5
Deyi Yang,Lin Tao,Qi Li,Shipeng Ning,Yanni Song
Introduction Cuproptosis, a novel form of cell death tied to copper homeostasis and protein lipoylation, holds significant promise for breast cancer treatment. However, its efficacy is severely hindered by the tumor microenvironment (TME) heterogeneity, such as hypoxia and elevated glutathione (GSH) levels.Methods Herein, we synthesized CuNI nanoparticles via a facile hydrothermal method, which could serve as both a copper carrier and a photothermal agent, to enhance the accumulation of copper in tumor site. Following intravenous injection, CuNI accumulated and persisted in tumors via the enhanced permeability and retention effect (EPR) effect. Subsequent gradient 808 nm laser irradiation and radiotherapy (RT) were administered, CuNI could convert light energy to heat energy, which could alleviate hypoxia TME, while RT further depleted GSH and synergistically generates reactive oxygen species (ROS) with CuNI, synergistically amplifying CuNi-mediated cuproptosis.Results This co-treatment triggered immunogenic cell death (ICD), activating dendritic cells and T-cell responses to reverse the “cold” immune microenvironment. In vivo studies demonstrated complete tumor suppression with no overt toxicity.Conclusion The CuNI + NIR + RT strategy, leveraging “cuproptosis/ICD synergy”, offers a novel paradigm for the clinical translation of cuproptosis in breast cancer.
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高影响因子
Acta Pharmaceutica Sinica B
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2026
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IF 14.6
Zitao Fan,Shiyou Li,Chen Xiao,Qiang wang,Zhijie Zhang,Ao hua,Qingqing Xu,Tian Yang,Jiayuan Li,Yue Pan,Baizhu Chen,Xiangliang Yang,Zhenwei Zou,Zifu Li
The metabolic plasticity of cancer stem cells (CSCs) enables them to adaptively switch between glycolysis, oxidative phosphorylation, and alternative fuels such as glutamine and fatty acids, promoting tumorigenesis and progression by ensuring survival under diverse environmental stresses. However, current therapeutic approaches targeting CSCs remain limited, particularly those relying on single metabolic interventions. By leveraging concurrent metabolic modulation and redox disruption to sensitize CSCs to cuproptosis, we prepared a polydopamine/hydroxyethyl starch-based nanoplatform (CH@PHF) for co-delivering copper-diethyldithiocarbamate (CuET) and HYL001. Specifically, HYL001 suppresses glutaminase (GLS) activity, thereby blocking glutamine metabolism and inhibiting glutathione (GSH) biosynthesis. This effect synergizes with CuET to collectively amplify oxidative stress in CSCs. Furthermore, the combination of HYL001 and CuET significantly elevates intracellular copper levels, particularly the cuprous form (Cu + ), thereby sensitizing CSCs to cuproptosis. This combined treatment effectively inhibits tumor growth and metastasis by targeting and eradicating breast cancer stem cells (BCSCs), offering a promising avenue for tumor therapy.
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高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2025
·Vol. 29
·期 11
·e70636
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IF 4.2
Hao Zhang,Guoyan Liu
Gastric cancer is a common malignant tumour. Copper‐induced cell death, a recently discovered form of metal ion‐related cell death, has garnered significant attention from researchers. We synthesised a multifunctional nanoparticle, ZnO@CuEA, and characterised its morphology using transmission electron microscopy. Cytotoxicity was analysed via CCK8 assays and calcein‐AM staining. The tumour‐targeting capability of ZnO@CuEA was validated using confocal microscopy and in vivo imaging experiments. RNA‐seq and proteomic analysis were conducted to assess changes in mRNA and protein expression before and after ZnO@CuEA treatment. Lysosomal β‐galactosidase staining was employed for cellular senescence detection, and protein expression levels were analysed via Western blot. Finally, in vivo experiments demonstrated the tumour‐inhibitory effect of ZnO@CuEA. ZnO@CuEA is a multifunctional nanoparticle capable of targeting tumour cells and inducing cuproptosis. In vivo experiments showed that ZnO@CuEA exhibits significant antitumor activity. The multifunctional nanoparticles synthesised in this study provide a novel therapeutic approach for cancer treatment.
研究领域:
肿瘤学
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分子生物学
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材料科学
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PubMed
高影响因子
ACS Nano
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2025
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IF 16
Tiaoyan Jiang,Tianying Jia,Yipengchen Yin,Tianyu Li,Xinran Song,Wei Feng,Sheng Wang,Li Ding,Yu Chen,Qin Zhang
Radiotherapy is crucial in local cancer management and needs advancements. Tumor cells elevate intracellular copper levels to promote growth and resist radiation; thus, targeted copper delivery to mitochondria could enhance radiotherapy by inducing cuproptosis in tumor cells. In this study, we engineered a multifunctional nanoliposome complex, termed Lipo-Ele@CuO2, which encapsulates both copper peroxide (CuO2) and the copper chelator elesclomol, which can delivery Cu ions to the mitochondria. The Lipo-Ele@CuO2 complex induces mitochondria-mediated cuproptosis in tumor cells and synergistically enhances the efficacy of radiotherapy. CuO2 acts as a copper donor and exhibits inherent sensitivity to acidic environments. Additionally, it depletes intracellular glutathione, thereby sensitizing cells to cuproptosis. Leveraging its pH-responsive properties in the acidic tumor microenvironment, the Lipo-Ele@CuO2 facilitate the controlled release of elesclomol, efficiently delivering copper ions to mitochondria at tumor sites. The combined in vitro and in vivo studies demonstrate that Lipo-Ele@CuO2-based therapy significantly improves antitumor efficacy and exhibits excellent safety profiles, effectively inducing cuproptosis in tumor cells and boosting the effectiveness of radiotherapy. Furthermore, metabolomic and transcriptomic analyses reveal that this combination therapy precipitates significant alterations in tumor energy metabolism, notably repressing genes related to iron–sulfur cluster assembly and glycolysis, thereby confirming the induction of cuproptosis. This therapeutic strategy provides a viable approach for addressing clinical radiotherapy resistance and demonstrates significant translational potential.
研究领域:
肿瘤学
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纳米医学
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辐射生物学
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代谢组学
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转化医学
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高影响因子
Advanced Healthcare Materials
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2024
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IF 10
Jinpeng Deng,Huilan Zhuang,Sijie Shao,Xuemei Zeng,Panpan Xue,Tingjie Bai,Xiaoman Wang,Shijie Shangguan,Yuanchun Chen,Shuangqian Yan,Wei Huang
Cuproptosis is dependent on mitochondrial respiration modulation by targeting lipoylated tricarboxylic acid cycle (TCA) cycle proteins, showing great potential in cancer treatment. However, the specific release of copper ions at mitochondrial is highly needed and still a major challenge to trigger cellular cuproptosis. Herein, a metal-organic framework-based nanoplatform (ZCProP) is designed for mitochondrial-targeted and ATP/pH-responsive Cu 2+ and prodigiosin release. The released Cu 2+ promotes aggregation of lipoylated protein and loss of Fe-S cluster protein, resulting in cell cuproptosis. In the meanwhile, Cu 2+ can concert with prodigiosin to induce mitochondrial dysfunction and DNA damage and enhance cell cuproptosis. Furthermore, this nanoplatform has an ability to deplete glutathione, which not only further promotes cuproptosis but also triggers cell ferroptosis by the suppression of glutathione peroxidase 4, an anti-ferroptosis protein. Collectively, the designed ZCProP nanoplatform can responsively release cargos at mitochondrial and realize a conspicuous therapeutic efficacy through a cuproptosis-mediated concerted effect. Along with its excellent biocompatibility, this nanoplatform may provide a novel therapeutic modality paradigm to boost cancer therapeutic strategies based on cuproptosis.
研究领域:
癌症治疗
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纳米技术
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生物化学
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药理学
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PubMed
高影响因子
ACS Applied Nano Materials
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2026
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IF 5.8
Yibo Song,Yixin Li,Shihao Zheng,Shu-Feng Zhou,Guowu Zhan
Copper-based nanomaterials hold immense potential for cancer therapy by inducing chemodynamic therapy and cuproptosis. However, their therapeutic efficacy is severely restricted by insufficient tumor accumulation, the potent antioxidant effects of elevated intracellular glutathione (GSH), and tumor adaptability to single-mechanism treatments. To address these challenges, we designed a pH/GSH dual-responsive nanosystem (CuSiO3@POM) by integrating molybdenum-based polyoxometalate (POM) clusters with a copper phyllosilicate platform. In the acidic tumor microenvironment (TME), POM drives in situ self-assembly into large aggregates, significantly enhancing tumor retention and local copper concentration. Upon cellular internalization, the elevated copper accumulation triggers cuproptosis; meanwhile, the overexpressed endogenous GSH reduces Cu2+ and Mo6+ to Cu+ and Mo5+, resulting in profound GSH depletion. Following this reduction, Cu+ catalyzes Fenton-like reactions to yield hydroxyl radicals (·OH), while Mo5+ generates singlet oxygen (1O2) via the Russell mechanism. This synergistic burst of reactive oxygen species triggers severe lipid peroxidation and subsequent ferroptosis. Furthermore, the reduced Mo5+ serves as an efficient agent for photothermal therapy (PTT) under NIR irradiation, which thermally amplifies the oxidative damage. By orchestrating cuproptosis, ferroptosis, and photothermal enhancement within a single TME-responsive platform, CuSiO3@POM provides a highly efficient multimodal strategy to overcome the limitations of conventional copper-based therapies.
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高影响因子
JOURNAL OF CONTROLLED RELEASE
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2026
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IF 12.4
Jinli Pang,Jiaojiao Tao,Lianxiao Zhang,Ying Lu,Jianhui Yang,Mengya Wang,Tianze Jiang,Xia Zhao
An oxygen-pump microneedle system is developed for deep drug penetration and hypoxia alleviation. • Synergistic cuproptosis and disulfidptosis are achieved via a MIRV-inspired strategy. • GOx-mediated GSH depletion sensitizes cuproptosis and triggers disulfidptosis. • The system triggers robust antitumor immunity and inhibits melanoma growth and lung metastasis. Cuproptosis and disulfidptosis are new types of programmed cell death with great potential for tumor immunotherapy, but their efficacy is severely restricted by the hypoxic microenvironment and metabolic reprogramming of tumors. Herein, we develop an oxygen-pump microneedle system (CPGH@OMN) co -loading glucose oxidase (GOx) and copper-polyphenol nanoparticles (CP), using sodium percarbonate (SPC) as an in situ oxygen generator and hyaluronic acid (HA) as a tumor-targeting carrier. SPC-mediated oxygen generation acts as a booster to promote deep drug penetration, and downregulates hypoxia-inducible factor-1α (HIF-1α) to alleviate tumor hypoxia. GOx depletes glucose and nicotinamide adenine dinucleotide phosphate (NADPH) to trigger disulfidptosis, which consumes glutathione (GSH) to sensitize cuproptosis. Copper ions from CPGH (CP-GOx-HA) induce robust cuproptosis under the favorable conditions of downregulated HIF-1α and GSH. The suppression of metabolic reprogramming in tumor cells by alleviating hypoxia and depleting NADPH and GSH significantly enhances anti-tumor immune responses. Animal experiment results demonstrate that CPGH@OMN significantly inhibits orthotopic tumor growth and lung metastasis. This oxygen-pump microneedle strategy integrating physical penetration enhancement and metabolic reprogramming provides a novel approach for melanoma immunotherapy. An oxygen-pump microneedle system (CPGH@OMN) inspired by the multiple independently targetable reentry vehicle (MIRV) strategy is developed to improve melanoma immunotherapy. In situ oxygen generation acts as a “booster” to boost deep drug penetration and relieve tumor hypoxia, while glucose oxidase and copper ions acts as “sub-warhead” to promote disulfidptosis and cuproptosis. CPGH@OMN effectively inhibits orthotopic melanoma growth and lung metastasis by enhancing immunogenic cell death. Download: Download high-res image (146KB) Download: Download full-size image
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PubMed
高影响因子
Acta Biomaterialia
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2025
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IF 9.6
Qinglin Wei,Xuejiao Song,Xiaorui Wang,Yawen Chen,Wenjun Wang,Ping Sun,Xiaochen Dong
Based on their distinctive manners of driving cell death, cuproptosis and pyroptosis exhibit significant potential in overcoming the apoptosis resistance of cancer cells. Nevertheless, limited copper concentrations and complex tumor microenvironment (TME) severely constrain the therapeutic efficacy. Herein, DSPE-PEG 2000 modified copper-nitrogen-doped carbon-based photocatalysts (Cu-NC@PEG) are developed as photo-activated reactive oxygen species (ROS) amplification systems to trigger pyroptosis and cuproptosis in a synergistic manner. Cu-NC@PEG enriches in tumor cells and generates a large amount of superoxide anions under the second near-infrared region (NIR-II) laser irradiation, followed by further induction of cell pyroptosis through caspase-mediated cleavage of Gasdermin D (GSDMD). The copper ions released from Cu-NC@PEG in the acidic TME can not only generate ·OH and consume the antioxidants to enhance ROS-induced pyroptosis, but also effectively activate cuproptosis through Cu + -mediated dihydrolipoamide S-acetyltransferase aggregation and Fe-S cluster protein loss. Simultaneously, the mitochondrial damage induced by pyroptosis leads to a considerable efflux of ATP and the restricted ATP availability could enhance the disruption of copper metabolic homeostasis, thereby potentiating cuproptosis. The increased tumor-inhibiting effects of the combined induction of cuproptosis and pyroptosis could be achieved. Statement of significance 1. NIR-II photo-activated copper-nitrogen-doped carbon-based photocatalysts (Cu-NC@PEG) were developed. 2. ROS amplification was achieved based on the photo catalytic properties and Fenton-like reaction of Cu-NC@PEG. 3. Therapeutic efficacy was enhanced via ROS-induced pyroptosis and Cu + -mediated cuproptosis.
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高影响因子
Matter
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2025
·
IF 17.5
Wenting Chen,Songjing Zhong,Qian Cai,Zhuoheng Jiang,Quanhong Hu,Chuyu Tang,Qinyu Zhao,Zhuo Wang,Shaobo Wang,Xinyu Zheng,Fei Liang,Hai-Dong Yu,Linlin Li
Cutaneous melanoma, a prevalent and highly aggressive malignancy with poor prognosis, frequently leads to postoperative recurrence, presenting a significant therapeutic challenge. One of the promising cancer therapeutic methods is the induction of cuproptosis, a copper-triggered modality of mitochondrial cell death. However, its therapeutic efficacy is often limited by insufficient copper uptake and intracellular accumulation. Herein, we present a flexible and self-powered electronic patch by integrating an ultra-thin triboelectric nanogenerator (TENG) with copper-loaded nitrogen-doped carbon nanoparticles (Cu(II)-NC NPs). Extensive experimental and molecular dynamics simulation results demonstrate that the triboelectric field efficiently modulates plasma membrane permeability and fluidity, facilitating the uptake of Cu(II)-NC NPs into melanoma cells. The resulting intracellular copper accumulation increases the production of hydroxyl radicals and the depletion of glutathione, synergizing with cuproptosis to amplify copper-induced cell death. In a mouse model with incomplete melanoma resection, the patch effectively inhibits melanoma recurrence, offering a novel therapeutic paradigm to promote cancer therapy.
研究领域:
肿瘤学
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生物医学工程
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材料科学
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高影响因子
Acta Pharmaceutica Sinica B
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2024
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IF 14.7
Xiaoyu Wu,Zijun Bai,Hui Wang,Hanqing Wang,Dahai Hou,Yunzhu Xu,Guanqun Wo,Haibo Cheng,Dongdong Sun,Weiwei Tao
Copper-based nanomaterials demonstrate promising potential in cancer therapy. Cu + efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione, initiating chemical dynamic therapy (CDT) and ferroptosis. Cuproptosis, a newly identified cell death modality that represents a great prospect in cancer therapy, is activated. However, active homeostatic systems rigorously keep copper levels within cells exceptionally low, which hinders the application of cooper nanomaterials-based therapy. Herein, a novel strategy of CRISPR-Cas9 RNP nanocarrier to deliver cuprous ions and suppress the expression of copper transporter protein ATP7A for maintaining a high level of copper in cytoplasmic fluid is developed. The Cu 2 O and organosilica shell would degrade under the high level of glutathione and weak acidic environment, further releasing RNP and Cu + . The liberated Cu + triggered a Fenton-like reaction for CDT and partially transformed to Cu 2+ , consuming intracellular GSH and initiating cuproptosis and ferroptosis efficiently. Meanwhile, the release of RNP effectively reduced the expression of copper transporter ATP7A, subsequently increasing the accumulation of cooper and enhancing the efficacy of CDT, cuproptosis, and ferroptosis. Such tumor microenvironment responsive multimodal nanoplatform opens an ingenious avenue for colorectal cancer therapy based on gene editing enhanced synergistic cuproptosis/CDT/ferroptosis.
研究领域:
生物技术
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纳米技术
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肿瘤学
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基因编辑
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PubMed
高影响因子
Advanced Science
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2024
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IF 14.3
Xufeng Lu,Xiaodong Chen,Chengyin Lin,Yongdong Yi,Shengsheng Zhao,Bingzi Zhu,Wenhai Deng,Xiang Wang,Zuoliang Xie,Shangrui Rao,Zhonglin Ni,Tao You,Liyi Li,Yingpeng Huang,Xiangyang Xue,Yaojun Yu,Weijian Sun,Xian Shen
The induction of cuproptosis, a recently identified form of copper-dependent immunogenic cell death, is a promising approach for antitumor therapy. However, sufficient accumulation of intracellular copper ions (Cu 2+ ) in tumor cells is essential for inducing cuproptosis. Herein, an intelligent cuproptosis-inducing nanosystem is constructed by encapsulating copper oxide (CuO) nanoparticles with the copper ionophore elesclomol (ES). After uptake by tumor cells, ES@CuO is degraded to release Cu 2+ and ES to synergistically trigger cuproptosis, thereby significantly inhibiting the tumor growth of murine B16 melanoma cells. Moreover, ES@CuO further promoted cuproptosis-mediated immune responses and reprogrammed the immunosuppressive tumor microenvironment by increasing the number of tumor-infiltrating lymphocytes and secreted inflammatory cytokines. Additionally, combining ES@CuO with programmed cell death-1 (PD-1) immunotherapy substantially increased the antitumor efficacy in murine melanoma. Overall, the findings of this study can lead to the use of a novel strategy for cuproptosis-mediated antitumor therapy, which may enhance the efficacy of immune checkpoint inhibitor therapy.
研究领域:
肿瘤学
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纳米技术
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免疫疗法
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细胞生物学
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PubMed
高影响因子
Science Advances
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2025
·Vol. 11
·期 7
·
IF 12.5
Meixiang Zhang,Xinran Song,Yu Qin,Yuanyuan Peng,Shanshan Zhang,Wei Feng,Hui Huang,Yu Chen,Jianqiao Zhou
Cuproptosis, a distinct cell death pathway, has been integrated into nanomedicine for disease theranostics. However, current nanosystems inducing cuproptosis rely on exogenous toxic copper ions, limiting the scope of biomaterials. Developing nanoplatforms that induce cuproptosis without exogenous copper holds substantial promise. Here, we engineered a two-dimensional iron (Fe) single-atom–doped molybdenum disulfide (MoS2) piezocatalyst (Fe-MoS2) for tumor therapy. Incorporating single Fe atoms enhances MoS2 piezoelectric polarization via charge redistribution and modulates Fe and Mo oxidation states, enabling multifaceted enzymatic activities, including peroxidase-, glutathione oxidase–, oxidase-, and catalase-like activities. Upon ultrasound stimulation, the Fe-MoS2 nanocatalyst generates reactive oxygen species and depletes glutathione via synergistic piezocatalytic and enzyocatalytic effects, disrupting copper ion homeostasis and inducing cuproptosis, concurrently triggering ferroptosis and ferritinophagy, which collectively enhances tumor suppression. This study represents the first paradigm to introduce a copper-free piezocatalyst for initiating cuproptosis, substantially advancing the applications of cuproptosis in tumor therapy.
研究领域:
纳米医学
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生物材料科学
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肿瘤学
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PubMed
高影响因子
危险品化学品经营许可证（带存储）