Advanced Science
·
2025
·
IF 14.1
Shuaishuai Xing,Yanbing Lin,Yi Sun,Xiaoping Yue,Qigang Fan,Jisheng Nie,Zhihong Zhang,Yajing Liu,Juntang Yang,Qingzheng Kang,Yanxin Wang,Haijun Yan,Chan Tian,Ying Chang,Huidong Zhang
Lithium (Li) batteries have been used worldwide, but few are recycled, thus, the waste Li has been widely spread into the environment and finally accumulated in human body. Cuproptosis is a newly reported Cu-dependent and programmed cell death form. The unclear pathogenesis of unexplained miscarriage (UM) largely restricts its clinical treatment and global human reproduction. In this study, a UM case-control study shows that Li levels in serum or villous tissues, the levels of cuproptosis in villous tissue, and UM are positively associated. Li-exposed mouse models further confirm that Li exposure causes placental cuproptosis to induce miscarriage. Mechanistically, Li exposure up-regulates FOXO1 expression levels and thus promotes FOXO1-mediated STEAP4 transcription, up-regulating STEAP4 levels. STEAP4 up-regulates intracellular Cu + ion levels and causes cuproptosis, which further induces miscarriage. The cellular mechanisms are consistent with those in UM villous tissues and Li-exposed mouse placental tissues. Finally, treatment with TTM to suppress cuproptosis or the therapeutic down-regulation of FOXO1 or STEAP4 could efficiently suppress placental cuproptosis and alleviate mouse miscarriage in the Li-exposed mouse models. Collectively, this study not only discovers new healthy risks of Li exposure and novel pathogenesis of Li-induced unexplained miscarriage but also reveals new biological targets for treatment against miscarriage.
研究领域:
生殖医学
·
毒理学
·
细胞生物学
·
环境卫生
·
分子生物学
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DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Hangyi Wu,Xiaoyu Lu,Yuhan Hu,J. Baatarbolat,Zhihao Zhang,Yiping Liang,Youwen Zhang,Ye Liu,Huixia Lv,Xin Jin
Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and disrupt intracellular Cu homeostasis. Extra intracellular Cu induces cuproptosis and chemodynamic therapy (CDT), which further cascades immunogenic cell death (ICD) and activates antitumor immune responses. However, the tumor immunosuppressive microenvironment (TIM) attenuates the efficiency of the immune response. Herein, a biomimic nanodrug (ECNM) is fabricated, of which ES, Cu 2+ and NLG919 (an IDO1 inhibitor) are integrated via a self-assembly process and subsequently coated with 4T1 cell membrane. ECNM can overcome the typical drawbacks of ES, ameliorating the stability and half-life of ES by membrane-coating and enhancing its tumor accumulation and internalization via homotypic targeting. It is worth mentioning that, the addition of NLG919 is also beneficial to the system circulation stability of ES and reduces the non-specific ES release. After internalization, ECNM dissociates via the glutathione-responsive process and exhibits comprehensive antitumor capabilities, including cuproptosis, CDT and TIM reversing, thereby eliciting ICD and optimizing the antitumor immune response. Furthermore, ECNM not only accelerates tumor regression but also gains a strong abscopal effect and displays the potential of tumor vaccination. Overall, ECNM can activate antitumor immunity via cuproptosis and CDT, together with TIM reversing, for cancer treatment.
研究领域:
肿瘤学
·
纳米医学
·
免疫治疗
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DOI
高影响因子
BIOMACROMOLECULES
·
2025
·
IF 5.4
Fangrong Tan,Yuandong Zeng,Donghua Dong,Yan Deng,Zhe Tang,LinGe Wang,Qianqian Yu
Cuproptosis offers a promising alternative to apoptosis-based cancer therapies but faces challenges, such as poor tumor drug accumulation, rapid clearance of copper ionophores, and high intracellular glutathione (GSH). Herein, we developed a GSH-responsive prodrug polymersome (PED@ICG) for copper-independent cuproptosis and synergistic photothermal therapy. Diethyldithiocarbamate (DTC) was covalently attached via disulfide bonds, ensuring a GSH-triggered release and intracellular GSH depletion. The amphiphilic polyprodrug formed stable polymersomes, and ICG coloading endowed imaging ability and NIR-activated photothermal heating. PED@ICG exhibited efficient cellular uptake through dynamin-mediated endocytosis, achieved deep tumor penetration, and selectively released DTC within the reductive tumor microenvironment. In vitro and in vivo studies demonstrated potent anticancer efficacy without the need for exogenous copper, while NIR irradiation further enhanced therapeutic outcomes through localized hyperthermia. This work offers a promising strategy for precise cuproptosis modulation and photothermal synergism, providing a clinically translatable nanoplatform for copper-independent tumor therapy.
研究领域:
纳米医学
·
癌症治疗
·
药物递送
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光热治疗
·
细胞死亡机制
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产品关联
DOI
PubMed
高影响因子
Small
·
2025
·
IF 12.1
Luoyingzi Xie,Jie Gong,Zhiqiang He,Weinan Zhang,Haoyu Wang,Shitao Wu,Xianxing Wang,Pijiang Sun,Lei Cai,Zhongjun Wu,Huaizhi Wang
Cancer is one of the most important challenges worldwide with an increasing incidence. However, most of patients with malignant cancer receiving traditional therapies have tumor recurrence and short-term 5-year survival. Herein, a novel Cu 2 O-MnO@PEG (CMP) nanomaterial is developed to treat tumors. CMP directly mediates cuproptosis in tumor cells. Meanwhile, CMP potentiates anti-tumor immune responses in the tumor microenvironment (TME) to induce tumor regression. CMP improves the tumor antigen processing and presentation of dendritic cells and tumor-associated macrophages, and further promotes CD8 + T cell responses, especially for cytotoxic CD8 + T cells and transitory exhausted CD8 + T cells. Additionally, CMP downregulates the proportion of Treg cells and CTLA-4 expression on Treg cells. Notably, CMP induces systemic immune responses against distant tumors and long-term immune memory. Furthermore, CMP synergized with PD-L1 mAb promotes tumor inhibition and sustains the anti-tumor efficacy post PD-L1 mAb treatment. Collectively, this strategy has the clinically therapeutic potential for tumors by facilitating cuproptosis in tumor cells and anti-tumor immune responses.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
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产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2022
·Vol. 10
·期 33
·6296-6306
·
IF 7.571
Yao Lu,Qingqing Pan,Wenxia Gao,Yuji Pu,Bin He
Platinum-based chemotherapy is widely used to treat various cancers. However, exogenous platinum is likely to cause severe side effects and drug resistance induced by upregulated glutathione (GSH) in cancer cells poses a threat to the management of cancer progression and recurrence. Anticancer copper–organic complexes are excellent candidates to substitute platinum-based chemotherapeutics, exhibiting lower systemic toxicity and even overcoming platinum-based chemotherapy resistance. Here, we report the GSH-resistance of copper(II) bis(diethyldithiocarbamate) (CuET) and its reversal of cisplatin resistance in non-small-cell lung cancer via cuproptosis. Electrochemistry and UV-vis spectroscopy studies demonstrate that CuET possesses a lower reduction potential and the reaction inertness with GSH. Importantly, CuET overcomes the drug resistance of A549/DDP cells and the anticancer effect is hardly affected by intracellular GSH levels. To improve the solubility and bioavailability, bovine serum albumin-stabilized CuET nanoparticles (NPs) are prepared and they have a high drug loading content of 27.5% and excellent physiological stability. In vitro studies manifest that CuET NPs augment the distributions in the cytosol and cytoskeleton, inducing cell death via cuproptosis in A549/DDP cells, which is distinctly different from the apoptosis pattern induced by cisplatin. In vivo antitumor evaluation shows that the nanomedicine has superior biosafety and potent antitumor activity in a cisplatin-resistant tumor model. Our study suggests that copper–organic complex-based nanosystems could be a powerful toolbox to tackle the platinum-based drug resistance and systemic toxicity concerns.
研究领域:
肿瘤学
·
药理学
·
生物化学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Jingzhe Zhang,Maosen Han,Jing Zhang,Mohnad Abdalla,Peng Sun,Zhenmei Yang,Cai Zhang,Ying Liu,Chen Chen,Xinyi Jiang
Small cell lung cancer (SCLC) is one of the most devastating type of human lung cancer and has a high propensity to metastasize into the brain. Cuproptosis recently has been defined as a copper dependent cell death, offers a new lens to develop the novel copper-based nanostructure inducing cuproptosis for suppressing tumor growth and metastasis. Here, we report a syphilis mimetic TP0751-peptide decorated stem cell membrane-coated copper-based metal organic framework (Cu-MOF) nanodelivery system for SCLC brain metastasis. The Cu-MOF is employed as nanocarrier to support siRNA with high loading efficiency, and its pH sensitivity facilitates endosomal disruption upon cellular uptake. Furthermore, the cell membrane coating Cu-MOF presents a good biocompatibility, high BBB transcytosis, and specific uptake by tumor cells within the brain. In vitro and in vivo trials have shown that TP-M−Cu−MOF/siATP7a exhibited high silencing efficiency against target gene, specifically blocked copper trafficking, increased copper intake, triggered cuproptosis, and improved therapeutic efficacy in SCLC brain metastasis tumor-bearing mice. Overall, the biomimetic nanodelivery platform presented here further offers a promising way of orchestrating gene therapy to target copper-dependent signalling for reprogramming copper metabolism and cuproptosis-based synergistic therapy in mice bearing brain metastases.
研究领域:
肿瘤学
·
纳米技术
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-17
·
IF 14.7
Guan Meng,Cheng Kai,Xie Xiao-Ting,Li Yong,Ma Meng-Wen,Zhang Bin,Chen Si,Chen Wei,Liu Bo,Fan Jin-Xuan,Zhao Yuan-Di
Cuproptosis is an emerging mode of programmed cell death for tumor suppression but sometimes gets resisted by tumor cells resist under specific mechanisms. Inhibiting copper transporter ATPase (ATP7A) was found to disrupt copper ion homeostasis, thereby enhancing the effect of cuproptosis and eventually inhibiting tumor invasion and metastasis. In this study, we develop a multifunctional nanoplatfrom based on Cu 9 S 8 (CAPSH), designed to enhance cuproptosis in tumor cells by specifically targeting ATP7A interference, while combining thermodynamic therapy with immune effects. The release of copper ions from CAPSH and the copper homeostasis interference by siRNA cooperatively increases the concentration of copper ions in tumor cells, which induces effectively cuproptosis and activates immune responses for suppressing development and metastasis of tumor. This nanoplatform simultaneously regulates cuproptosis from both principles of onset and development, facilitating the application of cuproptosis in tumor therapy.
研究领域:
肿瘤学
·
分子生物学
·
纳米技术
·
免疫学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Juan Wang,Junyu Wang,Jun Zhang,Haoran Ye,Dawei Wang,Ling Tao,Yongchao Yao,Ying Chen,Xiangchun Shen
As a notoriously incurable tumor, triple-negative breast cancer (TNBC) exhibits significant sensitivity to ferroptosis and the glutathione (GSH) antioxidant defense system plays a crucial role in its progression. Herein, we report a bimetallic chitosan/hyaluronic acid nanoparticle (5FCN, with a Fe/Cu mass ratio of 5:5) that employs a self-amplified dual mechanism of ferroptosis and cuproptosis for TNBC therapy. Hyaluronic acid in 5FCN specifically binds to the overexpressed CD44 receptor on TNBC cells. This allows 5FCN to enter cells via receptor-mediated endocytosis, then release metal ions in acidic environments. Released Fe 3+ and Cu 2+ react with GSH in tumor cells, weakening the antioxidant system and producing Fe 2+ and Cu + . These ions trigger Fenton/Fenton-like reactions with H 2 O 2 , generating toxic hydroxyl radicals (·OH) to boost ferroptosis. Meanwhile, high-valent Cu 2+ and Fe 3+ are produced, forming a cycle for GSH depletion and ·OH generation. As H 2 O 2 depletes, the rising Cu + level in cells causes lipoylated protein aggregation, amplifying cuproptosis. In vitro and in vivo studies demonstrated that 5FCN exhibited superior cell-killing efficacy against TNBC with few side effects. Collectively, 5FCN represents a potential drug to self-amplify ferroptosis/cuproptosis in TNBC.
研究领域:
肿瘤学
·
纳米医学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Yu-Yi Ling,Qing-Hua Shen,Liang Hao,Zhi-Yuan Li,Long-Bo Yu,Xiao-Xiao Chen,Cai-Ping Tan
Being a recently identified mode of programmed cell demise, the functional implications of cuproptosis in the genesis, progression, and therapeutic modulation of cancer remain largely unknown. Given that cuproptosis is predominantly elicited by cellular copper overload, notably attributable to the dysregulation of copper homeostasis within mitochondria, we designed a series of phosphorescent rhenium(I) complexes (Re1–Re5) as suborganelle-targeted copper ionophores. Among them, Re5 can successfully transport extracellular copper into mitochondria and the Golgi apparatus and especially enrich copper into mitochondria. Consequently, Re5 breaks the cellular redox balance and disturbs the energetic and metabolism pathways to induce cuproptosis. Finally, we prove that Re5 can promote immune responses and modulate cancer immune microenvironments. In all, we present here the first subcellular organelle-targeted copper ionophore and prove that cuproptosis-inducing small molecules are potent cancer immunotherapeutic candidates.
研究领域:
生物化学
·
肿瘤学
·
免疫学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2026
·
IF 5.1
Irfan Mehmud,Lei Peng,Yi Zhang,Rui Liang,Anguo Zhao,Dashi Deng,Fangteng Ma,Shaohua Zhang,Song Wu
Nanomedicine based approaches offer new prospects for cancer treatment by enabling localized delivery, improved tissue retention, and microenvironment response therapeutic activation. Bladder cancer remains challenging due to high recurrence rate and the limited effectiveness of conventional intravesical therapies largely resulting from insufficient tissue penetration and short drug residence time, especially under fluid washouts (urination). This study aims to develop a locally administered nanomedicine platform that exploits the anatomical and biochemical feature of bladder for enhanced therapeutic efficacy. We developed a copper integrated polydopamine based nanomedicine (uDHC) system synthesized in-situ within the bladder cavity via metal-assisted rapid polymerization. The resulting nanomedicine exhibit strong adhesion to bladder mucosa, enabling prolonged retention. Incorporation of urease allows utilization of endogenous urea present in urine generating localized physiochemical gradients that enhance nanomedicine penetration into tumor tissue. The sustained copper release disrupts mitochondrial copper homeostasis and induces cuproptosis by modulating key mitochondrial metabolic regulators. In parallel, the polydopamine matrix enables efficient near-infrared photothermal conversion amplifying tumor cell damage and promoting immunogenic cell death. In-vitro studies demonstrate cytotoxicity towards the bladder cancer cells with minimal effects on normal uroepithelial cells. In an orthotopic bladder cancer mouse model, intravesical administration of this nanomedicine system significantly suppresses tumor growth, particularly when combined with near-infrared irradiation. Overall, this multifunctional nanomedicine platform integrates localized delivery, microenvironment response activation, enhanced tissue penetration, and synergistic cuproptosis and photothermal effects, addressing key limitation of current intravesical therapies and supporting the translational potential of in-situ synthesized nanomedicine for localized bladder cancer treatment.
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Yang Liuxin,Cheng Yiyu,Qin Si,Jiang Jun,Zhong Shiyi,Bi Xinyue,Xu Jiali,Wang Kai,Qiu Shuang,Li Xiang
Cellular resilience to therapy often arises from adaptive
mechanisms
that safeguard iron–sulfur (Fe–S) proteins. Here, we
present a rational strategy to overcome such resilience by integrating
two synergistic vulnerabilities, copper toxicity and Fe–S cluster
homeostasis, into a single molecular scaffold. Inspired by a bacterial
sulfur mobilization (SUF) inhibitor, we hybridized its core structure
with a copper-transporting 8-hydroxyquinoline moiety to generate HDQ , HDQ-S , HDQ-Ph , and HDQ-Me . They coordinate copper via hydroxyquinoline and efficiently transport
copper into cancer cells, with HDQ-Me achieving an efficacy
comparable to that of the clinical copper ionophore elesclomol ( ES ). Strikingly, HDQ alone suppresses Fe–S
proteins across multiple functions, including respiration, iron homeostasis,
and DNA replication. HDQ -mediated copper loading triggers
cuproptosis hallmarks, DNA damage, and ATP collapse, generating a
synergistic lethality. This work establishes HDQs as
bifunctional tools that cotarget copper and Fe–S protein homeostasis,
validating a convergent therapeutic strategy against resilient cells.
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DOI
高影响因子
Small
·
2026
·
IF 11.8
Yunhui Zeng,Junshan Hu,Ruilian Chen,Hongxu Chen,Caili Chen,Jianguo Xu,Qing-Hua Xu,Rangrang Fan
Breast cancer remains a global health challenge with limited therapeutic options for metastatic cases. Cuproptosis, a copper-dependent cell death pathway, offers a novel anticancer strategy that is currently constrained by the poor solubility of copper complexes and lack of tumor selectivity. To overcome this limitation, a biomimetic nanoplatform was developed by co-encapsulating copper diethyldithiocarbamate (CuET) and a photothermal agent into epigallocatechin gallate-assisted nanoparticles, which was followed by coating with a hybrid cell membrane from cancer cells and programmed cell death protein 1 (PD-1)-overexpressing CTLL-2 cells. This strategy allowed synergistic induction of cuproptosis, mild photothermal therapy (PTT), and PD-1/programmed death-ligand 1 (PD-L1) checkpoint blockade. The nanoplatform exhibited excellent stability, photothermal efficiency, and tumor-targeting capability, resulting in responsive degradation within the tumor microenvironment. In vitro and in vivo studies using breast tumor models showed that these nanoparticles displayed potent cytotoxicity, causing immunogenic cell death and dendritic cell maturation. Transcriptomic analysis revealed significant enrichment of key biological pathways. Specifically, both immune-activation and cuproptosis-related pathways were markedly upregulated. The combination of mild PTT and PD-1/PD-L1 blockade enhanced CD8 + T-cell infiltration and established long-term immune memory. This multifunctional nanoplatform provides an integrated strategy for potentiating cuproptosis-augmented immunotherapy in breast cancer.
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高影响因子
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