JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Hajra Zafar,Jun Zhang,Faisal Raza,Xiuhua Pan,Zongwei Hu,Hanxiao Feng,Qi Shen
Cancer immunotherapy remains a significant challenge due to insufficient proliferation of immune cells and the sturdy immunosuppressive tumor microenvironment. Herein, we proposed the hypothesis of cuproptosis-lactate regulation to provoke cuproptosis and enhance anti-tumor immunity. For this purpose, copper-human serum albumin nanocomplex loaded gold nanocages with bacterial membrane coating (BAu-CuNCs) were developed. The targeted delivery and disassembly of BAu-CuNCs in tumor cells initiated a cascade of reactions. Under near infrared (NIR) laser irradiation, the release of copper-human serum albumin (Cu-HSA) was enhanced that reacted with intratumoral glutathione (GSH) via a disulfide exchange reaction to liberate Cu 2+ ions and exert cuproptosis. Subsequently, the cuproptosis effect triggered immunogenic cell death (ICD) in tumor by the release of damage associated molecular patterns (DAMPs) to realize anti-tumor immunity via robust production of cytotoxic T cells (CD8 + ) and helper T cells (CD4 + ). Meanwhile, under NIR irradiation, gold nanocages (AuNCs) promoted excessive reactive oxygen species (ROS) generation that played a primary role in inhibiting glycolysis, reducing the lactate and ATP level. The combine action of lower lactate level, ATP reduction and GSH depletion further sensitized the tumor cells to cuproptosis. Also, the lower lactate production led to the significant blockage of immunosuppressive T regulatory cells (Tregs) and boosted the anti-tumor immunity. Additionally, the effective inhibition of breast cancer metastasis to the lungs enhanced the anti-tumor therapeutic impact of BAu-CuNCs + NIR treatment. Hence, BAu-CuNCs + NIR concurrently induced cuproptosis, ICD and hindered lactate production, leading to the inhibition of tumor growth, remodeling of the immunosuppressive tumor microenvironment and suppression of lung metastasis. Therefore, leveraging cuproptosis-lactate regulation, this approach presents a novel strategy for enhanced tumor immunotherapy.
研究领域:
纳米技术
·
癌症免疫治疗
·
生物医学工程
·
分子生物学
·
诊疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Yibo Song,Guowu Zhan,Shu-Feng Zhou
Cuproptosis, a newly discovered cell death pathway, has shown great potential in cancer treatment. Herein, near-infrared (NIR) light-driven nanomotors (CuSiO 3 @Au-Pd NMs) are designed for cuproptosis-assisted synergistic therapy with autonomous mobility and improved cellular uptake and tumor penetration. Specifically, the released Cu 2+ ions from CuSiO 3 @Au-Pd NMs can induce the Fenton-like reaction, leading to the generation of hydroxyl radicals (·OH), accompanied by the depletion of glutathione within the MCF-7 cells. Additionally, the designed CuSiO 3 @Au-Pd NMs also exhibit excellent photothermal effects, which can further promote the production of ·OH, resulting in intensified oxidative stress and cellular apoptosis. Moreover, the enhanced tumor permeation efficiency and cellular uptake of CuSiO 3 @Au-Pd NMs via autonomous movement under self-thermophoretic forces are proved using 2D cellular experiments and 3D multicellular tumor spheroids. The resultant intracellular accumulation of Cu 2+ can induce the oligomerization of lipoylated proteins, leading to cuproptosis, along with the mitochondrial dysfunction pathway. More importantly, both in vitro and in vivo experiments show that CuSiO 3 @Au-Pd NMs could penetrate deeply into tumors and exhibit great anticancer efficacy through multimodal therapeutic methods. These findings manifest promising potentials of NIR-powered Cu-based NMs with high maneuverability for future smart and synergistic cancer therapy.
研究领域:
纳米技术
·
癌症研究
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生物医学工程
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诊疗学
·
材料科学
✓ 已验证
产品关联
DOI
高影响因子
Biomaterials Advances
·
2025
·
IF 6
Yixun Zhang,Wenjie Xie,Jinchuang Li,Zhenguo Liang,Xin Zhou,Zeheng Tan,Zhenjie Wu,Jundong Lin,Yangjia Zhuo,Fen Zou,Biyan Wen,Jianwei Chen,Shanghua Cai,Jianheng Ye,Yingke Liang,Jianming Lu,Huikang Yang,Weide Zhong,Ronghua Yang
Melanoma, a highly aggressive skin cancer, continues to challenge current therapeutic modalities due to its resistance and high mortality rates. Recent advancements highlight cuproptosis, a copper-driven form of programmed cell death, as a promising target for melanoma treatment. This study integrated machine learning and large-scale genomic data to identify FDX1 as a pivotal gene in cuproptosis-related pathways for melanoma. We developed a novel nanomedicine, ACM@MCHS-CuMOF@Dox, combining Mesoporous Carbon Hollow Spheres (MCHS) loaded with Copper-based Metal-Organic Frameworks (CuMOFs) and Doxorubicin (Dox), to exploit this discovery. The nanomedicine leverages a biomimetic approach by incorporating A375 cell membranes, enhancing tumor-targeted delivery. Physicochemical characterization confirms optimal drug loading and pH/GSH-responsive release profiles. In vitro studies demonstrate that ACM@MCHS-CuMOF@Dox inhibits melanoma cell proliferation, migration, and invasion, outperforming other formulations. Mechanistic investigations revealed that ACM@MCHS-CuMOF@Dox induced robust apoptosis and cuproptosis through FDX1 downregulation, thereby enhancing oxidative stress and therapeutic efficacy. These findings underscore the potential of combining machine learning-driven target identification with advanced nanomedicine for precision melanoma therapy. This approach offers a promising strategy for overcoming current treatment limitations and advancing personalized cancer care.
研究领域:
肿瘤学
·
纳米医学
·
生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2024
·
IF 5.3
Hui Zhang,Xuelin You,Ruihan Liu,You Wang,Fang Han,Juanyuan Hao,Yu Li
Cuproptosis efficiency is severely limited by insufficient Cu+ contents in tumors due to the easy oxidation of Cu+ into Cu2+ and the copper efflux mechanism. Herein, we develop a copper nanocarrier (MoSe2/CuO2) that can significantly enhance intracellular Cu+ for self-boosting cuproptosis-based synergistic antitumor therapy. Upon endocytosis by cancer cells, the acidic tumor microenvironment (TME) triggers the degradation of MoSe2/CuO2 to release Cu2+. MoSe2 then acts as a cocatalyst that promotes the reduction of released Cu2+ to Cu+, while oxidizing active Mo4+ to Mo6+, thereby triggering cuproptosis. Importantly, the produced Mo6+ is further returned to Mo4+ by endogenous glutathione (GSH) depletion, enhancing the cocatalytic effects of MoSe2 and resulting in a continuous Cu+ generation for self-boosting cuproptosis. Meanwhile, GSH-enhanced cocatalysis and MoSe2-mediated photothermal effect can significantly promote Cu-Fenton reactions, which not only downregulate Cu-ATPase to reduce Cu+ efflux and aggravate cuproptosis with higher efficacy but also activate caspase-3 to promote cell apoptosis. MoSe2/CuO2 exhibits excellent antitumor effects (94.9% tumor growth inhibition) and biosafety effects in vitro and in vivo. This work presents a strategy that enables high levels of Cu+ delivery by enhancing generation and reducing efflux for self-boosting cuproptosis–apoptosis synergistic therapy.
研究领域:
纳米技术
·
癌症研究
·
生物医学工程
·
治疗学
✓ 已验证
产品关联
DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Xian Qin,Li Zhu,Xuan An,Cheng Zhang,Jiawei Li,Fei Yan,Wenjin Zhang,Kai Qu,Kun Zhang,Wei Wu,Guicheng Wu
The establishment of hybrid cell membrane-camouflaged nanotherapeutics is crucial to preserve and impart their biological functionality inherited from the source cells. In this study, one side relies on the intrinsic affinity between the intracellular domain of Band 3 in the red blood cells membrane (Rm) and P4.2 peptide-modified nanoparticles (Rm-Que/Cu), promoting the self-assembly coupling-driven encapsulation of Rm on the surface of nanodrugs. On the other side, it involves integrating the bioengineered cell membrane with high Del-1 expression (Dm) with Rm-Que/Cu to form RDm-Que/Cu, targeting the role of integrin α v β 3 on tumor neovascularization and endothelial cells (ECs). This approach simultaneously integrates the multi-functions, including self-assembly encapsulation, targeted drug delivery, and on-demand drug release. Both in vitro and in vivo experimental results confirmed that RDm-Que/Cu were able to disrupt the cellular copper homeostasis, inhibit tumor angiogenesis, and induce cuproptosis. This discovery provides a feasible platform for the biomedical application of hybrid cell membrane-camouflaged biomimetic nanotechnology.
研究领域:
生物医学工程
·
肿瘤学
·
纳米医学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Haiyan Huang,Rui Zhang,Yu Luo,Kexin Zhang,Bingbing Duan,Gulizhaer Ainiwa,Yiting Ma,Yamei Miao,Lingxiao Zhang,Xiaofeng Zhu,Xiang Li,Kaiyang Wang
Modulating intratumoral copper homeostasis to trigger cuproptosis is a promising copper‑based anticancer strategy, but its clinical translation is hindered by the absence of precise spatiotemporal control over intracellular copper levels and ATP7A‑mediated active copper efflux. Here we report an ultrasound-activated copper molybdate nanoregulator, HCu 1.5 MoO 5 (HCMO), that releases copper on demand and reprograms copper flux in tumor cells under ultrasound. Once internalized, ultrasound activates HCMO to release copper ions, providing a sustained intracellular copper supply. In parallel, HCMO also generates reactive oxygen species that impair mitochondrial function and depress cellular ATP, thereby attenuating the activity of the ATP-dependent exporter ATP7A and narrowing copper efflux. This dual-axis imbalance, in situ copper supplement, and efflux limitation significantly disrupt cellular copper homeostasis, interrupt the tricarboxylic-acid cycle, induce mitochondrial dysfunction, further enhance copper accumulation, and eventually cause irreversible cuproptosis. Together with apoptosis and necroptosis, the coordinated damage releases damage-associated molecular patterns and induces immunogenic cell death. Overall, this spatiotemporally programmable strategy links materials, physical fields, and immunity in a closed framework to coordinately disrupt copper homeostasis, offering a generalizable route to on-demand cuproptosis therapy.
✓ 已验证
DOI
PubMed
高影响因子
Small
·
2026
·
IF 11.8
Jiarui Wang,Gao He,Jun Chen,Yongjue Qiu,Xujian Yang,Jilin Zhong,Hongpeng You,Lile Dong,Wuping Liao
Triple-negative breast cancer (TNBC) poses a severe clinical challenge due to high recurrence, metastasis, and chemoresistance. To address this, high-index facet (1 1 3) -distorted lanthanum cuprate (LCO) nanosheets are established. Ultrasound (US) activated LCO and amplified tumor suppression via the “metabolism-inflammation-immunity” cascade by synergistically activating cuproptosis/ions overload/pyroptosis and immunogenic cell death (ICD). Specifically, US activation of LCO efficiently generates reactive oxygen species (ROS) and reduces glutathione (GSH) levels, reversing the antioxidant tumor microenvironment. Enhanced Cu 2+ /Cu + conversion under US triggers cuproptosis, and La 3+ released from LCO acted as super calcium, enhancing mitochondrial Ca 2+ uptake and thereby inducing ions overload. These processes synergistically damage mitochondria, driving ROS accumulation and activating the NLRP3 inflammasome, ultimately triggering pyroptosis. This strategy achieves potent tumor cell killing and a remarkable 92.4% tumor inhibition rate. Collectively, LCO-induced synergistic cuproptosis/ions overload/pyroptosis activates robust antitumor immunity, offering a unique and promising paradigm for efficient TNBC therapy.
✓ 已验证
DOI
PubMed
高影响因子
iScience
·
2026
·Vol. 29
·期 4
·115438
·
IF 4.5
Jie Zhang,Chengying Lei,Guangzhe Zheng,Bingxue Nie,Yiju Wei,Yanqin Lu,Shuping Zhang
The FDA-approved disulfiram (DSF) is metabolized to diethyldithiocarbamate-copper (CuET) in vivo , exhibiting excellent anti-tumor activity in various types of tumors. Although cuproptosis and ferroptosis are both reported to be involved in the tumor-killing effects of CuET, the specific crosstalk mechanism remains poorly understood. Herein, we found that CuET increased the concentration of copper ions significantly in non-small cell lung cancer (NSCLC) cells, thereby triggering the process of cuproptosis. Simultaneously, we observed an increase in lipid peroxidation (LPO) and ferroptosis. Mechanistically, CuET interacts directly with polyunsaturated phospholipids to generate free radicals, leading to LPO and ferroptosis, with limited dependence on iron accumulation. Additionally, lipid composition changes induced by CuET might also contribute to ferroptosis. In vivo anti-tumor experiments verified copper-mediated cell death. We uncovered that CuET induced ferroptosis through a copper-triggered, non-canonical, and radical-dependent pathway. Therefore, our data elucidate a therapeutic approach for NSCLC by co-targeting cuproptosis and ferroptosis. Biochemistry; Cell biology; Cancer
✓ 已验证
DOI
PubMed
高影响因子
iScience
·
2026
·
IF 4.5
Jiali He,Yanghao Hu,Pengfei Liu,Da Li,Yanqi Huang,Junlei Liu,Zihao Xia,Hongshuai Liu,Wenying Li,Zhisen Shen
Laryngeal squamous cell carcinoma (LSCC) has a poor prognosis because it is often diagnosed late and chemotherapy causes substantial side effects. To improve efficacy and reduce toxicity, we developed a tumor microenvironment-responsive nanoplatform, 5-fluorouracil-loaded copper-doped carbon dots (5-Fu@CuCDs). The nanocomposite was synthesized by a one-step hydrothermal method, showed a uniform spherical morphology of about 15.7 nm, and achieved a drug loading rate of about 30%. Structural analyses confirmed successful copper doping and stable drug incorporation. Under weakly acidic tumor microenvironment conditions, the nanoplatform catalyzed hydroxyl radical generation from hydrogen peroxide and depleted intracellular glutathione, thereby enhancing oxidative stress. Density functional theory calculations further supported its high peroxidase-like catalytic activity. In vitro, the nanoplatform was efficiently taken up by laryngeal cancer cells, promoted copper accumulation and oxidative stress, and showed stronger antitumor activity than free 5-fluorouracil or copper-doped carbon dots, while maintaining good biocompatibility.
✓ 已验证
DOI
PubMed
高影响因子
Materials Today Bio
·
2026
·
IF 11
Linhao Jing,Shuaijun Zhao,Chenguang Sun,Fangfang Cui,Yaning Xia,Yupeng Shi,Weijie Wang
Immunotherapy has reshaped cancer treatment, yet its efficacy in many solid tumors remains limited by an immunosuppressive microenvironment and insufficient antigen presentation. As a central gatekeeper of antitumor immunity, the cGAS-STING pathway represents a key axis for converting tumor-intrinsic stress into productive immune priming. Here, we propose an integrated strategy that couples immunogenic tumor cell death with tumor-restricted cGAS-STING activation and adjuvant-amplified innate signaling. Cuproptosis, a recently identified copper-dependent cell-death program, can act as an endogenous trigger of tumor-intrinsic cGAS-STING activation, providing a promising avenue to link cytotoxicity with immune stimulation. We engineered a biomimetic, tumor-responsive nanoplatform (Cu-R837@CM) by co-assembling Cu 2+ with the TLR7 agonist R837 and cloaking the core with homologous tumor cell membranes to enhance tumor targeting and intratumoral retention. In vitro, Cu-R837@CM released Cu 2+ under acidic conditions, inducing glutathione depletion and ROS accumulation, promoting DLAT aggregation and mitochondrial dysfunction, increasing intracellular 2′3′-cGAMP, and activating cGAS-STING signaling. Concurrently, R837 enhanced dendritic-cell maturation and cytokine production, thereby improving antigen presentation. In vivo, Cu-R837@CM markedly inhibited tumor growth, increased CD4 + /CD8 + T-cell infiltration, and remodeled the tumor immune microenvironment toward an antitumor phenotype. Notably, combining Cu-R837@CM with PD-L1 blockade achieved complete tumor regression and significantly prolonged survival. Collectively, Cu-R837@CM offers a clinically translatable nanoadjuvant paradigm that integrates cuproptosis-driven cGAS-STING activation with TLR7 co-stimulation for hepatocellular carcinoma immunotherapy.
✓ 已验证
DOI
PubMed
高影响因子
APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY
·
2026
·
IF 3.5
Zhou Fengfeng,Li Chenglin,Che Fengyuan
To explore the effect of Licochalcone A on cuproptosis in glioma and the underlying mechanism, U87 MG and U251 cells were treated with 10, 20, and 30 µM Licochalcone A for 24 h. Key assays including immunofluorescence, TEM, mitochondrial membrane potential and morphological analysis, as well as other cuproptosis-related indexes were detected. Furthermore, the cuproptosis activator elesclomol, inhibitor TTM, and Ras activator ML-098 were used. An in vivo nude mouse xenograft model was established. Our results demonstrated that Licochalcone A triggered cuproptosis in a dose-dependent manner, and in U87 and U251 cells, 30 µM Licochalcone A treatment increased the Cu²⁺ accumulation by 2.86 ± 0.67 folds and 1.96 ± 0.39 folds, elevated pyruvic acid levels by 2.15 ± 0.23 folds and 2.57 ± 0.46 folds, reduced mitochondrial membrane potential by 34.13 ± 1.70% and 40.43 ± 9.05%, downregulated the protein expression of FDX1 and LIAS, and increased cellular ROS levels by 4.74 ± 0.85 folds and 5.10 ± 2.16 folds, respectively. These changes were accompanied by obvious mitochondrial swelling and cristae disruption, resulting in a significant inhibition of cell proliferation. Mechanistically, it promoted cuproptosis by inactivating RAS/ERK. In vivo, 10 mg/kg Licochalcone A reduced tumor volume/weight by 42.27 ± 11.63%/45.13 ± 13.15%, with consistent protein changes (FDX1, LIAS, RAS, p-MEK and p-ERK). Collectively, it induces glioma cuproptosis via inactivating RAS/ERK, providing a potential therapeutic target.
✓ 已验证
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Ziwei Chen,Jia Liu,Manjia Zheng,Minhua Mo,Xiaowen Hu,Chang Liu,Janak Lal Pathak,Lijing Wang,Liangjiao Chen
Yttrium oxide nanoparticles (Y 2 O 3 NPs), extensively utilized rare earth nanoparticles, exhibited a diverse range of applications across various fields, which leading to increased human exposure. Moreover, potential neurotoxic risks have been associated with their use, yet the underlying mechanism remains unclear. The present study aimed to investigate the effects of Y 2 O 3 NPs on cognitive function in rats with a particular focus on elucidating the pivotal role played by astrocytes in this process. The results demonstrated that Y 2 O 3 NPs induced cognitive and memory impairment in rats, copper (Cu) accumulation and cuproptosis of astrocytes as contributing factors. Furthermore, we elucidated that Y 2 O 3 NPs induced astrocytes cuproptosis by inhibiting TRIM24/DTNBP1/ATP7A signaling pathway-mediated cellular Cu efflux. We provide, for the first time, the important involvement of astrocytes in Y 2 O 3 NPs-induced neurotoxicity, elucidating that cuproptosis as the primary mode of cell death. These results offer valuable insights for the future safe application of rare earth nanoparticles in field of neurology.
研究领域:
神经科学
·
毒理学
·
纳米技术
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）