Advanced Healthcare Materials
·
2025
·
IF 9.6
Xing Ge,Shuyue Deng,Lilin Chen,Feng Feng,Tianye Fang,Yu Ding,Hui Jiang,Jun Yang,Xinmei Liu,Jianjun Dai,Lei Yang,Yanmin Ju
Fungal infections pose a significant global public health threat, particularly candidemia and biofilm formation. Current antifungal drugs have limitations due to their toxicity and drug resistance. Ion interference therapy, particularly cuproptosis, shows significant potential for disease treatment. Herein, nano copper-chelate Cu(DDC) 2 @BSA (CDB) is synthesized for antifungal research and the mechanism of cuproptosis-like death is investigated. Initially, CDB demonstrates a strong inhibitory effect on multiple fungi and exhibits strong antifungal activity against two fluconazole-resistant clinical isolates. The decrease in ATPase activity and mitochondrial membrane potential indicates that the antifungal mechanism may involve mitochondrial dysfunction. Subsequently, transcriptome analysis reveals significant alterations in genes related to copper ions transport and regulation, oxidative phosphorylation, and mitochondrial function. Additionally, copper ions overload is observed, along with an increase in heat shock protein 70 levels and a decrease in lipoic acid synthetase protein expression. Given that biofilms hinder drug penetration, quaternary ammonium chitosan microneedles are employed in combination with CDB to penetrate the biofilm barrier and enhance the antifungal effect. Overall, this study provides new insight into the cuproptosis-like death mechanism in fungi and presents a promising strategy for fungal infection treatment through the combination of nano copper–chelate and microneedle delivery system.
研究领域:
微生物学
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药理学
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分子生物学
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生物医学工程
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PubMed
高影响因子
ACS Applied Nano Materials
·
2026
·
IF 5.8
Guanheng Wang,Lin Li,Biao Xue,Yu Li,Yaling Zhang,Jiapeng Wang,Yulei Cui,Chunlei Li,Xiuwen Zheng
In this study, a pH-responsive Cu-doped zeolitic imidazolate framework-8 nanoplatform was coloaded with paclitaxel and doxorubicin for synergistic tumor therapy. Hyaluronic acid modification on the outer surface of the nanomaterials enhances tumor targeting via CD44 receptor-mediated endocytosis. ZIF-8, derived from metal–organic frameworks, is an excellent nanocapsulator capable of specifically responding to the acidic tumor microenvironment. Upon reaching the tumor site, it rapidly degrades, releasing copper ions and chemotherapeutic drugs to exert antitumor effects. Copper ions consume endogenous hydrogen peroxide and glutathione through Fenton-like reactions, thereby generating cytotoxic reactive oxygen species, enhancing chemodynamic therapy efficiency, and inducing cuproptosis. The released PTX and DOX not only exert chemotherapeutic effects but also induce pyroptosis by activating the classical pathway mediated by caspase-3 and Gasdermin E. Due to excessive activation of the Wnt/β-catenin signaling pathway, PTX faces drug resistance in the treatment of triple-negative breast cancer, whereas DOX can inhibit this pathway by promoting β-catenin degradation. These therapies act synergistically to trigger immunogenic cell death, release damage-associated molecular patterns, promote dendritic cell maturation, activate T cells, and effectively reshape the immunosuppressive tumor microenvironment. This multimodal nanoplatform demonstrates remarkable potential as an antitumor treatment.
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高影响因子
ACS Nano
·
2026
·
IF 17.3
Zhuo Xiqian,Li Yunfeng,Qiu Ling,Aishajiang Reyida,Lei Pengpeng,Wang Tiejun,Yu Duo
Radiotherapy plays a pivotal role in the management of
nonsmall-cell
lung cancer (NSCLC), particularly for patients who are not candidates
for surgical intervention. Despite its significance, the issue of
radioresistance remains a substantial challenge in the treatment of
the NSCLC. Therefore, it is crucial to uncover new targets to enhance
radiotherapy and investigate the mechanisms underlying radioresistance.
Cuproptosis, as an emerging form of cell death dependent on intracellular
copper (Cu) ions, remains unclear in its role in radioresistant NSCLCs.
This study investigates the development of radioresistant NSCLC models,
focusing on the role of the FOS-like antigen 1 (FOSL1) as a significant
factor in mediating radioresistance. The FOSL1 gene is downregulated
in radioresistant cells. Overexpression of FOSL1 induces mitochondrial
damage and dysfunction, causing cuproptosis in radioresistant cells.
To tackle the challenge of radioresistance in NSCLC, we propose an
innovative nanostrategy focused on cuproptosis, aiming to enhance
the efficacy of radiotherapy specifically in radioresistant NSCLC.
This intervention could significantly enhance an increase in intracellular
Cu 2+ concentration and glutathione depletion while also
increasing irradiation (IR)-induced oxidative stress and mitochondrial
damage. The resulting mitochondrial dysfunction leads to tricarboxylic
acid cycle disruption and Fe–S cluster protein destabilization.
These cumulative effects ultimately induced cuproptosis and enhanced
the response of radioresistant NSCLC cells to IR. Our findings highlight
the potential of combining cuproptosis targeting with nanotechnology
to enhance the efficacy of radiotherapy, presenting a promising strategy
to address radioresistance in clinical contexts.
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Advanced Science
·
2025
·
IF 14.1
Lichao Zhu,Zhisheng Guo,Yu Luo,Haiyan Huang,Kexin Zhang,Bingbing Duan,Renmiao Peng,Haochen Yao,Chao Liang,Kaiyang Wang
The spatiotemporal sequential treatment strategy of promoting rapid separation of charge carriers, amplifying oxidative stress, increasing the low content of intracellular Cu, enhancing cuproptosis, and cascading activation of immunotherapy is considered one of the most effective techniques for improving the comprehensive therapy of tumors. Herein, copper tungstate (CuWO₄, CWO) nanoparticles with ultrasmall bandgap (1.71 eV) is developed as both piezoelectric-catalysis agents and copper nanocarriers for synergistic sono-enhanced cuproptosis. Owing to the unique bandgap microstructure, exposure to ultrasound (US) significantly increase the generation of reactive oxygen species (ROS) and the release of Cu 2+ from CWO. Additionally, ≈60% of glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) are consumed in situ, leading to oxidative stress, ferroptosis, and cuproptosis in cancer cells. This cascading approach induces substantial mitochondrial dysfunction and the release of damage-associated molecular patterns (DAMPs), which promotes immunogenic cell death (ICD) and augments antitumor immunity. Both in vitro and in vivo studies have shown that this sono-enhanced cuproptosis-based therapy could effectively suppress tumor growth. Overall, this study investigates a novel Structure-Function therapeutic approach that combines piezoelectric catalysis, ferroptosis, cuproptosis, and cascade activation of immune regulation, opening up new possibilities for addressing the challenges associated with conventional cuproptosis therapy.
研究领域:
肿瘤学
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生物材料学
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免疫学
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PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2025
·
IF 5.6
Yun Gao,Renlu Han,Zhen Guo,Zekai Zhuang,Jie Fu,Yafei Hou,Jiancheng Yu,Keqi Tang
Cuproptosis is a currently discovered programmed cell death modality driven by copper (Cu) ions, which shows potential application prospects in overcoming apoptotic resistance in cancer therapy due to its unique mechanism. Nevertheless, the efficiency of cuproptosis is restricted by strict Cu metabolism regulation. Herein, elesclomol (ES) and glucose oxidase (GOx) co-loaded CuFe 2 O 4 (CF) nanoplatform (termed as CFEG) was elaborately engineered to boost cuproptosis through multi-pathway copper metabolisms regulation. After triggered by tumor-overexpressed glutathione (GSH), the released ES continuously chelated and targeted transport Cu ions through a shuttle mechanism to mitochondria where cuproptosis was initiated, which dramatically improved the influx efficiency of Cu. Additionally, GOx-mediated glucose oxidation reaction together with Cu and Fe ions stimulated Fenton reaction simultaneously amplified intracellular oxidative pressure by hydrogen peroxide (H 2 O 2 ) self-supply and subsequent hydroxyl radical (•OH) generation, which down-regulated Cu exporter ATP7A expression and inhibited Cu ions efflux, thereby exacerbating cuproptosis. Furthermore, the consumption of GSH simultaneously reduced the chelation of GSH with Cu and promote the •OH generation, further potentiating the occurrence of cuproptosis. Collectively, such the multi-pathway copper metabolisms regulation including improved Cu influx, inhibited Cu efflux and GSH depletion significantly boosted cuproptosis, which synergized with photothermal effect of CF to efficiently repressed the growth of tumor in mice without causing systemic toxicity. This work provides a multivariate mode for enhanced tumor cuproptosis therapy, and may also inspire the design of advanced cuproptosis-related nanomedicine system.
研究领域:
生物医学工程
·
癌症治疗
·
纳米医学
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DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Han Shi,Zhiqiang Xie,Junrong Zhang,Fengchun Lu,Haoteng Luo,Pengfei Guo,Meichen Jiang,Zongqi Weng,Xin Luo,Bing Chen,Heguang Huang,Tianhong Teng
Reprogramming of branched-chain amino acid (BCAA) metabolism is a key mechanism promoting pancreatic cancer progression. While gabapentin (Gp) can inhibit BCAA catabolism by targeting branched-chain amino acid aminotransferase 1 (BCAT1), its efficacy is limited by inefficient delivery and compensatory mitochondrial metabolism. To address this, we developed a novel copper ionophore-functionalized mesoporous silica nanoplatform (XQ/Gp@CMSNs) for synergistic cuproptosis and tumor-starvation therapy. The designed nanoparticles exhibit excellent pancreatic cancer-targeting capability via XQ-2d aptamer modification and acid-responsive drug release within the tumor microenvironment. Upon internalization, XQ/Gp@CMSNs simultaneously induce mitochondrial copper overload and disrupt BCAA metabolism, leading to dihydrolipoamide S-acetyltransferase (DLAT) oligomerization, ferredoxin 1 (FDX1) downregulation, and tricarboxylic acid (TCA) cycle suppression. Both in vitro and in vivo studies demonstrated potent antitumor efficacy with minimal systemic toxicity. Metabolomic analyses further confirmed synergistic BCAA metabolic inhibition and copper-induced mitochondrial dysfunction. This work presents a promising metabolic intervention strategy for pancreatic cancer through targeted nanomedicine.
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CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Yi Sun,Guixiang Lv,Zheng Hu,Mengyu Chen,Wuxuan Liu,Mayumi Ikeda-Imafuku,Tatsuya Fukuta,Kazunori Kadota,Xiangwei Li,Enze Li
The aggressive nature of oral squamous cell carcinoma (OSCC) and its highly immunosuppressive tumor microenvironment (TME) present significant challenges for effective treatment, urgently demanding advanced multi-modal therapeutic strategies. In this study, we designed a self-reinforced dual cascade nanoreactor (A@CuCD), delivered via a thermosensitive hydrogel, to execute a synergistic therapeutic strategy. The A@CuCD nanoreactors are co-assembled from copper nanoclusters (Cu NCs) and artesunate (ART) encapsulated within γ-cyclodextrin (γ-CD). This multifunctional engineering platform operates synergistically through a bifunctional system: it leverages the thermosensitive properties of the hydrogel to enable localized, on-demand retention and controlled release of A@CuCD at the tumor site, thereby efficiently inducing cuproptosis. The resulting immunogenic cell death (ICD) then further promotes cytotoxic T lymphocyte (CTL) infiltration and induces macrophage M1 polarization, consequently reversing immunosuppression and comprehensively remodeling the tumor microenvironment. Simultaneously, the intrinsic cholesterol-scavenging capability of γ-CD within A@CuCD not only enhances OSCC cell sensitivity to cuproptosis but also significantly downregulates programmed death-ligand 1 (PD-L1) expression by disrupting lipid raft structures, effectively suppressing tumor immune evasion. Utilizing single-cell RNA sequencing, we provide a systemic understanding of the hydrogel-mediated TME reprogramming process, elucidating the intricate interplay between cuproptosis and immune activation pathways. This engineered hydrogel platform effectively translates localized precise delivery into powerful systemic anti-tumor immunity, offering a highly promising and clinically translatable strategy for overcoming OSCC therapeutic resistance, conquering “cold” immune tumors, and achieving durable anti-tumor immunity.
研究领域:
纳米医学
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癌症生物学
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免疫治疗
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生物材料
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生物工程
·
药剂学
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高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Guanhong Liu,Rongze Tang,Congcong Wang,Dehong Yu,Zhenxin Wang,Haochen Yang,Jia Wei,Shunhua Zhu,Fenglei Gao,Feng Yuan,Bin Pan
Cuproptosis and ferroptosis are difficult to synergize in tumor suppression due to their spatiotemporal asynchrony and mechanistic dispersion. Therefore, we proposed a new paradigm of Ferroptosis-Cuproptosis self-recycling. An iron‑sulfur cluster (Fe-S) metabolic collapse was constructed by hyaluronic acid (HA)-functionalized bimetallic nano-enzymes (HA@CuCo-NC) to initiate this tumoricidal mechanism. HA@CuCo-NC specifically accumulates in osteosarcoma cells through HA-mediated targeting. The multi-enzyme activity triggers a surge of reactive oxygen species (ROS) in the tumor microenvironment, which, along with Co 2+ , induces ferroptosis. This leads to severe mitochondrial damage and glutathione (GSH) depletion, which in turn activates the cuproptosis cascade. Cuproptosis causes Fe-S protein degradation and Fe 2+ release into the labile iron pool (LIP) by inhibiting Fe-S cluster formation and dihydrolipoamide acetyltransferase (DLAT) oligomerization. The released Fe 2+ enhances oxidative stress and promotes membrane disassembly via the Fenton reaction. The two act synergistically to form a dynamic self-reinforcing cycle: Ferroptosis-related mitochondrial damage exacerbates the toxicity of Cu 2+ . Cuproptosis-released Fe 2+ further activates ferroptosis. In vivo experiments demonstrated that HA@CuCo-NC significantly inhibited the growth of osteosarcoma in situ without causing systemic toxicity. This research introduces a novel approach to treating solid tumors by reconstructing the metabolic interaction network of copper and iron.
研究领域:
肿瘤学
·
纳米医学
·
分子生物学
·
细胞死亡机制
·
金属代谢
·
转化医学
·
氧化应激
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PubMed
高影响因子
Theranostics
·
2026
·Vol. 16
·期 3
·1281
·
IF 13.3
Jiayi Hu,Xiaoyi Bao,Meihua Ting,Yecheng Tao,Ran Li,Guosheng Fu,Fuyu Qiu,Jing Zhao,Wenbin Zhang
Rationale: Myocardial ischemia-reperfusion injury (MIRI) poses a critical clinical challenge due to intertwined oxidative stress and cuproptosis-driven cell death. Current therapies inadequately address dual-pathology mechanisms (ROS overproduction and copper dysregulation), while conventional drug delivery lacks spatiotemporal precision. Methods: A ROS-responsive hydrogel (OD@G4CAsi-FDX1) was engineered via dynamic Schiff base crosslinking between oxidized dextran (OD) and polyamidoamine dendrimers (PAMAM G4). The hydrogel co-encapsulates antioxidant caffeic acid (CA) and FDX1-targeted siRNA (si-FDX1). In vitro biocompatibility, ROS scavenging, and mitochondrial protection were assessed in primary cardiomyocytes. In vivo efficacy was evaluated in a murine MIRI model following intramyocardial hydrogel injection. Cardiac function, infarct size, and molecular markers were analyzed. Results: In vitro , it reduced ROS, preserved mitochondrial membrane potential, and suppressed pro-inflammatory cytokines. In vivo , it reduced infarct size, suppressed cuproptosis markers, and improved cardiac function. Mechanistically, si-FDX1 blocked DLAT oligomerization, while CA neutralized ROS, synergistically restoring redox homeostasis. This efficacy was enabled by sustained ROS-triggered release. Conclusions: OD@G4CAsi-FDX1 hydrogel dual-targets ROS and cuproptosis via a single injectable platform, overcoming limitations of conventional mono-mechanistic therapies. It demonstrates significant cardioprotection and clinical potential for MIRI management.
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CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Hui Li,Jie Geng,Min Mu,Susu Xiao,Chenqian Feng,Lihua Zhou,Yuanxiang Wang,Wei Yu,Rangrang Fan,Bo Han,Gang Guo
The nanoheterojunction (NbCuF@MR) enables tumor-specific copper delivery. • Its TME-responsive design minimizes systemic toxicity and off-target effects. • The cascade amplifies oxidative stress to activate robust ICD. • Cuproptosis–immunomodulation–metabolic interference reprograms the TME. • It enhances immune infiltration, converting “cold” tumors into “hot” ones. Cuproptosis, an emerging copper-dependent programmed cell death, offers a promising strategy for cancer therapy. However, its clinical translation is hindered by non-targeted Cu release, causing systemic toxicity and limited efficacy. To overcome this, we developed a folate-targeted nanoheterojunction photosensitizer, NbCuF@MR, for tumor-specific copper delivery. This system responds to the tumor microenvironment to release active components, leading to mitochondrial copper accumulation, aggregation of lipoylated dihydrolipoamide S -acetyltransferase (DLAT), and induction of cuproptosis. Under 808 nm laser irradiation, Nb 2 C generates mild phototherapy effects that combine to enhance cuproptosis while producing ROS and O 2 . Furthermore, this cascade reactions promotes immunogenic cell death (ICD). Together with loaded R848 and MTX, the system reprograms the immunosuppressive tumor microenvironment through metabolic modulation and amplified cuproptosis, activating a robust antitumor immune response. This stimulates M1 macrophage polarization, DC maturation, and cytotoxic T-cell infiltration, effectively inhibiting both local and distant tumor growth and metastasis. In conclusion, this work offers an innovative strategy leveraging metabolic interference and enhanced cuproptosis to activate potent antitumor immunity. Download: Download high-res image (159KB) Download: Download full-size image
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-19
·
IF 10.6
Chen Yang,Tian Hailong,Zhang Xiaodian,Nice Edouard C.,Huang Canhua,Zhang Haiyuan,Zheng Shaojiang
Limited drug accumulation and an immunosuppressive microenvironment are the major bottlenecks in the treatment of glioblastoma multiforme (GBM). Herein, we report a copper-coordination driven brain-targeting nanoassembly (TCe6@Cu/TP5 NPs) for site-specific delivery of therapeutic agents and efficient immunotherapy by activating the cGAS-STING pathway and downregulating the expression of PD-L1. To achieve this, the mitochondria-targeting triphenylphosphorus (TPP) was linked to photosensitizer Chlorin e6 (Ce6) to form TPP-Ce6 (TCe6), which was then self-assembled with copper ions and thymopentin (TP5) to obtain TCe6@Cu/TP5 NPs. This nanoassembly effectively accumulated in tumor sites through the copper transport mechanism. Meanwhile, TCe6@Cu/TP5 could induce mitochondrial impairment by photodynamic therapy (PDT) mediated reactive oxygen species (ROS) accumulation and Cu 2+ triggered cuproptosis, resulting in evoking the AMP-activated protein kinase (AMPK) pathway to degrade PD-L1, and activating the cGAS-STING pathway to enhance anti-tumor immunity. Moreover, TP5 significantly promoted the proliferation and differentiation of dendritic cells (DCs) and T lymphocytes to further amplify the cancer immunity cycle. Collectively, our TCe6@Cu/TP5 NPs effectively facilitate drug accumulation and activate systemic antitumor immunity in vitro and in vivo, providing an innovative solution across the BBB that potentiates GBM immunotherapy. Graphical
研究领域:
癌症研究
·
纳米技术
·
免疫学
·
神经科学
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PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Zhuoran Yang,Zhuo Li,Chunyu Yang,Li Meng,Wei Guo,Liqiang Jing
Cuproptosis offers a promising and selective therapeutic strategy for cancer therapy. To fully realize its potential, the development of novel cuproptosis therapeutic agents and the achievement of efficient copper release are critical steps forward. Herein, closely-contacted Cu 2 O-CoWO 4 nanosheet heterojunctions (CCW-NH) are successfully synthesized using an in-situ process for cuproptosis therapy. The efficient release of copper ions from CCW-NH can be triggered by ultrasound irradiation, primarily due to the generation of superoxide radicals as the sonodynamic agents via the Z-scheme charge transfer mechanism. When subjected to the combined effects of ultrasound and laser irradiation, the effective release of copper ions is increased by 1.7 times compared to the untreated group, significantly enhancing the efficiency of cuproptosis. And the incorporation of CCW-NH and L-arginine into the temperature-sensitive injectable hydrogel (HP-CCW@LA) ultimately achieved a tumor inhibition rate of up to 95.1%. L-arginine, serving as a reducing agent, enabled the sustained release of highly active Cu + during treatment. Notably, after treating tumors with HP-CCW@LA, the tumor microenvironment is leveraged to promote copper ion conversion, which offers the potential for monitoring tumor therapy efficacy through magnetic resonance imaging. This work offers a novel integrated strategy for the development of new cuproptosis agents and therapeutic evaluation.
研究领域:
癌症治疗
·
纳米技术
·
材料科学
·
医学成像
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高影响因子
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