ACS Nano
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2025
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IF 16
Hui Wang,Weitao Yang,Yan Xu,Weiwei Zeng,Dinghua Liu,Tianming Cui,Yanjing Yun,Chang Liu,Zhuoyao Wu,Bingbo Zhang
Monovalent copper (Cu(I)) drives cuproptosis and catalytic therapy, yet its rapid oxidation reduces the activity. We developed bioinspired Cu(I)-bovine serum albumin single-atom nanozymes (Cu(I)-BSA SAzymes) via mild biomineralization, achieving stability (>90 days) and dual enzyme-like activities (peroxidase (POD)/catalase (CAT)) to convert tumor H2O2 into cytotoxic reactive oxygen species (ROS) while alleviating hypoxia. These SAzymes deplete glutathione to amplify oxidative stress and release Cu(I), which aggregates dihydrolipoamide S-acetyltransferase (DLAT) to induce cuproptosis─distinct from apoptosis/ferroptosis. Mechanistically, transcriptomics analyses suggest that Cu(I)-BSA SAzymes exerted their effects by regulating the oxidative stress and energy metabolism in 4T1 cells. The tumor microenvironment further mediates SAzymes aggregation and in situ transformation into paramagnetic Cu(II), enabling self-amplified T1-weighted MRI contrast for real-time activation monitoring. In breast (4T1) and colon (CT26) tumors, Cu(I)-BSA SAzymes suppress growth by 68.8% and 80.3% ([Cu] = 4 mg kg–1). This study reports a stable Cu(I) platform for catalytic-plus-cuproptosis theranostics.
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Signal Transduction and Targeted Therapy
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2025
·Vol. 10
·期 1
·1-18
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IF 52.7
Yue Yan,Li Shuoyuan,Su Qiang,Wan Xufeng,Li Qiaochu,Zhang Zhuang,Xu Hong,Zheng Fuyuan,Zhang Yangming,Tong Le,Cao Jian,Zhao Long,Chen Xiaoting,Li Qi,Zeng Yi,Wang Haoyang,Deng Yi,Zhou Zongke,Wang Duan
Conventional antibiotic strategies often fail to consistently suppress escaping planktonic bacteria and even induce antibiotic resistance, allowing implant-associated infections (IAIs) to persist. In this study, we demonstrated an antibiotic-free coating engineered with an herbal bioheterojunction featuring a shell-in-shell structure where Cu 2 O forms the core, strontium (Sr) is loaded in the inner shell, and curcumin (Cur) is nucleated in situ at the outer heterointerface (Cu 2 O-Sr/Cur). Ultrasound-triggered reactive oxygen species (ROS) generation by the outer heterostructure (Cu 2 O/Cur), coupled with Cu(I)-induced cuproptosis-like bacterial death, achieved antibacterial rates of 99.56% against S. aureus and 99.43% against E. coli . When ultrasonication ceases, the released Cu(I) undergoes disproportionation reactions to form Cu(II), which can chelate with Cur to form Cu-Cur metal complexes. These complexes exhibit enhanced antioxidative properties through self-catalytic regulation, the scavenging of ROS, and the activation of anti-inflammatory M2 macrophage phenotype. Moreover, strontium release from the inner shell simultaneously suppressed osteoclast activity and promoted osteogenesis, resulting in trabecular number and thickness increases of 129.03% and 56.71%, respectively, compared with those in control group. Therefore, our work establishes a sequential treatment strategy for the antibacterial properties and osteointegration ability of IAIs.
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WORLD JOURNAL OF GASTROENTEROLOGY
·
2025
·Vol. 31
·期 34
·109825
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IF 5.4
Peng-Tuo Xiao,Chang-Feng Li,Yuan-Da Liu,Jing Zhong,Xi-Lun Cui,Chang Liu,Wei Yang
BACKGROUND Colorectal cancer (CRC) is a major global health burden. B cell CLL/lymphoma 10 (BCL10), a key component of the caspase recruitment domain protein-BCL10-mucosa-associated lymphoid tissue lymphoma paracaspase complexes, is upregulated in CRC and associated with poor patient prognosis, suggesting its potential role in CRC development and progression. Cuproptosis, a novel form of programmed cell death, has emerged as a promising therapeutic strategy for cancer. AIM To explore the role of BCL10 in regulating the sensitivity of CRC cells to cuproptosis. METHODS A series of in vitro and in vivo experiments were conducted using CRC cell lines and CRC mouse models to evaluate the effects of BCL10 on CRC cell proliferation, migration, invasion, and sensitivity to copper-induced cell death. Mechanistic studies were performed to elucidate the underlying molecular pathways. RESULTS BCL10 promoted CRC cell proliferation, migration, and invasion, while its knockdown had the opposite effects. BCL10 also influenced the sensitivity of CRC cells to cuproptosis, with BCL10 overexpression enhancing resistance and its knockdown increasing sensitivity. The mechanism involved BCL10 modulating the expression of DLAT, a key protein in the copper-induced cell death pathway, through activation of the nuclear factor kappa-B (NF-κB) signaling pathway. CONCLUSION BCL10 promotes CRC growth and regulates the sensitivity of CRC cells to cuproptosis by activating the NF-κB signaling pathway and modulating DLAT expression. These findings provide a molecular basis for developing BCL10-targeted therapies for CRC.
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ADVANCED MATERIALS
·
2025
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IF 26.8
Bin Liu,Xiaorui Chen,Yanlin Zhu,Hao Chen,Jia Tan,Zhuang Yang,Jing Li,Pan Zheng,Lili Feng,Qingqing Wang,Shili Gai,Lei Zhong,Piaoping Yang,Ziyong Cheng,Jun Lin
To improve the efficiency and application prospects of metal peroxides in tumor therapy, the synthesis of bimetallic peroxides via simple yet effective approaches will be highly significant. In this work, hyaluronic acid modified zinc-copper bimetallic peroxides (ZCPO@HA) nanoparticles are synthesized through a one-step symbiotic method by co-hydrolysis of zinc acetate and copper acetate in weakly alkaline solution, followed by modification with sodium hyaluronate. Upon decomposition in the tumor microenvironment, ZCPO@HA nanoparticles can generate a considerable content of hydroxyl radical (·OH) by Fenton-like reaction between Cu 2+ and self-compensating hydrogen peroxide, while downregulating the expression of glutathione peroxidase 4 to induce ferroptosis. The abundant release of Cu 2+ leads to the aggregation of dihydrolipoamide S-acetyltransferase and the reduction of iron-sulfur cluster proteins, causing cuproptosis. The immunogenic cell death of tumor cells releases abundant damage associated molecular patterns, effectively activating the adaptive immune response. Zn 2+ and ·OH cause mitochondrial damage, leading to the release of a substantial amount of mitochondrial DNA. This subsequently activates the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway, enhancing the innate immune response. In conclusion, it synthesizes a new type of bimetallic peroxides by one-step symbiosis for activating anti-tumor immunotherapy combined with immune checkpoint inhibitor.
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Materials Today Bio
·
2025
·
IF 10.2
Xiaoyuan Yi,Huaying Xie,Kunzhao Huang,Jianzhang Luo,Wen Li,Qingyu Zeng,Feifei He,Wuxiang Shi,Duo Wang,Liyan Wang
Activating a robust immune response is an effective strategy for achieving tumor eradication. In this study, copper-based metal-organic framework nanoparticles (referred to as FA-PZ@MOF NPs), which have the ability to simultaneously induce cuproptosis and pyroptosis in tumor cells, were designed to utilize the synergistic effects of cuproptosis and pyroptosis to trigger immunogenic cell death (ICD). This can inhibit tumor growth, migration, and metastasis while enabling efficient antitumor immunotherapy. The nano inducer targets hepatocellular carcinoma tumor cells via folic acid, dissociates and releases copper ions in the tumor microenvironment (TME), which has a high glutathione concentration, leading to copper ion overload, thereby mediating cuproptosis. Additionally, the released ZnO 2 generates substantial amounts of H 2 O 2 and Zn 2+ in the acidic environment, enhancing the Cu 2+ -based Fenton-like reaction for chemokinetic therapy. This exacerbates the reactive oxygen species (ROS) storms and mitochondrial damage, and combined with the action of Polyphyllin VI (PPVI), induces pyroptosis and cuproptosis. This multilayered interaction strategy also triggers robust ICD while inhibiting hepatocellular carcinoma tumor metastasis and invasion.
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ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Wenying Zhang,Jingjing Su,Wenran Zhou,Runan Chen,Yihua Zhao,Pengchao Sun,Yongxing Zhao
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation and joint destruction. The pathogenesis is fundamentally driven by the tumor-like proliferation of fibroblast-like synoviocytes of RA (RAFLS), which agitates chronic inflammatory cascades and progressive tissue destruction. Cuproptosis is a new cell death pathway that relies on copper (Cu) ionophores to transport Cu into cells and has emerged as an attractive strategy for disease intervention. Herein, we first revealed hyperactive glycolysis as a key mechanism to resist cuproptosis in RAFLS by single-cell RNA sequencing. Accordingly, we proposed a hypothesis that inhibiting glycolysis could amplify cuproptosis, which was validated by utilizing PFK15 as a glycolysis inhibitor and elesclomol-copper (ES-Cu) as a cuproptosis inducer. Subsequently, a biomimetic liposome (EC/P@L-RFM) was developed to specifically codeliver ES-Cu and PFK15 to RAFLS by the fusion of RAFLS membrane (RFM) with the dual drug-encapsulated liposome. In vitro, ES-Cu-driven cuproptosis was potently boosted by PFK15-mediated glycolysis blockage and specifically induced cell death in RAFLS following the RFM fusion, which was attributed to enhanced tricarboxylic acid cycle flux by activating the glutamine-glutamate-α-ketoglutaric acid metabolic axis. In vivo, EC/P@L-RFM significantly alleviated RA symptoms by simultaneously suppressing glycolysis and amplifying cuproptosis, reaffirming the therapeutic potential of EC/P@L-RFM for RA.
研究领域:
风湿病学
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分子生物学
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免疫学
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转化医学
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药物递送系统
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细胞代谢
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Journal of Gastrointestinal Oncology
·
2026
·Vol. 17
·期 3
·135
·
IF 2.1
Linhui Chen,Zi Wang,Yanjun Guo,Chenyang Li,Guoxin Zhang
Background The identification of cuproptosis offers novel insights into therapeutic strategies for neoplastic diseases. We explore whether cuproptosis and cuproptosis-related genes (CRGs) could provide novel perspectives for the prognosis and treatment of gastric cancer patients. Methods RNA sequencing data of gastric cancer patients were retrieved from The Cancer Genome Atlas Program (TCGA), CRGs in gastric cancer were analyzed through bioinformatics methods. Subsequent experiments, including Western blotting (WB), quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, 5-Ethynyl-2’-deoxyuridine assay, Cell Counting Kit-8 assay, Transwell assay, transmission electron microscopy, and xenograft tumor formation in nude mice, were conducted to further validate the biological role of the key CRG PDE3B in gastric cancer. Results We confirmed CP, MAP2K2, and PDE3B as key genes for the prognostic classifier. Knockdown of PDE3B effectively suppressed the pro-tumorigenic functions in gastric cancer cell malignant proliferation and progression. Elesclomol-CuCl 2 (ES-Cu) triggered canonical cuproptosis features in gastric cancer cells, and PDE3B expression was downregulated during this process. Notably, the inhibition of PDE3B significantly potentiated ES-Cu induced cuproptosis. Conclusions We characterized the landscape of CRG dysregulation in gastric cancer, verified that ES-Cu exhibited a significant cytotoxic effect on gastric cancer, and elucidated the pivotal role of PDE3B in gastric cancer.
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Materials Today Chemistry
·
2026
·
IF 7.4
Shuoye Yang,Jinpeng Wang,Qianqian Cheng,Huajian Yuan,Lin Ju,Xin Wang,Suxi Liu,Ruolan Song,Ning Li,Lu Zhang,Peng Li
Chemotherapy drugs are often associated with toxic side effects and low bioavailability, while solid tumors like breast cancer frequently exhibit multidrug resistance, which limits the clinical efficacy of chemotherapy and other monotherapies. To address these challenges, there is a need for the development of efficient delivery systems capable of transporting various therapeutic agents while introducing novel programmed death mechanisms to achieve synergistic antitumor effects. In this study, zeolite imidazole-8 (ZIF-8) was utilized as a core carrier to load doxorubicin (DOX) and photothermal agent CuS, and further coated by folic acid (FA)-functionalized red blood cell membranes (RBCM) to fabricate the FRCZD delivery system. This system possessed the capacity to target breast cancer MCF-7 cells and their drug-resistant strain, MCF-7/ADR cells. Notably, DOX and CuS were rapidly released in response to both the tumor microenvironment (TME) and near-infrared radiation (NIR). Under light stimulation, CuS induced photothermal therapy (PTT), which further enhanced localized drug accumulation while catalyzing H 2 O 2 to produce toxic hydroxyl radicals (⋅OH) that triggered chemodynamic therapy (CDT). Moreover, excessive intake of Cu 2+ led to mitochondrial metabolic dysfunctions that ultimately initiated cuproptosis. The results demonstrated that FRCZD combined with NIR accelerated cell apoptosis while interfering with cell cycle distribution, consequently inhibiting tumor cell proliferation and migration. In vivo experiment results further corroborated that FRCZD + NIR significantly inhibited tumor growth more effectively than other experimental groups while exhibiting favorable biological safety profiles. Overall, the integrated platform FRCZD could substantially enhance treatment outcomes by inducing cuproptosis in conjunction with chemotherapy, PTT, and CDT approaches, thus holding promise for advancing therapies against drug-resistant tumors.
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Small
·
2023
·
IF 13.3
Shuaijun Lu,Hailong Tian,Bowen Li,Lei Li,Hao Jiang,Yajie Gao,Lin Zheng,Canhua Huang,Yuping Zhou,Zhongyan Du,Jia Xu
Drug resistance is one of the leading causes of treatment failure in current cancer chemotherapy. In addition to the classical drug efflux transporter-mediated chemoresistance, cancer cells with stemness features play a crucial role in escaping the maximum impact of chemotherapy. To sensitize cancer chemotherapy, in a novel approach, the hedgehog pathway inhibitor ellagic acid (EA) is coordinated with Cu 2+ to develop nanoscale metal–organic frameworks (EA-Cu), which are then loaded with doxorubicin (DOX) and modified with targeted chondroitin sulfate (CS) to form the CS/E-C@DOX nanoplatform (CS/NPs). Notably, EA inhibits stemness maintenance by suppressing the hedgehog pathway, while Cu 2+ further decreases stemness features of tumor cells by disrupting mitochondrial metabolism, effectively enhancing DOX-mediated chemotherapy. Meanwhile, EA can act synergistically with Cu 2+ to cause mitochondrial dysfunction and cuproptosis, which effectively decreases ATP levels and subsequently suppresses the activity of P-glycoprotein (P-gp), thus reducing drug efflux and sensitizing DOX-mediated chemotherapy. Additionally, the attached CS endows CS/NPs with specific tumor targeting properties, whereas EA-Cu endows this nanoplatform with pH/glutathione (GSH) dual-responsive release behavior. Taken together, CS/NPs exhibited excellent antitumor effects by inducing cuproptosis and significantly inhibiting cancer cell stemness, which has great potential for overcoming cancer chemoresistance.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2025
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IF 9.7
Qingdong Li,Yuanyuan Cui,Zhenhong Xia,Wenjuan Gao,Jianmin Xiao,Zhen Zhao,Lei Yang,Guilong Zhang,Zhengyan Wu
Immunotherapy has emerged as a promising approach for melanoma treatment. However, the efficacy of traditional immune checkpoint inhibitors (ICIs) remains limited due to the immunosuppressive tumor microenvironment. In this study, a novel nano-immune agonist, pLCGM-OVA, was developed to induce cuproptosis and activate the cGAS-STING pathway, thereby enhancing melanoma immunotherapy. The pLCGM-OVA was synthesized by conjugating PDGFB with liposomes that encapsulate CuGdMn nanoclusters (CGM) and ovalbumin (OVA). Upon exposure to the acidic microenvironment of tumours, pLCGM-OVA undergoes degradation, releasing Cu ions, Mn ions, and free OVA. This release triggers reactive oxygen species-mediated cuproptosis and activates the cGAS-STING pathway via Mn, leading to the subsequent induction of immunogenic cell death (ICD). Simultaneously, free OVA and ICD antigens are presented to dendritic cells (DCs), promoting their maturation and enhancing cytotoxic T lymphocyte infiltration, thus improving the efficacy of tumour immunotherapy. In vitro and in vivo studies demonstrated that pLCGM-OVA significantly inhibited tumour growth and recurrence with minimal systemic toxicity, owing to the combined effects of cuproptosis and immunotherapy. Moreover, pLCGM-OVA exhibited excellent T 1 contrast (9.26 mM −1 s −1 ), significantly enhancing T 1 -weighted magnetic resonance imaging signals of tumours, facilitating accurate melanoma diagnosis. Overall, this work presents a highly promising candidate for the development of potent immune agonists for melanoma treatment.
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Materials Today Bio
·
2025
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IF 10.2
Yuting Zhao,Jiayu Yuan,Yao Qi,Mengdi Sun,Yifei Zhang,Ge Zhang,Xiangchen Su,Mingzhu Song,Ruizhen Lv,Yijie Shi,Liang Zhao
Effective therapies for Glioblastoma (GBM) are often challenging by virtue of the intracranial location of GBM tumors, molecular heterogeneity, high recurrence rate, and overall resistance to treatment. Therefore, we proposed the development of doxorubicin (DOX) loaded molecularly imprinted nanocomposites (DOX@MINPs-TRF/ChO) using transferrin (TRF) and cholesterol (ChO) as dual-template and Cu nanoparticles (Cu@BSNs) as a functional monomer for enhancing the treatment of GBM. The results showed that DOX@MINPs-TRF/ChO specifically and effectively adsorbed TRF in blood circulation and subsequently enhanced the brain tumor targeting capability via specific binding with transferrin receptors (TfR) highly expressed on the surface of GL261 cells. After intracellular internalization, DOX@MINPs-TRF/ChO conferred lysosome escape via proton sponge effects and demonstrated GSH responsive intracellular release of DOX and Cu 2+ with the participation of disulfide bonds. As a result, it not only potentiated the synergistic induction of cuproptosis/apoptosis but also enhanced immunogenic cell death (ICD) effect. Furthermore, DOX@MINPs-TRF/ChO downregulated both PD-1 and PD-L1 expression through the specifical adsorption of ChO, remodeling the ChO metabolism axis in tumor regions and maintaining the immune-checkpoint blockade (ICB) effect. Collectively, DOX@MINPs-TRF/ChO induced synergistic cuproptosis/ICB/ICD and represented a potent strategy for enhancing treatment in GL261 glioma-bearing mice.
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JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2025
·Vol. 44
·期 1
·1-25
·
IF 12.8
Wang Pengyu,Guo Weihua,Liu Shuyue,Li Shouyi,Li Jiaqi,Ding Bowen,Yin Fengyi,Yang Yang,Li Xingjiang,Cao Pei,Ma Chaozhe,Zhang Wanying,Song Yidan,Geng Yating,Liu Lantao,Hu Jing,Hao Jihui,Feng Yukuan
Background Copper accumulation triggers mitochondrial-driven cell death, known as cuproptosis, offering a promising mechanism for targeted cancer therapy. Recent studies have highlighted the critical role of intratumoral copper levels in regulating the expression of programmed cell death ligand-1 (PD-L1), suggesting that copper-induced cuproptosis not only enhances cancer cell death but may also amplify the effects of anti-PD-L1 antibodies (αPD-L1). However, in tumors where monotherapy with αPD-L1 shows limited efficacy, particularly in pancreatic ductal adenocarcinoma (PDAC), the role of copper-induced cuproptosis in enhancing αPD-L1 treatment efficacy and its underlying mechanisms remain unclear. Meanwhile, inadequate tumor drug accumulation and glycolysis significantly restrict the efficacy of cuproptosis. To address these challenges, we have synthesized a novel nanozyme, Pt@PCN-Cu, designed to stabilize intracellular copper accumulation and effectively induce cuproptosis. Additionally, we aim to determine whether this strong induction of cuproptosis can synergize with αPD-L1 to enhance cancer therapy, ultimately paving the way for novel strategies to improve PDAC treatment. Methods Pt@PCN-Cu was synthesized via a one-pot method, and its therapeutic potential was assessed in combination with αPD-L1 for the treatment of PDAC. Initially, the material’s properties were characterized, and its efficient cellular uptake was confirmed. Anti-tumor efficacy was evaluated by inducing cuproptosis in PDAC cell lines and xenograft models. RNA sequencing (RNA-seq) was utilized to identify key regulators involved in the modulation of PD-L1 expression by cuproptosis. Lastly, the therapeutic efficacy of Pt@PCN-Cu combined with αPD-L1 was evaluated in vivo, focusing on tumor growth inhibition and immune modulation within the tumor microenvironment (TME). Results Pt@PCN-Cu demonstrates excellent physicochemical properties and remarkable cascade catalytic activity, providing a solid foundation for further in vitro and in vivo studies. In vitro, Pt@PCN-Cu efficiently transports copper and induces cuproptosis primarily through mitochondrial dysfunction. Mechanistic studies show that Pt@PCN-Cu triggers the dissociation of hexokinase 2 (HK2) from mitochondria, leading to a reduction in HK2 activity. This decline in HK2 activity impairs glycolysis, a metabolic pathway essential for tumor energy metabolism, which in turn results in elevated PD-L1 levels. In vivo, Pt@PCN-Cu demonstrates excellent safety and accumulates at the tumor site in a subcutaneous PDAC mouse model, inducing cuproptosis. Moreover, the combination of Pt@PCN-Cu with αPD-L1 further enhanced its therapeutic efficacy and effectively reprogrammed the immunosuppressive TME. Conclusion This study presents strong evidence confirming the safety and therapeutic potential of Pt@PCN-Cu in PDAC treatment. Importantly, Pt@PCN-Cu not only induces cuproptosis but also significantly enhances antitumor efficacy in combination with αPD-L1 by regulating PD-L1 expression through HK2 modulation. These findings underscore a more effective and innovative approach for treating PDAC.
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