CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Xiang Ling,Hanchen Zhang,Dongsheng Tang,Yanqing Gong,Haihua Xiao,Xuesong Li
The discovery of cuproptosis provides a new perspective for copper overload treatment of cancer. However, the existing copper ion carriers only show oversimplified copper consignment and limited anti-tumor effect, which limits their further clinical application. Herein, we first design and synthesize two copper (II) complexes Py-Cu and TPE-Cu for synergistic cuproptosis, ferroptosis, and apoptosis anticancer therapy. In vitro , Py-Cu and TPE-Cu could induce dihydrolipoamide S -acetyltransferase (DLAT) aggregation, leading to cellular cuproptosis in PC-3 and CT-26 cells. Meanwhile, Py-Cu and TPE-Cu can amplify cellular oxidative stress by simultaneously boosting reactive oxygen species (ROS) production and depleting reduced glutathione (GSH), causing down-regulation of glutathione peroxides 4 (GPX4) expression and inducing ferroptosis. Moreover, Py-Cu and TPE-Cu could induce efficient apoptosis in vitro . To specifically release drugs at the tumor site, Py-Cu and TPE-Cu were co -assembled with hypoxia-responsive polymer PAL into nanoparticles, named NanoPy-Cu and NanoTPE-Cu, respectively. In vivo , NanoPy-Cu and NanoTPE-Cu showed superior tumor suppression effect both in the CT-26 tumor-bearing BALB/c mice model and ovarian (OV) cancer PDX-bearing BALB/c nude mice model. Here, we first reported two copper (II) complexes with unexpected broad anti-tumor activity, which synergized with cuproptosis, ferroptosis, and apoptosis to kill tumor cells.
研究领域:
肿瘤学
·
纳米医学
·
细胞生物学
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金属毒性
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活性氧信号转导
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高影响因子
MATERIALS & DESIGN
·
2026
·
IF 8.2
Feng Li,Wei Tian,Quan Ma,Weiliang Qian,Binghua Liu,Yanan Zhang,Kailong Zhang,Yongliang Chen,Fan Zhao
A copper-phloretin nanoplatform (Cu-Phl MPN) selectively targets respiration-active prostate cancer cells through cuproptosis vulnerability. • Cu-Phl MPNs block GLUT1-mediated glucose uptake, suppressing copper efflux and chelation to amplify intracellular Cu + accumulation. • The nanoplatform synergistically triggers apoptosis and cuproptosis, achieving potent antitumor efficacy with high biosafety. Prostate cancer (PCa) cells, characterized by sustained high mitochondrial respiratory activity following malignant transformation, possess intrinsic sensitivity to cuproptosis, rendering them suitable candidates for cuproptosis-induced therapies. By exploiting this metabolic vulnerability, tumor microenvironment-responsive copper-based metal-phenolic networks (Cu-Phl MPNs) were developed via self-assembly of Cu 2+ and phloretin to synergistically induce of apoptosis and cuproptosis in respiration-active PCa cells. Following cellular internalization, Cu-Phl MPNs underwent glutathione (GSH) responsive degradation, co-releasing Cu + and Phl. The liberated Phl specifically interrupted GLUT1-mediated intracellular glucose supply, suppressing ATP and NADPH synthesis. ATP depletion downregulated the copper exporter ATP7A and curbed copper efflux, while impaired NADPH production compromised GSH regeneration and diminished copper chelation, collectively facilitating intracellular Cu + accumulation. The accumulated Cu + drove a Fenton-like reaction to generate reactive oxygen species, which disrupted redox homeostasis and triggered mitochondrial apoptosis. Meanwhile, cuproptosis could be efficiently activated under the combination of excess Cu + and inherent sensitivity. Both in vitro and in vivo results demonstrated that Cu-Phl MPNs exerted potent and selective antitumor efficacy against respiration-active LNCaP cells while exhibiting minimal toxicity toward glycolysis-dependent PC3 cells, with favorable biosafety profiles. This work presents a metabolism-directed nanoplatform that aligns therapeutic mechanisms with tumor intrinsic features for precision PCa therapy. Download: Download high-res image (197KB) Download: Download full-size image
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Wenya Li,Xiyao Zhang,Ying Huang,Yangyang Guo,Hao Zhang,Weiying Ge,Yuxin Xie,Yiming Li,Zhen Zhou,Wenjie Ni,Zhe Zheng,Jianmin Li,Yang Zhao
Background: Prostate cancer (PCa) is characterized by a unique metabolic dependency on the hyperactivated tricarboxylic acid (TCA) cycle, creating a distinct vulnerability to cuproptosis-a copper-dependent form of regulated cell death. However, metabolic plasticity allows tumor cells to evade single-pathway inhibition through compensatory glycolysis, limiting the efficacy of copper-based therapies. Therefore, there is an urgent need to develop integrated nanoplatforms capable of orchestrating a dual-pathway metabolic blockade to overcome this therapeutic resistance. Results: Herein, we engineered a self-assembling copper-epigallocatechin gallate (EGCG) nanoreactor (Cu-EQ NP) designed to execute a synchronized dual-metabolic assault. The Cu-EQ NPs leverage the tumor microenvironment to release copper ions that trigger TCA-dependent cuproptosis, while the EGCG component simultaneously inhibits key glycolytic enzymes to prevent metabolic escape. Mechanistically, this lethality is self-amplified by EGCG-quinone-mediated depletion of glutathione (GSH) and the downregulation of the ATPase copper-transporting beta (ATP7B) efflux pump, leading to irreversible intracellular copper accumulation. Furthermore, we demonstrate that this metabolic collapse is highly immunogenic. In a syngeneic RM-1 mouse model, Cu-EQ NP-induced immunogenic cell death (ICD) released damage-associated molecular patterns (DAMPs) that successfully transformed the immunologically "cold" tumor microenvironment. This remodeling was characterized by enhanced dendritic cell maturation, M2-to-M1 macrophage repolarization, and robust infiltration of cytotoxic CD8 + T cells, resulting in potent tumor regression. Conclusions: The Cu-EQ nanoreactor represents a precision nanomedicine strategy that converts the specific metabolic vulnerabilities of PCa into a fatal weakness. By integrating dual-metabolic disruption with robust immune activation, this platform offers a promising therapeutic paradigm for overcoming resistance in advanced prostate cancer.
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PubMed
高影响因子
Science China-Materials
·
2026
·
IF 7.7
Dong Ganlin,Zou Meizhen,Li Shuting,Wang Yahuan,Liu Yan,Hu Liefeng
Copper-based synergistic therapy integrating chemodynamic therapy and cuproptosis holds great promise for tumor treatment due to its streamlined processes and enhanced efficacy. However, its clinical translation is hampered by the potential long-term toxicity, low catalytic efficiency, off-target effects, and ion efflux of copper. Herein, we developed metabolizable ultrasmall benzothiazole-based covalent organic framework nanodots (COF NDs) through a click condensation reaction followed by liquid exfoliation. The dense donor-acceptor configurations endow the NDs with a high photothermal conversion efficiency (51.16%), while the bisthiazole motifs enable specific Cu 2+ /Cu + chelation (0.56:0.44), facile PEGylation, and mitochondrial targeting. These features collectively enhance physiological stability and enable tumor-specific photothermal-catalytic synergy. Importantly, mitochondrial accumulation of the NDs elevates intracellular copper to a critical threshold, thereby inducing cuproptosis and effectively suppressing tumor growth and metastasis. Furthermore, the NDs are efficiently excreted via renal and fecal pathways, demonstrating favorable bio-compatibility and highlighting their strong clinical potential as copper-based nanotherapeutics.
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高影响因子
MedComm-Oncology
·
2026
·Vol. 5
·期 3
·e70098
·
IF 8.5
Qiang Shen,Qu Leng,Kaihui Wu,Guorui Li,Yiyou Mao,Jun Wu,Ziyi Song,Zhihai Deng,Hangyang Peng,Jun Zou,Jiamin Wang,Ping Liu,Zihao Zou,Zhaojun Pan,Jianfeng Zhong,Yubin Li,Nan Deng,Xiangming Mao,Daojun Lv
Cuproptosis, a copper-dependent form of regulated cell death, represents a potential metabolic vulnerability in cancer. However, the upstream regulators of this process in prostate cancer (PCa) remain unclear. This study identified long noncoding RNA (lncRNA) LIPE-AS1 as a key suppressor of cuproptosis in PCa. Elevated levels of LIPE-AS1 were observed in PCa, which inversely correlated with the core cuproptosis gene ferredoxin 1 ( FDX1 ). Silencing LIPE-AS1 sensitized cells to the cuproptosis inducer elesclomol-Cu (Ele-Cu), an effect that was reversible through copper chelation. Mechanistically, cytoplasmic LIPE-AS1 functioned as a competing endogenous RNA (ceRNA) by sponging miR-330-3p, thereby derepressing its target MGAT5 . MGAT5 subsequently modulated the expression of cuproptosis-associated proteins FDX1, dihydrolipoamide S -acetyltransferase (DLAT), and dihydrolipoamide S -succinyltransferase (DLST). Rescue experiments demonstrated that MGAT5 overexpression (MGAT5-OE) reversed the cuproptosis sensitivity induced by LIPE-AS1 knockdown. In vivo studies revealed that LIPE-AS1 depletion synergized with elesclomol to suppress tumor growth. Collectively, the LIPE-AS1/miR-330-3p/MGAT5 axis is defined as a critical pathway restraining cuproptosis in PCa, providing a mechanistic basis for targeting this circuit to overcome therapy resistance. Graphical LIPE-AS1 is markedly upregulated and serves as a competitive endogenous RNA that sponges miR-330-3p. This sequestration relieves miR-330-3p-mediated repression of MGAT5, leading to elevated MGAT5, which subsequently suppresses cuproptosis-related proteins FDX1, DLAT, and DLST, thus diminishing cuproptosis sensitivity. Importantly, disrupting this axis with Elesclomol enhances cuproptosis and suggests a potential therapeutic strategy for this malignancy.
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高影响因子
Advanced Science
·
2026
·
IF 14.1
Lei Wu,Jintong Na,Xiyu Liu,Dongsheng Tang,Zhungang Yang,Zheng Cao,Xinyue He,Haihua Xiao,Liping Zhong,Yuan Liao,Yongxiang Zhao
Cuproptosis, an emerging form of programmed cell death, is capable of inducing mitochondrial dysfunction. Moreover, the PI3K-AKT-mTOR signaling pathway contributes to tumor cell progression by reprogramming mitochondrial morphology and function. In this study, we have designed copper complex nanoparticles (NP Cu ) and PI3K-AKT-mTOR inhibitor Alpelisib nanoparticles (NP ALP ) that enhance the efficacy of cuproptosis-based therapies. NP Cu triggers mitochondrial dysfunction and promotes the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), while NP ALP inhibits the PI3K-AKT-mTOR signaling pathway to induce apoptosis. The combination of these two nanoparticles (NP Cu +NP ALP ) effectively activates the antitumor responses in the tumor microenvironment (TME). When combined with an anti-programmed cell death protein 1 antibody (α-PD-1), NP Cu +NP ALP significantly inhibits tumor progression and activates antitumor immunity, offering a promising strategy for liver cancer treatment.
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2026
·
IF 11
Yangyang Lu,Yan Li,Hongyang Yan,Xueying Sun,Xin Li,Yuanyuan Fang,Siyi Zhang,Jingwen Tian,Xin Wang,Cheng Luo,Wensheng Qiu,Weiwei Qi
Neutrophils combat tumors through a distinct enzymatic cascade involving superoxide dismutase (SOD) and myeloperoxidase (MPO), a biocatalytic mechanism that offers a promising platform for novel antitumor strategies. However, the clinical translation of natural enzymes is hindered by inherent limitations, including poor stability and high immunogenicity. In this context, nanozymes have emerged as advanced tools for tumor therapy, with the development of cascade catalytic nanosystems representing a major research frontier. This study designed multifunctional copper-caffeic acid metal-phenolic networks (Cu-CA MPNs). Upon lysosomal entry, the nanozyme mimics the neutrophil's SOD-MPO cascade to continuously generate substantial reactive oxygen species (ROS), notably hypochlorous acid (HOCl). This process directly damages lysosomes, promotes mitochondrial ROS accumulation, and upregulates the expression of GSDMD-N and GSDME-N, ultimately triggering pyroptosis. Simultaneously, Cu-CA MPNs released from ruptured lysosomes cause abnormal copper ion accumulation within mitochondria. This enhances oligomerization of the DLAT protein and downregulates key metabolic proteins-including ACO2, ETFDH, LIAS, and FDX1-thereby inducing cuproptosis. In a tumor-bearing mouse model, Cu-CA MPNs demonstrated potent antitumor efficacy and favorable biosafety. This work provides a new perspective for tumor catalytic therapy using nanozymes that simulate the neutrophil enzymatic cascade.
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DOI
PubMed
高影响因子
ACS Nano
·
2026
·Vol. 20
·期 34
·23975-23991
·
IF 17.3
Xia Lili,Chao Xiangxuan,Zhao Zitong,Zhou Xiaozhen,Wu Chenyao,Song Xinran,Zhou Wenli,Li Yuyao,Feng Wei,Chen Yu
Bioorthogonal chemistry provides a compelling strategy
for in situ
cytotoxin generation. However, the clinical translation of conventional
bioorthogonal catalysts is impeded by poor tumor accumulation, insufficient
targeting specificity, limited in vivo catalytic efficiency, and inadequate
spatiotemporal control. Meanwhile, excessive lactate accumulation
in the tumor microenvironment (TME) drives metabolic reprogramming,
malignant progression, and therapeutic resistance. Here, we develop
a living bacterial hybrid reactor by integrating Shewanella oneidensis MR-1 (S.o) with Cu(II)-based zeolitic imidazolate
frameworks to enable metabolism-guided and tumor-confined bioorthogonal
catalysis. Exploiting the intrinsic hypoxia tropism of S.o, the hybrid
reactor selectively accumulates within the TME. In the lactate-rich
tumor, endogenous lactate drives bacterial reduction of inert Cu(II)
to active Cu(I), enabling in situ catalyst activation and concurrent
lactate depletion. The generated Cu(I) catalyzes a localized azide–alkyne
cycloaddition between systemically administered prodrugs, producing
a combretastatin A-4-like cytotoxin. Simultaneously, intracellular
Cu(I) overload induces cuproptosis, while lactate depletion disrupts
tumor metabolic homeostasis, together eliciting a synergistic triple
antitumor effect. This work establishes a generalizable paradigm in
which living bacterial vectors function as both tumor-targeting carriers
and self-sustaining biochemical reactors, overcoming key limitations
of conventional bioorthogonal catalysis and enabling precise, tumor-confined
therapeutic activation.
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高影响因子
Acta Biomaterialia
·
2026
·
IF 10.4
Chao Xu,Muzhen He,Nuo Lin,Xiaoqian Ma,Lixuan Ren,Shileng Chen,Lu Liu,Haizhen Ding,Peifei Liu,Qunying Shi,Ke Hu,Zhujun Pan,Yimin Li,Hongmin Chen,Fangqin Xue
s High-dose radiotherapy is known to enhance cuproptosis, and when combined with copper–coordinated delivery to tumors, it shows promise as a synergistic treatment mechanism. In this study, we present a simple method for synthesizing stimuli-responsive copper-iodide nanoparticles using a commercial, insoluble copper-iodide powder that emitted a strong radioluminescence matching the absorbance of the clinical dye indocyanine green. The copper-iodide nanoparticles efficiently absorbed and transferred radiation energy to ICG activating an X-ray-induced photodynamic therapy (X-PDT) mechanism. After accumulating in tumors, the low-dose X-PDT process first generated reactive oxygen species to induce cell death. The tumor microenvironment then caused the copper-iodide nanoparticles to decompose and release copper and iodide ions, which promoted cuproptosis. X-PDT followed by ion-induced cell death achieved 87.7% tumor regression in CT26 tumor-bearing mice without systemic toxicity. This work establishes a therapeutic paradigm that exploits metal metabolism dysregulation to potentiate radiation-based therapies. Statement of significance Stimuli-responsive copper-iodide nanoparticles were synthesized and induced by X-ray-induced photodynamic therapy to decompose, releasing copper and iodide ions that caused tumor cell death. (1) Commercial copper–iodide powder exhibited strong radioluminescent properties and formed stable nanoparticles with the clinical dye indocyanine green, which realized X-ray-induced photodynamic therapy under X-ray irradiation. (2) After accumulating in tumors and following X-ray-induced photodynamic therapy, the decomposition of copper-iodide nanoparticles in the tumor tissue induced cell death.
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DOI
PubMed
高影响因子
MATERIALS & DESIGN
·
2025
·
IF 7.9
Li Ma,Sihong Guo,Xinlei Yang,Hongyu Gao,Jie Chen
The combination of apoptosis-ferroptosis-cuproptosis provides a beneficial method for enhancing the curative effect of ovarian cancer (OC). In this study, we design and synthesize a nano-drug delivery platform, HTC@DOX, which is achieved by the self-assembly of an amphipathic molecule HA-SS-TOS-DTPA, Cu 2+ , and doxorubicin (DOX). HTC@DOX bring the combination of chemotherapy (CT) from DOX and the chemodynamic therapy (CDT) from Cu 2+ . In vitro and in vivo experimental results show that HTC@DOX have excellent stability and glutathione responsiveness. This platform efficiently and purposely targets tumor sites, and destroy OC cells through the synergy of CT and CDT by induce apoptosis-ferroptosis-cuproptosis, thus enhancing the anti-cancer efficacy with a tumor reduction rate of 92.3 %. In addition, the results of electrocardiogram, ultrasound and histopathological staining demonstrate that HTC@DOX have superior biological safety and alleviate the cardiotoxicity caused by DOX alone. The results of bulk RNA sequencing and western blot show the alterations of apoptosis, ferroptosis, and cuproptosis related indicators, which further corroborates the anti-tumor efficacy of HTC@DOX. In brief, this study verifies the feasibility and effectiveness of the combination of CT and CDT in the treatment of OC by inducing apoptosis-ferroptosis-cuproptosis, offering an innovative approach for the treatment of cancer.
研究领域:
肿瘤学
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药剂学
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生物医学工程
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DOI
高影响因子
ADVANCED MATERIALS
·
2024
·
IF 27.4
Shuoyuan Li,Yan Yue,Wenqi Wang,Mingyue Han,Xufeng Wan,Qiaochu Li,Xiaoting Chen,Jian Cao,Yangming Zhang,Jiyao Li,Jianshu Li,Lei Cheng,Jiaojiao Yang,Duan Wang,Zongke Zhou
Implant-associated infections (IAIs) are the main cause of prosthetic implant failure. Bacterial biofilms prevent antibiotic penetration, and the unique metabolic conditions in hypoxic biofilm microenvironment may limit the efficacy of conventional antibiotic treatment. Escaping survival bacteria may not be continually eradicated, resulting in the recurrence of IAIs. Herein, a sonosensitive metal-organic framework of Cu-TCPP (tetrakis(4-carboxyphenyl) porphyrin) nanosheets and tinidazole doped probiotic-derived membrane vesicles (OMVs) with high-penetration sonodynamic therapy (SDT), bacterial metabolic state interference, and bacterial cuproptosis-like death to eradicate IAIs is proposed. The Cu-TCPP can convert O 2 to toxic 1 O 2 through SDT in the normoxic conditions, enhancing the hypoxic microenvironment and activating the antibacterial activity of tinidazole. The released Cu(II) under ultrasound can be converted to Cu(I) by exogenous poly(tannic acid) (pTA) and endogenous glutathione. The disruption of the bacterial membrane by SDT can enhance the Cu(I) transporter activity. Transcriptomics indicate that the SDT-enhanced Cu(I) overload and hypoxia-activated therapy hinder the tricarboxylic acid cycle (TCA), leading to bacterial cuproptosis-like death. Moreover, the OMVs-activated therapy can polarize macrophages to a M2-like phenotype and facilitate bone repair. The sonodynamic biofilm microenvironment modulation strategy, whereby the hypoxia-enhanced microenvironment is potentiated to synergize SDT with OMVs-activated therapy, provides an effective strategy for antibacterial and osteogenesis performance.
研究领域:
生物材料
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纳米技术
·
生物医学工程
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传染病学
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免疫学
·
骨科学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Jia Yao,Pengtao Chen,Dingqi Xie,Jianqingchen Chen,Xiao Lin,Yujin Xu
Radiotherapy (RT) is a widely used clinical treatment for cancer, leveraging ionizing radiation; however, some patients exhibit resistance to radiation due to insufficient reactive oxygen species (ROS) production. Copper-based nanomaterials represent a promising class of antitumor agents capable of generating abundant ROS. In this study, R837 and Cu2–xSe were incorporated into PLGA (50:50)20k-PEG2k-iRGD to develop a targeted nanomaterial for tumor therapy. These nanoparticles effectively induced cuproptosis, inhibited tumor cell proliferation, remodeled the tumor immune microenvironment (TME), and promoted immunogenic cell death (ICD), thereby enhancing the efficacy of PD-1 checkpoint blockade therapy (αPD-1). Furthermore, our results demonstrated that the Cu2–xSe(R837)-iRGD nanoformulations, in combination with radiotherapy, promoted the infiltration of CD8+ T cells and activated antitumor immune responses in vivo. In conclusion, our study confirmed that Cu2–xSe(R837)-iRGD nanoformulations combined with radiotherapy yielded promising therapeutic outcomes and held potential for clinical application in osteosarcoma (OS) treatment.
研究领域:
肿瘤学
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纳米医学
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免疫治疗
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辐射生物学
·
生物无机化学
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DOI
PubMed
高影响因子
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