Small
·
2025
·
IF 12.1
Jiaojiao Tao,Yu Dong,Bingjie Wang,Teng Wang,Aijia Zhang,Shuang Li,Rui Chen,Yanguo Su,Tianze Jiang,Xia Zhao
Immunotherapy is a promising new approach for tumor treatment. However, its clinical application is hindered by insufficient immunogenicity, hypoxia, and immunosuppressive tumor microenvironment (TME). Here, oxygen pump microneedles (OPMNs) loaded with zinc-doped copper sulfide nanoflowers (ZCS NFs) and PD-L1 small interfering RNA (siPD-L1) (OPMNs-ZCS@siPD-L1) are developed for boosting tumor immunotherapy. OPMN-ZCS@siPD-L1 enhances tumor immunogenicity through ZCS NFs by inducing cuproptosis, reverses TME through siPD-L1, and promotes drug penetration, and ameliorates hypoxia through oxygen bubbles. More importantly, cuproptosis-induced mitochondrial DNA (mtDNA) together with Zn 2+ co-activate the STING pathway, triggering a robust immune response. OPMN-ZCS@siPD-L1 increases the sensitivity to cuproptosis and induces immunogenic cell death (ICD) in vivo and in vitro, which significantly inhibits tumor progression and metastasis. The novel strategy of “increasing the throttle” (cuproptopsis-mediated STING activation & ICD effect) combined with “releasing the brake” (PD-L1 inhibition & hypoxia improvement) provides a new approach for enhancing percutaneous tumor immunotherapy.
研究领域:
肿瘤学
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免疫学
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纳米医学
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生物材料学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Shiyao Song,Xingfeng Qiu,Shaoqing Huang,Huixuan Tian,Ruihan Pu,Jingyi Huang,Jiayin Su,Yan-Lai Tang,Libin Huang,Xuequn Luo,Weiling He,Qingfeng Ni,Weijing Zhang
The clinical application of tyrosine kinase inhibitors (TKIs) is rapidly growing and has emerged as a cornerstone in the treatment of both solid tumors and hematologic malignancies. However, resistance to TKI targets and disease progression remain inevitable. Nanocarrier-mediated delivery has emerged as a promising strategy to overcome the limitations of the TKI application. We utilized the facile modification of lignin polyhydroxyl groups to synthesize cystine-grafted lignin–copper coordinated nanoparticles for TKI delivery via the Mannich reaction. The materials exhibited a stable, uniform morphology and effectively encapsulated and delivered a variety of TKI inhibitors. Moreover, we optimized the fabrication process and found that the material could release the encapsulated drug in response to both pH and GSH. These nanoparticles significantly enhanced the therapeutic activity of TKIs both in vitro and in vivo through cuproptosis while demonstrating good biosafety. We propose a novel strategy for the targeted delivery of TKI inhibitors by combining cuproptosis with modified lignin. This approach not only offers new strategies for the clinical application of TKIs but also provides novel insights and inspiration for the modified use of lignin.
研究领域:
药学
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材料科学
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肿瘤学
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纳米技术
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
·
IF 7.7
Chao Xie,Qili Sun,Jingle Chen,Bingsheng Yang,Huiwen Lu,Zhanpeng Liu,Yucong Li,Kai Li,Bin Tang,Lijun Lin
Cuproptosis affects osteosarcoma locally, and the exploitation of cuproptosis-related biomaterials for osteosarcoma treatment is still in its infancy. We designed and synthesized a novel injectable gel of Cu ion–coordinated Tremella fuciformis polysaccharide (TFP–Cu) for antiosteosarcoma therapy. This material has antitumor effects, the ability to stimulate immunity and promote bone formation, and a controlled Cu 2+ release profile in smart response to tumor microenvironment stimulation. TFP–Cu can selectively inhibit the proliferation of K7M2 tumor cells by arresting the cell cycle and promoting cell apoptosis and cuproptosis. TFP–Cu also promoted the M1 polarization of RAW264.7 cells and regulated the immune microenvironment. These effects increased osteogenic gene and protein expression in MC3T3-E1 cells. TFP–Cu could significantly limit tumor growth in tumor-bearing mice by inducing tumor cell apoptosis and improving the activation of anti-CD8 T cell-mediated immune responses. Therefore, TFP–Cu could be a potential candidate for treating osteosarcoma and bioactive drug carrier for further cancer-related applications.
研究领域:
生物材料学
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肿瘤学
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免疫学
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骨再生医学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Fan Zhao,Hongyan Yu,Chen Wang,Junchen Xu,Hao Gao,Yao Ying,Wangchang Li,Juan Li,Jingwu Zheng,Liang Qiao,Shenglei Che,Jing Yu
Cuproptosis, ferroptosis, and reactive oxygen species (ROS)-involved apoptosis are all bound by the overexpressed glutathione (GSH) in tumor microenvironment (TME). Herein, a dual GSH depletor is developed based on copper/iron bimetal gallic acid phenolic networks (CuFeGA MPNs) for combination tumor therapy by GSH depletion boosted apoptosis/ferroptosis/cuproptosis simultaneously. The CuFeGA MPNs are dissociated following exposure to the highly expressed GSH, causing the release of large quantities of GA, Fe 2+ , and Cu + . The released GA then further consumes the residual GSH. In conjunction with the GSH response-consumption behavior, the GSH depletion is achieved by those dual GSH consumption procedures. Subsequently, the expression of glutathione peroxides 4 (GPX4) is down-regulated by GSH depletion for further accumulation of lipid peroxides (LPO). Moreover, intracellular ROS levels are improved via Fenton reaction with released Cu + and Fe 2+ , leading to buildup of LPO concurrently. Eventually, excess ROS can activate mitochondria-associated apoptosis, and the surge of LPO initiates ferroptosis without GSH homeostasis. Meanwhile, the oligomerization of lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and decline of iron-sulfur cluster protein are induced by excessive Cu + in the absence of GSH chelation, activating cuproptosis. This work provides a feasible approach for the realization of multiple mechanisms combined tumor therapy.
研究领域:
癌症生物学
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材料科学
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纳米技术
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生物化学
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治疗学
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DOI
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-17
·
IF 14.7
Huang Yanli,Wan Xufeng,Su Qiang,Zhao Chunlin,Cao Jian,Yue Yan,Li Shuoyuan,Chen Xiaoting,Yin Jie,Deng Yi,Zhang Xianzeng,Wu Tianmin,Zhou Zongke,Wang Duan
Implant-associated infections due to the formation of bacterial biofilms pose a serious threat in medical healthcare, which needs effective therapeutic methods. Here, we propose a multifunctional nanoreactor by spatiotemporal ultrasound-driven tandem catalysis to amplify the efficacy of sonodynamic and chemodynamic therapy. By combining piezoelectric barium titanate with polydopamine and copper, the ultrasound-activated piezo-hot carriers transfer easily to copper by polydopamine. It boosts reactive oxygen species production by piezoelectrics, and facilitates the interconversion between Cu2 + and Cu + to promote hydroxyl radical generation via Cu + -catalyzed chemodynamic reactions. Finally, the elevated reactive oxygen species cause bacterial membrane structure loosening and DNA damage. Transcriptomics and metabolomics analysis reveal that intracellular copper overload restricts the tricarboxylic acid cycle, promoting bacterial cuproptosis-like death. Therefore, the polyetherketoneketone scaffold engineered with the designed nanoreactor shows excellent antibacterial performance with ultrasound stimulation and promotes angiogenesis and osteogenesis on-demand in vivo.
研究领域:
生物医学工程
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纳米技术
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传染病
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材料科学
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分子生物学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2025
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IF 9.6
Yanan Fu,Huisong Hao,Yixuan Fang,Shengjie Sun,Simin Wen,Yuanqi Liu,Jia Tang,Tianqi Wang,Meiying Wu
The traditional copper ion carrier, elesclomol, relies on transporting extracellular copper ions into cells. However, the limited extracellular copper ions hinder the copper accumulation inside cells, limiting the cuproptosis effects and thus reducing its therapeutic efficacy in cancer treatment. Although metal peroxides are effective in transporting metals and inducing oxidative stress, their application is constrained by poor safety. To address these challenges, we develop a safe bicelle nanosystem for metal peroxide delivery. Typically, the assembly of lipid-based nanoparticles into non-spherical shapes requires stabilizing agents such as membrane-stabilizing proteins (MSPs). In this study, the hydrophobic effect within the bicelle cavities is leveraged to encapsulate copper peroxide (CP), ensuring efficient delivery. CP forms a stabilizing ring around the bicelle, mimicking the function of MSPs to reinforce bicelle stability. Furthermore, considering the inhibitory effect of reduced glutathione (GSH) on cuproptosis, a GSH-sensitive derivative of doxorubicin (cDOX) is designed to reduce intracellular GSH levels. In tumor cells, cDOX interacts with CP to preferentially induce cuproptosis and oxidative stress, facilitating chemoimmunotherapy. These interactions collectively address the challenges of cuproptosis in cancer treatment by promoting efficient copper ion accumulation, effective induction of oxidative stress, and robust immunogenic cell death, providing a promising strategy for cancer therapy.
研究领域:
肿瘤学
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药剂学
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纳米医学
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DOI
PubMed
高影响因子
Materials Today Bio
·
2024
·
IF 8.7
Lin Ye,Congcong Yu,Jiechao Xia,Kainan Ni,Yejin Zhang,Xiaozhang Ying,Dingqi Xie,Yang Jin,Rongtai Sun,Ruikang Tang,Shunwu Fan,Shasha Yao
Reactive Oxygen Species (ROS) refers to a highly reactive class of oxidizing species that have the potential to induce cellular apoptosis and necrosis. Cuproptosis, a type of cell death, is primarily associated with the effects of copper ions. However, the specific relationship between ROS, cuproptosis, and osteosarcoma (OS) remains relatively unexplored. Additionally, there is limited research on the use of cuproptosis in conjunction with oxidative stress for treating OS and inhibiting tumor-induced bone destruction. To address these gaps, a novel treatment approach has been developed for OS and neoplastic bone destruction. This approach involves the utilization of glutathione (GSH) and pH-responsive organic-inorganic mesoporous silica nanoparticles@Cu 2 S@oxidized Dextran (short for MCD). The MCD material demonstrates excellent cytocompatibility, osteogenesis, tumor suppression, and the ability to inhibit osteoclast formation. The specific mechanism of action involves the mitochondria of the MCD material inhibiting key proteins in the tricarboxylic acid (TCA) cycle. Simultaneously, the generation of ROS promotes this inhibition and leads to alterations in cellular energy metabolism. Moreover, the MCD biomaterial exhibits promising mild-temperature photothermal therapy in the second near-infrared (NIR-II) range, effectively mitigating tumor growth and OS-induced bone destruction in vivo .
研究领域:
肿瘤学
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生物医学工程
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药理学
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产品关联
DOI
PubMed
高影响因子
Antioxidants
·
2026
·Vol. 15
·期 6
·722
·
IF 8.2
Quan Zhu,Yangyang Zhang,Xinyi Zhu,Huijuan Zhang,Chuyu Xiao,Yingying Yang,Ting Huang,Jun Lu,Chang Liu,Chunjing Chen,Yueyuan Zhou,Tao Liu,Biyuan Liu,Fangguo Lu
Ferroptosis and cuproptosis are promising anti-tumor treatment strategies. Elesclomol (ES) is a kind of common cuproptosis inducer, and cisplatin (DDP) is a commonly used drug in liver cancer chemotherapy, which can induce cells to undergo ferroptosis. Both of these cell death processes require inducing cells to generate oxidative stress. Therefore, elesclomol and cisplatin may have a synergistic effect in anti-tumor treatment. Here, we designed an active oxygen-responsive nano-delivery system and conducted in vitro and in vivo to study the synergistic anti-liver cancer effect of elesclomol and cisplatin. Our data showed that the elesclomol nanoparticles can effectively inhibit the growth of liver cancer cells and showed extremely low organ toxicity. Elesclomol exhibited a synergistic effect with cisplatin in vitro, but the combined treatment of the two did not outperform single drug treatment in vivo. The reason might be that the nuclear factor erythroid 2-related factor 2 (Nrf2) protein in liver cancer cells is feedback-expressed, inhibiting the oxidative stress effects induced by elesclomol and cisplatin. Therefore, this study provides reference data for exploring the mechanism of elesclomol’s synergistic anti-liver cancer treatment with cisplatin and offers a feasible strategy for future precise liver cancer treatment and improving chemotherapy efficacy.
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 2
·1667
·
IF 5.6
Shengqi Huo,Qian Wang,Wei Shi,Lulu Peng,Yue Jiang,Mengying Zhu,Junyi Guo,Dewei Peng,Moran Wang,Lintong Men,Bingyu Huang,Jiagao Lv,Li Lin
Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by persistent hyperglycemia play an essential role in cardiotoxicity. To clarify whether cuproptosis was involved in AGEs-induced cardiotoxicity, we analyzed the toxicity of AGEs and copper in AC16 cardiomyocytes and in STZ-induced or db/db-diabetic mouse models. The results showed that copper ionophore elesclomol induced cuproptosis in cardiomyocytes. It was only rescued by copper chelator tetrathiomolybdate rather than by other cell death inhibitors. Intriguingly, AGEs triggered cardiomyocyte death and aggravated it when incubated with CuCl2or elesclomol–CuCl2. Moreover, AGEs increased intracellular copper accumulation and exhibited features of cuproptosis, including loss of Fe–S cluster proteins (FDX1, LIAS, NDUFS8 and ACO2) and decreased lipoylation of DLAT and DLST. These effects were accompanied by decreased mitochondrial oxidative respiration, including downregulated mitochondrial respiratory chain complex, decreased ATP production and suppressed mitochondrial complex I and III activity. Additionally, AGEs promoted the upregulation of copper importer SLC31A1. We predicted that ATF3 and/or SPI1 might be transcriptional factors of SLC31A1 by online databases and validated that by ATF3/SPI1 overexpression. In diabetic mice, copper and AGEs increases in the blood and heart were observed and accompanied by cardiac dysfunction. The protein and mRNA profile changes in diabetic hearts were consistent with cuproptosis. Our findings showed, for the first time, that excessive AGEs and copper in diabetes upregulated ATF3/SPI1/SLC31A1 signaling, thereby disturbing copper homeostasis and promoting cuproptosis. Collectively, the novel mechanism might be an alternative potential therapeutic target for DCM.Keywords:cuproptosis;advanced glycosylation end products;diabetic cardiomyopathy;SLC31A1
研究领域:
心脏病学
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糖尿病
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分子生物学
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细胞信号传导
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病理生理学
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产品关联
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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DOI
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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PubMed
高影响因子
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
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