International Journal of Nanomedicine
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2025
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IF 6.5
Yutong Chen,Jin Wang,Daniel Zheng,Weiyu Zhang
Objective Radioimmunotherapy (RIT) is a promising treatment for deep-seated and metastatic tumors, but its efficacy is limited by the immunosuppressive tumor microenvironment (TME) and a narrow therapeutic window. This study aimed to develop a novel nanoplatform to overcome these constraints by simultaneously sensitizing tumors to radiation, inducing cuproptosis, and reprogramming the immunosuppressive TME.Methods We engineered a PEGylated copper-loaded black phosphorus nanoplatform (BPNS@Cu-PEG). Its functionality as a radiosensitizer and cuproptosis inducer was evaluated. The mechanisms of TME reprogramming were investigated, including glutathione (GSH) depletion, reactive oxygen species (ROS) amplification, hypoxia alleviation, and M2-to-M1 macrophage repolarization. Furthermore, we systematically evaluated its antitumor immune effects in vitro and in vivo.Results BPNS@Cu-PEG was synthesized with a high copper incorporation rate of 93%. In vitro cellular assays confirmed that the internalized nanoplatform effectively induced cuproptosis and immunogenic cell death (ICD) while simultaneously regulating the TME. In vivo, BPNS@Cu-PEG not only potently inhibited tumor progression and stimulated robust antitumor immunity under low-dose radiotherapy but also exhibited an excellent safety profile.Conclusion This work establishes a copper-based, low-dose radioimmunotherapy strategy. The BPNS@Cu-PEG nanoplatform presents a viable and potent strategy to counteract radioresistance and promote systemic antitumor immunity, potentially broadening the therapeutic application and safety profile of RIT.
研究领域:
纳米医学
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癌症免疫治疗
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放射肿瘤学
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肿瘤生物学
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材料科学
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-22
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IF 12.6
Deng Wen,Chen Yuan,Bai Yongke,Shang Haojie,Wu Jian,Zhong Zichen,Ba Xiaozhuo,Tong Yonghua,He Yu,Jiang Kehua,Tang Kun
Immunotherapy has become a promising and transformative approach for treating advanced or treatment-resistant bladder cancer (BCa). However, its efficacy remains limited due to the immunosuppressive tumor microenvironment (TME) and insufficient immune cell infiltration. Photothermal therapy (PTT), which could cause immunogenic cell death (ICD) in tumor tissue, has been explored as a synergistic approach for bladder cancer immunotherapy. Yet, thermal resistance in cancer cells often undermines the effectiveness of PTT. To address these challenges, we proposed a novel strategy that combines PTT with cuproptosis, a recently identified form of ICD, by engineering Tim-3-overexpressing T cell membrane-coated nanoparticles (Tim3@PHSM@IC) to enhance BCa immunotherapy. The overexpression of Tim-3 on the T cell membrane enabled precise targeting of tumor cells and competitively inhibited the Tim-3 receptor on T cells through recognition of Galectin-9. In vitro, Tim3@PHSM@IC nanoparticles effectively induced photothermal cytotoxicity and robust cuproptosis. In vivo, these nanoparticles significantly inhibited tumor growth in multiple BCa mouse models. Flow cytometry (FCM) and RNA sequencing (RNA-seq) analyses revealed that Tim3@PHSM@IC nanoparticles reprogrammed the TME by activating immune-related genes and enhancing ICD This study highlights the potential of Tim3@PHSM@IC nanoparticles in overcoming the immunosuppressive TME and improving the efficacy of BCa immunotherapy by integrating PTT and cuproptosis.
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CHEMICAL ENGINEERING JOURNAL
·
2025
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IF 13.2
Shuaiyin Zhang,Xinran Xie,Ming Liu,Zhixin Li,Yang Ye,Liang Peng,Kexing Lyu,Xiaomei Sun,Yuan Yuan,Zhijun Zhang,Weiping Wen,Zhaoxu Tu
Chemoresistance and the immunosuppressive tumor microenvironment (TME) severely constrain the current cancer therapy, which is a global clinical challenge. To address these issues, we engineered TPEC@CM, a biomimetic nanoplatform that synergizes chemotherapy with cuproptosis induction. This system employs homologous cancer cell membrane-coated Ti 3 C 2 nanosheets for targeted delivery, co-loaded with a cisplatin (DDP) prodrug succinato diamminedichloroplatinum (SDDP) and a copper ionophore complex (Elesclomol-Cu). The biomimetic coating ensures tumor-specific accumulation of the payloads while minimizing off-target toxicity. Upon reaching the tumor site, SDDP depletes intracellular glutathione (GSH), thereby reducing copper chelation and unleashing Pt (II)-mediated DNA damage and apoptosis. Concurrently, Elesclomol-Cu disrupts mitochondrial copper homeostasis, inducing cuproptosis via dihydrolipoamide S -acetyltransferase (DLAT) oligomerization and Fe S cluster protein degradation, ultimately collapsing mitochondrial integrity and metabolic activity. Crucially, the synergistic chemo-cuproptosis effect provokes immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) that drive dendritic cell maturation and reprogram the immunosuppressive TME. RNA-seq analysis of DDP-resistant MC38 cells revealed heightened mitochondrial metabolic pathways, sensitizing the tumor cells to cuproptosis, resulting in reversed DDP resistance by TPEC@CM. Furthermore, TPEC@CM treatment with anti-programmed death-ligand 1 (anti-PD-L1) checkpoint blockade amplified anti-tumor efficacy, highlighting its potential for combinatorial tumor therapy. This study pioneers a dual-pathway strategy—combining chemotherapy and cuproptosis—to dismantle chemoresistance and amplify immune responses, presenting a clinically translatable paradigm for cancer therapy.
研究领域:
肿瘤学
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生物医学工程
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免疫学
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材料科学
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DOI
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Journal of Materials Chemistry B
·
2025
·
IF 5.7
Penghui Wang,Runming Zhong,Yingzhe Wu,Lingli Jin,Yanan Zhang,Kailong Zhang,Fan Zhao
Sonodynamic therapy (SDT) is a promising noninvasive cancer treatment with deep tissue penetration, but its therapeutic efficacy is limited by insufficient reactive oxygen species (ROS) production. Herein, we developed copper-based sonosensitizer (CCG MPNs) by coordinating copper ions (Cu2+) with chlorin e6 (Ce6) and gallic acid (GA) for dual-amplified ROS-mediated tumor therapy and cuproptosis induction. CCG MPNs dissociate in the high-glutathione (GSH) tumor microenvironment, releasing Cu ions, Ce6, and GA. GA rapidly depletes GSH, enhancing tumor cell sensitivity to ROS and cuproptosis. Additionally, the released Cu+ ions generate cytotoxic hydroxyl radicals via a highly efficient Fenton reaction and ultrasound (US) activation of Ce6 produces singlet oxygen, amplifying ROS-mediated apoptosis by evoke chemodynamic therapy (CDT) and SDT. Moreover, the yielded ROS would cut off the ATP supply, resulting in a decrease in the expression of the copper transporter protein ATP7A. Large accumulations of intracellular Cu+ ions can be more readily induce cuproptosis by promoting lipoylated protein aggregation. In vitro and in vivo anti-tumor studies showed that CCG MPNs group under US treatment exhibited better anti-tumor performance. This multimodal approach overcomes the limitations of the tumor microenvironment, offering a synergistic strategy to enhance tumor therapy efficiency through combined ROS generation and cuproptosis activation.
研究领域:
生物医学工程
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肿瘤学
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纳米医学
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光化学
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材料科学
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PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Qing-Hua Shen,Long-Bo Yu,Shan-Ming Yao,Zhi-Yuan Li,Qi-Qi Zhang,Peng Wang,Cai-Ping Tan
Metalloenzyme mimics based on small molecules are valuable therapeutic candidates, but there are few reports on their mechanism of action. Inspired by natural enzymes, we designed two Cu–Fe bimetallic multienzyme mimetics (CuFc1 and CuFc2). Due to the coordination of the bimetallic centers, CuFc1 exhibits mimetic activities for multiple enzymes, including peroxidase (POD), catalase (CAT), superoxide dismutase (SOD), and glutathione oxidase (GSHOx). CuFc1 can catalyze cascade reactions from •O2– and H2O2 to O2 and •OH, which leads to a storm of reactive oxygen species and causes cuproptosis and ferroptosis in cancer cells simultaneously. As CuFc1 treatment upregulates the expression of PD-L1, it acts synergistically with the PD-L1 inhibitor (BMS-1) to remodel the tumor immune microenvironments and stimulates intense anticancer immune responses in vivo. In summary, through reasonable molecular design, we first demonstrate the enormous potential of metallo small molecule-based multienzyme mimics in cancer immunotherapy.
研究领域:
生物无机化学
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癌症生物学
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免疫治疗
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酶学
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金属药物
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PubMed
高影响因子
MATERIALS & DESIGN
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2026
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IF 8.2
Yuman Dong,Jieru Li,Xinyu Zhang,Weihao Jiao,Siyuan Hou,Huiguo Qing,Wentao Zhang,Juanjuan Liu,Pengcheng Du,Zeyuan Yu,Zuoyi Jiao
Redox-responsive ICMNs enable tumor-specific Cu 2+ / Icaritin co-delivery. • Released Icaritin amplifies cuproptosis via ROS generation, and GSH depletion. • ICMNs triggers immunogenic cell death and activates antitumor immunity. • ICMNs inhibits tumor growth, extends survival, and lacks systemic toxicity. Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited therapeutic options, largely due to its metabolic adaptability and immunosuppressive tumor microenvironment. Cuproptosis has emerged as a promising therapeutic strategy, however, its efficacy in solid tumors is constrained by intracellular redox buffering and insufficient bioavailable copper. Here, we developed a redox-responsive copper-based nanoplatform (ICMNs) by integrating icaritin (ICA) into a copper metal-organic framework to synergistically induce cuproptosis and immunotherapy. After cell internalization, ICMNs underwent glutathione (GSH)-triggered disassembly, co-releasing Cu 2+ and ICA. Mechanistically, ICMNs elevated intracellular reactive oxygen species levels by ∼ 145-fold while depleted GSH by 56%, thereby amplifying oxidative stress and mitochondrial dysfunction. Furthermore, ICMNs triggered prominent immunogenic cell death, evidenced by a 5.4-fold increase in calreticulin exposure, enhanced HMGB1 release, and ATP secretion, which promoted dendritic cell maturation and CD8 + T-cell activation. In patient-derived organoids, ICMNs reduced organoid viability by over 85%. In PDAC KPC subcutaneous transplant tumor mouse models, ICMNs achieved an 85.6% tumor inhibition rate and significantly prolonged median survival (41.5 vs. 15 days) without obvious systemic toxicity. Collectively, our findings demonstrate that redox potentiates copper-induced tumor cell death and antitumor immunity, offering a promising nanotherapeutic strategy for PDAC treatment. Download: Download high-res image (159KB) Download: Download full-size image
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Luyao Xu,Jing Feng,Shihao Xu,Mingli Jin,Xianyue Bai,Hui Zhang,Minghui Zhu,Shengmin Lin,Jiaxing Song,Cuixia Lu
Multimodal targeted combination therapy that harnesses synergistic effects has emerged as a transformative paradigm in cancer therapy, progressively replacing traditional monotherapy. Herein, we report a tumor microenvironment (TME)-responsive multifunctional nanoplatform Cu-Ce6@DHA NPs (CCD NPs), which is self-assembled through the coordination of Cu²⁺, the antitumor drug dihydroartemisinin (DHA), and the photosensitizer chlorin e6 (Ce6). This nanoplatform enables the near-infrared-triggered combination of cuproptosis and ferroptosis for tumor treatment. Upon internalization by tumor cells, these nanoparticles undergo glutathione (GSH)-triggered disintegration, releasing their encapsulated payloads within the TME. The released Ce6 mediates potent photodynamic therapy (PDT) under laser irradiation, and DHA undergoes GSH-dependent activation to generate cytotoxic reactive oxygen species (ROS) and suppresses glutathione peroxidase 4 (GPX4), thereby amplifying ferroptotic cell death. Concurrently, the released copper ions deplete intracellular GSH and further inhibit GPX4, which exacerbates lipid peroxidation and promotes ferroptosis. Notably, the intracellular accumulation of copper ions disrupts mitochondrial metabolism by destabilizing iron-sulfur cluster (Fe-S) proteins and inducing oligomerization of lipoylated lipoylated dihydrolipoamide S-acetyltransferase (DLAT), ultimately triggering cuproptosis. Therefore, our findings establish a novel nanoplatform that simultaneously exploits metabolic vulnerabilities (via cuproptosis), redox imbalances (via ferroptosis), and photodynamic effects, providing a promising multimodal therapeutic strategy for cancer treatment.
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高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2025
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IF 9.7
Lihua Wang,Yang Deng,Xionghongcan Zhou,Kaiyue Song,Cong Jiang,Feng Zhao,Xianglong Li
Cuproptosis holds promise for breast cancer therapy, yet systemic copper delivery risks off-target toxicity, and intrinsic tumor resistance mechanisms limit its therapeutic efficacy. To overcome this obstacle, a biodegradable hybrid nanomedicine (designated CaO 2 @CuPDA) was designed to dual-amplify cuproptosis through Ca 2+ -overload and photothermal effects for potent immunotherapy. The nanomedicine comprises a calcium peroxide (CaO 2 ) core encapsulated within a copper–polydopamine shell, which stabilizes CaO 2 against premature hydrolysis and confers tumor microenvironment-responsive behavior, photothermal capability, and controlled Cu 2+ release. Upon exposure to the acidic, glutathione (GSH)-rich tumor microenvironment, CaO 2 @CuPDA disintegrates, concurrently releaseing Cu 2+ /Ca 2+ and generating H 2 O 2 . The Fenton-like reaction catalyzed by GSH-reduced Cu + converts H 2 O 2 into hydroxyl radicals, elevating intracellular oxidative stress. Simultaneously, FDX1-mediated reduction of excess Cu 2+ to Cu + inhibits the synthesis of iron‑sulfur cluster proteins to trigger cuproptosis. Critically , this cuproptosis degree is dramatically potentiated by Ca 2+ -overload, increased ROS, and photothermal effects. The amplified cuproptosis elicits robust releasing damage-associated molecular patterns (DAMPs) that activate dendritic cells and recruit cytotoxic T lymphocytes, leading to potent antitumor immunity and suppressed tumor growth in vivo. This work presents a safe and efficient nanoplatform for cuproptosis potentiation, providing a novel strategy for breast cancer treatment.
研究领域:
纳米医学
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癌症治疗
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生物无机化学
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光热治疗
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免疫治疗
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活性氧信号传导
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药物递送系统
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高影响因子
ACS Nano
·
2025
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IF 16
Wenxian Zhang,Zhi-Yuan Feng,Zhe Feng,Rui Lian,Zheng Liu,Jingjing Zhang
Despite the promise of cuproptosis in antitumor therapy, developing strategies to enhance its therapeutic efficacy within the tumor microenvironment remains a challenge. Inspired by the chronotherapy that manipulate circadian rhythms to enhance drug effectiveness, herein we report for a CRISPR-customized copper-DNA nanoplatform (Cu-RNP) that synergistically induces multimodal cell death, including potentiated cuproptosis, by manipulating circadian and metabolic pathways. Cu-RNP integrates coordination-driven self-assembly of Cu2+-DNA nanospheres with Cas13d/crRNA ribonucleoproteins targeting BMAL1. Upon cellular internalization, the acidic and reducing endo/lysosomal environment triggers Cu-RNP disassembly, releasing RNP to silence BMAL1 and disrupt circadian oscillations, leading to WEE1 downregulation and p21 upregulation, thereby inducing apoptosis. Simultaneously, liberated Cu2+ generates cytotoxic hydroxyl radicals for chemodynamic therapy (CDT) and concurrently depletes GSH, promoting mitochondrial copper overload for cuproptosis. Importantly, we demonstrate that silencing BMAL1 disrupts circadian rhythms, inhibits glycolysis, enhances mitochondrial respiration, and redirects metabolic flux to the TCA cycle, thereby amplifying the cell’s vulnerability to copper-induced cuproptosis. In vitro and in vivo results demonstrate that Cu-RNP sensitizes cancer cells to cuproptosis and elicit strong antitumor response through the synergistic combination of cuproptosis, CDT, apoptosis, and circadian-metabolic modulation. This study demonstrates a mechanistic link between BMAL1-regulated circadian rhythms and cuproptosis sensitivity, suggesting a potential treatment strategy for multimodal, cuproptosis-potentiating cancer therapies.
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高影响因子
Science Advances
·
2024
·Vol. 10
·期 15
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IF 11.7
Kerong Chen,Anwei Zhou,Xinyuan Zhou,Jielei He,Yurui Xu,Xinghai Ning
Disruptions in metal balance can trigger a synergistic interplay of cuproptosis and ferroptosis, offering promising solutions to enduring challenges in oncology. Here, we have engineered a Cellular Trojan Horse, named MetaCell, which uses live neutrophils to stably internalize thermosensitive liposomal bimetallic Fe-Cu MOFs (Lip@Fe-Cu-MOFs). MetaCell can instigate cuproptosis and ferroptosis, thereby enhancing treatment efficacy. Mirroring the characteristics of neutrophils, MetaCell can evade the immune system and not only infiltrate tumors but also respond to inflammation by releasing therapeutic components, thereby surmounting traditional treatment barriers. Notably, Lip@Fe-Cu-MOFs demonstrate notable photothermal effects, inciting a targeted release of Fe-Cu-MOFs within cancer cells and amplifying the synergistic action of cuproptosis and ferroptosis. MetaCell has demonstrated promising treatment outcomes in tumor-bearing mice, effectively eliminating solid tumors and forestalling recurrence, leading to extended survival. This research provides great insights into the complex interplay between copper and iron homeostasis in malignancies, potentially paving the way for innovative approaches in cancer treatment.
研究领域:
肿瘤学
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纳米技术
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治疗学
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生物医学工程
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DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Wei Zhang,Ziling Chen,Chen Xiong,Lizhen Yuan,Jing-Jing Hu,Jun Dai,Fan Xia,Xiaoding Lou
Cuproptosis is a type of metabolic cell death and exhibits great potential for cancer treatment. However, currently, most cuproptosis-based therapies are primarily effective in tumor cells reliant on mitochondrial respiration, limiting their broader application. The Warburg effect highlights that many tumors predominantly rely on glycolysis to meet their rapid metabolic demands, but glycolysis-dependent cells are less sensitive to copper ions than their mitochondrial-respiration-dependent counterparts, making it difficult to induce cuproptosis in these cells. Herein, we designed a copper-loaded peptide-based nanoparticle (MHRC@Cu) to enhance cuproptosis by metabolic reprogramming in a wider range of glycolysis-dependent tumor cells. Specifically, triggered by the acidic environment and laser irradiation, MHRC@Cu effectively released Cu2+ inside the cells. Then the peptide-conjugated probe (MHRC) reprogrammed glycolysis-dependent tumor cells, making them more dependent on mitochondrial respiration and increasing their sensitivity to copper ions. Additionally, the H2O2 generated by the photodynamic effect underwent Fenton reaction with Cu2+ in situ, producing highly toxic ·OH, which depleted GSH and disrupted copper efflux protein, thereby exacerbating copper deposition in cells. Through these synergistic mechanisms, MHRC@Cu significantly enhanced cuproptosis in glycolysis-dependent tumor cells, achieving up to 96% inhibition of tumor growth. This copper-loaded peptide-based nanoparticle offers a versatile and potent strategy for enhancing cuproptosis and may inspire the development of advanced self-assembled nanotherapeutic platforms.
研究领域:
癌症治疗
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纳米技术
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生物化学
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细胞生物学
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PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2023
·
IF 7.5
Wenchang Yang,Yaxin Wang,Yongzhou Huang,Jiaxian Yu,Tao Wang,Chengguo Li,Lei Yang,Peng Zhang,Liang Shi,Yuping Yin,Kaixiong Tao,Ruidong Li
Cuproptosis, a novel copper-induced cell death pathway, is linked to mitochondrial respiration and mediated by protein lipoylation. The discovery of cuproptosis unfolds new areas of investigation, particularly in cancers. The present study aimed to explore the role of cuproptosis in colorectal cancer progression. The genetic alterations of cuproptosis in colon cancer were evaluated using a database. MTT assays, colony formation, and flow cytometry were used to examine the effect of elesclomol-Cu and 4-Octyl itaconate (4-OI) on colorectal cancer cell and oxaliplatin-resistant cell viability. The anti-tumor effect of elesclomol with 4-OI was verified in vivo assay. The results showed that FDX1, SDHB, DLAT, and DLST genes were more highly expressed in normal tissues than those in primary tumor tissues. Patients with high expressions of these genes in tumor tissues had a better prognosis. Using MTT assay and colony formation analysis, elesclomol-Cu pulse treatment showed significant inhibition of cell viability in HCT116, LoVo, and HCT116-R cells. In addition, flow cytometry revealed elesclomol-Cu significantly promoted apoptosis. Tetrathiomolybdate, a copper chelator, markedly inhibited cuproptosis. Subsequently, we found 2-deoxy- D -glucose, a glucose metabolism inhibitor, sensitized cuproptosis. Furthermore, galactose further promoted cuproptosis. Interestingly, 4-OI significantly enhanced cuproptosis which was irrelevant to ROS production, apoptosis, necroptosis, or pyroptosis pathways. Aerobic glycolysis was inhibited by 4-OI through GAPDH, one of the key enzymes of glycolysis, sensitizing cuproptosis. Meanwhile, FDX1 knockdown weakened the ability of 4-OI to promote cuproptosis. In vivo experiments, 4-OI with elesclomol-Cu showed better anti-tumor effects. These results indicated that elesclomol-Cu rapidly halted cell growth in colorectal cancer cells and oxaliplatin-resistant cell line. Importantly, we revealed that 4-OI inhibited aerobic glycolysis by targeting GAPDH to promote cuproptosis.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
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