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A Stimulus‐Responsive Ternary Heterojunction Boosting Oxidative Stress, Cuproptosis for Melanoma Therapy

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Yuqi Huang
Yuqi Huang
Yuqi Huang
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Cheng Chen
Cheng Chen
Cheng Chen
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Huarong Tan
Huarong Tan
Huarong Tan
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Shuqing Dong
Shuqing Dong
Shuqing Dong
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Abstract and Figures

Cuproptosis, a recently discovered copper‐dependent cell death, presents significant potential for the development of copper‐based nanoparticles to induce cuproptosis in cancer therapy. Herein, a unique ternary heterojunction, denoted as HACT, composed of core–shell Au@Cu2O nanocubes with surface‐deposited Titanium Dioxide quantum dots and modified with hyaluronic acid is introduced. Compared to core–shell AC NCs, the TiO2/Au@Cu2O exhibits improved energy structure optimization, successfully separating electron‐hole pairs for redox use. This optimization results in a more rapid generation of singlet oxygen and hydroxyl radicals triggering oxidative stress under ultrasound radiation. Furthermore, the HACT NCs initiate cuproptosis by Fenton‐like reaction and acidic environment, leading to the sequential release of cupric and cuprous ions. This accumulation of copper induces the aggregation of lipoylated proteins and reduces iron‐sulfur proteins, ultimately initiating cuproptosis. More importantly, HACT NCs show a tendency to selectively target cancer cells, thereby granting them a degree of biosecurity. This report introduces a ternary heterojunction capable of triggering both cuproptosis and oxidative stress‐related combination therapy in a stimulus‐responsive manner. It can energize efforts to develop effective melanoma treatment strategies using Cu‐based nanoparticles through rational design.
Establishment and characterization of HACT NCs. A) TEM images of AC NCs. B) TEM images of ACT NCs (Scale bars are 50 and 200 nm). C) EDX element mapping of HACT NCs. D, E) The diameters distribution curve and zeta potential of the AC, ACT, and HACT NCs. F) UV/Vis spectroscopy of Au, AC, and HACT NCs. G) Impedance curves of AC, ACT, TiO2, and HACT NCs. H) XPS spectrum of HACT NCs. I–K) XPS spectra of Au 4f, Cu 2p, and Ti 2p in HACT NCs.
Establishment and characterization of HACT NCs. A) TEM images of AC NCs. B) TEM images of ACT NCs (Scale bars are 50 and 200 nm). C) EDX element mapping of HACT NCs. D, E) The diameters distribution curve and zeta potential of the AC, ACT, and HACT NCs. F) UV/Vis spectroscopy of Au, AC, and HACT NCs. G) Impedance curves of AC, ACT, TiO2, and HACT NCs. H) XPS spectrum of HACT NCs. I–K) XPS spectra of Au 4f, Cu 2p, and Ti 2p in HACT NCs.
… 
The generation of ROS in HACT NCs through both SDT and CDT processes. A) A schematic illustration of specific probes facilitate ROS detection. B) Generation of ¹O2 in the SDT process measured using SOSG as the probe. C) Production of ∙OH in the SDT and CDT using MB as the probe. D) Production of ∙OH in HACT + US + H2O2 group under different time was measured by MB. E) The degradation curves of MB during the various groups of processing were analyzed. F,G) Production of ∙OH under different H2O2 concentrations using TMB as the probe without US radiation or with US radiation. H) The process of generating ∙OH by HACT NCs with the use of US irradiation under varying concentrations of H2O2 was investigated. The Michaelis‐Menten and Lineweaver‐Burk fitting curves of ∙OH generation I,J) without or K,L) with US radiation. M,N) ESR spectra of ¹O2 trapped by TEMP and ∙OH trapped by DMPO under different groups.
The generation of ROS in HACT NCs through both SDT and CDT processes. A) A schematic illustration of specific probes facilitate ROS detection. B) Generation of ¹O2 in the SDT process measured using SOSG as the probe. C) Production of ∙OH in the SDT and CDT using MB as the probe. D) Production of ∙OH in HACT + US + H2O2 group under different time was measured by MB. E) The degradation curves of MB during the various groups of processing were analyzed. F,G) Production of ∙OH under different H2O2 concentrations using TMB as the probe without US radiation or with US radiation. H) The process of generating ∙OH by HACT NCs with the use of US irradiation under varying concentrations of H2O2 was investigated. The Michaelis‐Menten and Lineweaver‐Burk fitting curves of ∙OH generation I,J) without or K,L) with US radiation. M,N) ESR spectra of ¹O2 trapped by TEMP and ∙OH trapped by DMPO under different groups.
… 
In vitro cellular experiments illustrating the internalization of HACT NCs and the induction of cuproptosis. A) The mechanism of HACT NCs induced cuproptosis. B) The assessment of the degradation characteristics of HACT NCs under various conditions. C) Results of intracellular Cu content measurement. D) Fluorescence images of B16F10 cells treated with ACT NCs or HACT NCs after 0, 1, 4, and 8 h intervention (Scale bar is 50 µm). E) Schematic diagram presents the 3D spherical B16F10 cells model. F) Uptake of ACT NCs or HACT NCs by B16F10 spheroids after 4 h of incubation. Z‐stack imaging capture from the lowermost section and moving toward the central region with a spacing of 10 µm (Scale bar is 50 µm). G) LIAS and FDX1 protein expression in B16F10 cells after different concentrations of HACT NCs treatment. H,I) Gray analysis the expression of LIAS and FDX1 protein. In panels (H,I), data are presented as mean ± SD and were statistically analyzed using one‐way ANOVA. (n = 3 per group).
In vitro cellular experiments illustrating the internalization of HACT NCs and the induction of cuproptosis. A) The mechanism of HACT NCs induced cuproptosis. B) The assessment of the degradation characteristics of HACT NCs under various conditions. C) Results of intracellular Cu content measurement. D) Fluorescence images of B16F10 cells treated with ACT NCs or HACT NCs after 0, 1, 4, and 8 h intervention (Scale bar is 50 µm). E) Schematic diagram presents the 3D spherical B16F10 cells model. F) Uptake of ACT NCs or HACT NCs by B16F10 spheroids after 4 h of incubation. Z‐stack imaging capture from the lowermost section and moving toward the central region with a spacing of 10 µm (Scale bar is 50 µm). G) LIAS and FDX1 protein expression in B16F10 cells after different concentrations of HACT NCs treatment. H,I) Gray analysis the expression of LIAS and FDX1 protein. In panels (H,I), data are presented as mean ± SD and were statistically analyzed using one‐way ANOVA. (n = 3 per group).
… 
Confirmation of safety and oxidative stress triggered by HACT NCs. A) Cell viability of B16F10 cells and HaCat cells after treatment with different HACT concentrations. B) The confocal images of B16F10 cells that were treated with JC‐1 staining (Scale bar is 50 µm). C) The apoptosis markers including CC3, Bax, and Bcl‐2 were assessed by WB. D–F) Gray analyzes the expression of Bax, Bcl‐2, and CC3 protein through the utilization of diverse treatments on B16F10 cells. G) The Annexin V‐FITC and PI staining assays were performed using flow cytometry after various treatments. In panels (D–F), data are presented as mean ± SD and were statistically analyzed using one‐way ANOVA. (n = 3 per group).
Confirmation of safety and oxidative stress triggered by HACT NCs. A) Cell viability of B16F10 cells and HaCat cells after treatment with different HACT concentrations. B) The confocal images of B16F10 cells that were treated with JC‐1 staining (Scale bar is 50 µm). C) The apoptosis markers including CC3, Bax, and Bcl‐2 were assessed by WB. D–F) Gray analyzes the expression of Bax, Bcl‐2, and CC3 protein through the utilization of diverse treatments on B16F10 cells. G) The Annexin V‐FITC and PI staining assays were performed using flow cytometry after various treatments. In panels (D–F), data are presented as mean ± SD and were statistically analyzed using one‐way ANOVA. (n = 3 per group).
… 
The combined treatment efficacy of HACT NCs in B16F10 cells. A) Captured images showcasing the colony formation assay following experimental manipulation within distinct groups. B) Fluorescence microscope pictures of B16F10 cells labeled with the Ki‐67 marker were acquired for different treatment groups (Scale bar is 50 µm). C) Fluorescence microscope pictures of B16F10 cells labeled with the γ‐H2AX marker were acquired for different treatment groups (Scale bar is 10 µm). D) Fluorescence images of B16F10 cells comet experiment after corresponding processing (Scale bar is 100 µm). E) The CCK‐8 test checked the vitality of B16F10 cells following different treatment options. The cells were divided into 6 groups: 1) control (PBS); 2) US; 3) AC+US; 4) ACT+US; 5) HACT+US; 6) HACT+US+H2O2. (n = 3 per group).
+3
The combined treatment efficacy of HACT NCs in B16F10 cells. A) Captured images showcasing the colony formation assay following experimental manipulation within distinct groups. B) Fluorescence microscope pictures of B16F10 cells labeled with the Ki‐67 marker were acquired for different treatment groups (Scale bar is 50 µm). C) Fluorescence microscope pictures of B16F10 cells labeled with the γ‐H2AX marker were acquired for different treatment groups (Scale bar is 10 µm). D) Fluorescence images of B16F10 cells comet experiment after corresponding processing (Scale bar is 100 µm). E) The CCK‐8 test checked the vitality of B16F10 cells following different treatment options. The cells were divided into 6 groups: 1) control (PBS); 2) US; 3) AC+US; 4) ACT+US; 5) HACT+US; 6) HACT+US+H2O2. (n = 3 per group).
… 
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RESEARCH ARTICLE
www.small-journal.com
A Stimulus-Responsive Ternary Heterojunction Boosting
Oxidative Stress, Cuproptosis for Melanoma Therapy
Yuqi Huang, Cheng Chen, Huarong Tan, Shuqing Dong, Yiping Ren, Minghao Chao,
Hanrong Yan, Xiang Yan, Guan Jiang,* and Fenglei Gao*
Cuproptosis, a recently discovered copper-dependent cell death, presents
significant potential for the development of copper-based nanoparticles to
induce cuproptosis in cancer therapy. Herein, a unique ternary heterojunction,
denoted as HACT, composed of core–shell Au@Cu2O nanocubes with
surface-deposited Titanium Dioxide quantum dots and modified with
hyaluronic acid is introduced. Compared to core–shell AC NCs, the
TiO2/Au@Cu2O exhibits improved energy structure optimization,
successfully separating electron-hole pairs for redox use. This optimization
results in a more rapid generation of singlet oxygen and hydroxyl radicals
triggering oxidative stress under ultrasound radiation. Furthermore, the HACT
NCs initiate cuproptosis by Fenton-like reaction and acidic environment,
leading to the sequential release of cupric and cuprous ions. This
accumulation of copper induces the aggregation of lipoylated proteins and
reduces iron-sulfur proteins, ultimately initiating cuproptosis. More
importantly, HACT NCs show a tendency to selectively target cancer cells,
thereby granting them a degree of biosecurity. This report introduces a ternary
heterojunction capable of triggering both cuproptosis and oxidative
stress-related combination therapy in a stimulus-responsive manner. It can
energize efforts to develop effective melanoma treatment strategies using
Cu-based nanoparticles through rational design.
1. Introduction
Melanoma, the deadliest skin cancer, originates from
melanocytes’ malignant transformation. While advances in
biological understanding and new therapies targeting driver
genes and immune checkpoints have improved prognosis,
Y. Huang, C. Chen, H. Tan, S. Dong, Y. Ren, M. Chao, H. Yan, X. Yan,
F. Gao
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy
Xuzhou Medical University
Xuzhou, Jiangsu , P. R. China
E-mail: flgao@xzhmu.edu.cn
Y. Huang, C. Chen, H. Tan,S. Dong, Y.Ren, M. Chao, X. Yan, G. Jiang, F. Gao
Department of Dermatology
Aliated Hospital of Xuzhou Medical University
Xuzhou, Jiangsu , P. R. China
E-mail: dr.jiangguan@xzhmu.edu.cn
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/./smll.
DOI: 10.1002/smll.202401147
challenges like low response rates and re-
sistance to current therapies still hinder
further progress in melanoma treatment.[]
Therefore, it is crucial to develop ad-
vanced therapeutic strategies that can de-
liver targeted, controllable and multi-level
damage to melanoma. Since its discovery
in , various strategies have been de-
veloped to induce or enhance cupropto-
sis for cancer treatment. The creation of
nano-systems to trigger cuproptosis eec-
tively bypasses the limitations of traditional
small-molecule drugs, oering new oppor-
tunities in cancer therapy.[]Additionally,
within the cytoplasm, copper ions initiate
a Fenton-like reaction with hydrogen per-
oxide (HO), generating highly toxic hy-
droxyl radicals (∙OH) that aid in chemo-
dynamic therapy (CDT) for cancer treat-
ment. Compared to other metal ions in-
volved in Fenton-like reactions (such as
iron, cerium, manganese, and cobalt), cop-
per ions are particularly eective, showing
increased cellular toxicity.[]The high toxic-
ity of copper ions significantly limits their
use in biomedical applications. However,
when copper-based nanomaterials are used
in vivo, they do not circulate as free ions, thereby reducing po-
tential damage to normal cells. This eective mitigation allows
safer therapeutic applications. It is highly desirable to design a
single nanocomposite that can simultaneously induce the accu-
mulation of reactive oxygen species (ROS) and cuproptosis, e-
ciently halting the progression of malignant tumors.
The metal oxide semiconductors such as cuprous oxide (CuO)
have been widely investigated as excellent photocatalysts.[]Via
catalytic reactions facilitated by metal oxide semiconductors, elec-
trons (e−) and holes (h+) are separated, subsequently engaging in
intricate interactions with HO and oxygen (O) to produce ROS
including superoxide radical (O
−)and·OH.[]Nevertheless, ow-
ing to the quick e−and h+recombination from the band struc-
ture, conventional semiconductors are limited by the poor quan-
tum yield of ROS.[]This inherent limitation highly hinders fur-
ther biomedical research and clinical application. Accordingly, a
multitude of strategies have been developed to prevent carrier re-
combination. These methods encompass the integration of semi-
conductors with other semiconductors or noble metals like gold
(Au), platinum (Pt), and silver (Ag).[]The mechanism employed
to overcome carrier recombination is coordinated redistribution
Small 2024,20,  ©  Wiley-VCH GmbH
2401147 (1 of 15)
... Ultrasound-triggered generation of singlet oxygen and hydroxyl radicals by NPs effectively eliminated melanoma cells [140] Gallic acid-Fe (III) and PTX-assembled NPs Formation of intracellular ROS by NPs under ultrasound treatment resulted in mitochondrial damage, lipid peroxidation, and apoptosis in melanoma cells [141] Magnetic field-responsive Chitosan biofilm containing iron oxide NPs Hyperthermic conditions generated by NPs under AMF caused a significant elimination of MNT-1 melanoma cells [142] Curcumin and magnetic NPs-loaded thermo-sensitive nanofibers Hyperthermic conditions induced by AMF significantly enhanced curcumin release, leading to a marked reduction in B16F10 cell survival [143] J Nanopart Res ...
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Background: Acute myeloid leukemia (AML) is a highly heterogeneous cluster of hematologic malignancies. Leukemic stem cells (LSCs) are one of the culprits for the persistence and relapse of AML. The discovery of copper-induced cell death, namely cuproptosis, gives bright insights into the treatment of AML. Analogous to copper ions, long non-coding RNAs (lncRNAs) are not bystanders for AML progression, especially for LSC physiology. Uncovering the involvement of cuproptosis-related lncRNAs in AML will benefit clinical management. Methods: Detection of prognostic relevant cuproptosis-related lncRNAs are carried out by Pearson correlation analysis and univariate Cox analysis with RNA sequencing data of The Cancer Genome Atlas-Acute Myeloid Leukemia (TCGA-LAML) cohort. After the least absolute shrinkage and selection operator (LASSO) regression and the subsequent multivariate Cox analysis, a cuproptosis-related risk score (CuRS) system was derived to weigh the risk of AML patients. Thereafter, AML patients were classified into two groups by their risk property which was validated with principal component analysis (PCA), risk curves, Kaplan-Meier survival analysis, the combined receiver operating characteristic (ROC) curves, and nomogram. Variations in biological pathways and divergences in immune infiltration and immune-related processes between groups were resolved by GSEA and CIBERSORT algorism, respectively. Response to chemotherapies were scrutinized as well. The expression profiles of the candidate lncRNAs were examined by real-time quantitative polymerase chain reaction (RT-qPCR) and the specific mechanisms of lncRNA FAM30A were determined by transcriptomic analysis. Results: We fabricated an efficient prognostic signature named CuRS incorporating 4 lncRNAs (TRAF3IP2-AS1, NBR2, TP53TG1, and FAM30A) relevant to immune environment and chemotherapy responsiveness. The relevance of lncRNA FAM30A with proliferation, migration ability, Daunorubicin resistance and its reciprocal action with AUF1 were demonstrated in an LSC cell line. Transcriptomic analysis suggested correlations between FAM30A and T cell differentiation and signaling, intercellular junction genes. Conclusions: The prognostic signature CuRS can guide prognostic stratification and personalized AML therapy. Analysis of FAM30A offers a foundation for investigating LSC-targeted therapies.
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Type-I AIE Photosensitizer Loaded Biomimetic System Boosting Cuproptosis to Inhibit Breast Cancer Metastasis and Rechallenge
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  • May 2023
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Cuproptosis shows good application prospects in tumor therapy. However, the copper efflux mechanism and highly expressed intracellular reducing substances can inhibit the cuproptosis effects. In this study, a platelet vesicle (PV) coated cuprous oxide nanoparticle (Cu2O)/TBP-2 cuproptosis sensitization system (PTC) was constructed for multiple induction of tumor cuproptosis. PTC was prepared by physical extrusion of AIE photosensitizer (TBP-2), Cu2O, and PV. After the biomimetic modification, PTC can enhance its long-term blood circulation and tumor targeting ability. Subsequently, PTC was rapidly degraded to release copper ions under acid conditions and hydrogen peroxides in tumor cells. Then, under light irradiation, TBP-2 quickly enters the cell membrane and generates hydroxyl radicals to consume glutathione and inhibit copper efflux. Accumulated copper can cause lipoylated protein aggregation and iron-sulfur protein loss, which result in proteotoxic stress and ultimately cuproptosis. PTC treatment can target and induce cuproptosis in tumor cells in vitro and in vivo, significantly inhibit lung metastasis of breast cancer, increase the number of central memory T cells in peripheral blood, and prevent tumor rechallenge. It provides an idea for the design of nanomedicine based on cuproptosis.
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