International journal of nanomedicine · 2026
A Multifunctional Metal-Based Nanomedicine for Copper Sequestration, in situ Toxification, and Immune Activation Against Metastatic Cancer.
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Meng Yingcai, Wang Weinan, Guo Wei, Huang Jiaxin, Zhou Wenhu, Hu Jianming
Аннотация
OBJECTIVE: Tumor metastasis remains the principal cause of cancer-related mortality. However, current therapies often fail to effectively control both primary and disseminated lesions. Copper ions (Cu2⁺) are increasingly being recognized as key regulators of tumor progression, metastasis, and immune evasion. Leveraging their tumor-promoting properties as therapeutic targets is a promising anticancer strategy.
METHODS: In this study, a multifunctional nanoplatform based on hyaluronic acid (HA)-stabilized and manganese-diethyldithiocarbamate (MnET) complex-loaded manganese dioxide (MnO2) nanosheets, denoted as MMH (MnET@MnO2-HA), was designed to deplete Cu2⁺ in the tumor microenvironment and simultaneously generate bioactive copper-diethyldithiocarbamate (CuET) in situ. MMH was systematically evaluated in terms of drug release, Cu2+ sequestration, in situ toxicity, and immune activation against primary and metastatic tumors, through both in vitro and in vivo experiments using animal models.
RESULTS: MMH exhibited CD44-targeted uptake, GSH- and pH-responsive drug release, and tumor-selective bioactivity. MMH efficiently scavenged Cu2⁺ within tumor cells, leading to the formation of CuET, which induced immunogenic cell death (ICD), marked by the release of damage associated molecular patterns (DAMPs). This process facilitated M1 macrophage repolarization, CD8⁺ T cell infiltration, and the activation of type I interferon signaling via Mn2⁺-mediated interferon regulatory factor 3 (IRF3) phosphorylation. Furthermore, MMH suppressed epithelial-mesenchymal transition (EMT) and vascular endothelial growth factor A (VEGF-A) expression, thereby impairing angiogenesis and metastatic spread. In murine 4T1 breast cancer models, MMH potently inhibited both primary and distant metastatic tumors without systemic toxicity.
CONCLUSION: MMH would be a promising approach for treating aggressive and metastatic cancers through metal-based immunometabolic intervention.
METHODS: In this study, a multifunctional nanoplatform based on hyaluronic acid (HA)-stabilized and manganese-diethyldithiocarbamate (MnET) complex-loaded manganese dioxide (MnO2) nanosheets, denoted as MMH (MnET@MnO2-HA), was designed to deplete Cu2⁺ in the tumor microenvironment and simultaneously generate bioactive copper-diethyldithiocarbamate (CuET) in situ. MMH was systematically evaluated in terms of drug release, Cu2+ sequestration, in situ toxicity, and immune activation against primary and metastatic tumors, through both in vitro and in vivo experiments using animal models.
RESULTS: MMH exhibited CD44-targeted uptake, GSH- and pH-responsive drug release, and tumor-selective bioactivity. MMH efficiently scavenged Cu2⁺ within tumor cells, leading to the formation of CuET, which induced immunogenic cell death (ICD), marked by the release of damage associated molecular patterns (DAMPs). This process facilitated M1 macrophage repolarization, CD8⁺ T cell infiltration, and the activation of type I interferon signaling via Mn2⁺-mediated interferon regulatory factor 3 (IRF3) phosphorylation. Furthermore, MMH suppressed epithelial-mesenchymal transition (EMT) and vascular endothelial growth factor A (VEGF-A) expression, thereby impairing angiogenesis and metastatic spread. In murine 4T1 breast cancer models, MMH potently inhibited both primary and distant metastatic tumors without systemic toxicity.
CONCLUSION: MMH would be a promising approach for treating aggressive and metastatic cancers through metal-based immunometabolic intervention.