Responsive ROS‐Augmented Prodrug Hybridization Nanoassemblies for Multidimensionally Synergitic Treatment of Hepatocellular Carcinoma in Cascade Assaults

Responsive ROS‐Augmented Prodrug Hybridization Nanoassemblies for Multidimensionally Synergitic Treatment of Hepatocellular Carcinoma in Cascade Assaults

Abstract The rapid deterioration and progression of hepatocellular carcinoma (HCC) is intimately associated with copper ion overload, and integrating the cuproptosis mechanism for the treatment of HCC presents a promising prospect. Nevertheless, cell death complexity renders efficient removal of all...

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Main Authors: Yingjie Zeng, Yuening Cao, Senmiao Ren, Chaozheng Zhang, Jianan Liu, Ke Liu, Yan Wang, Hongyu Chen, Fengjiao Zhou, Xiuli Yang, Xian Ge, Tingting Zhang, Tianbao Wang, Yao He, Defang Li, Chuantao Zhang, Jun Lu
Format: Article
Language:English
Published: Wiley 2025-08-01
Series:Advanced Science
Subjects:
cascade assaults
cuproptosis
hepatocellular carcinoma
oxidative stress
prodrug hybridization nanoassembly
Online Access:https://doi.org/10.1002/advs.202501420
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Summary:Abstract The rapid deterioration and progression of hepatocellular carcinoma (HCC) is intimately associated with copper ion overload, and integrating the cuproptosis mechanism for the treatment of HCC presents a promising prospect. Nevertheless, cell death complexity renders efficient removal of all HCC cells insufficient solely relying on the cuproptosis pathway. Herein, the GSH‐responsive prodrug hybridization nanoassembly CA‐4S2@ES‐Cu is exploited, which targets the delivery of copper ions to mitochondria via Elesclomol, contributing to mitochondrial dysfunction and evoking cuproptosis. Simultaneously, CA‐4S2 depletes GSH to release CA‐4, disrupting microtubule function and suppressing HCC cell proliferation and angiogenesis, to realize a dual attack against copper ion‐mediated deterioration and metastasis of HCC. Furthermore, both in the HCC mouse model synergistically elicit oxidative stress to amplify the cuproptosis effect and release activated immunogenetic cell death to initiate a vigorous antitumor immune response in cascade assault modality. Conclusively, the multilevel synergistic assault penetrates the limitations of single therapy and implements a multidimensional targeted treatment for HCC.
ISSN:2198-3844

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