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 HCC cells insufficient solely relying on the cuproptosis pathway. Herein, the GSH‐responsive prodrug hybridization nanoassembly CA‐4S 2 @ES‐Cu is exploited, which targets the delivery of copper ions to mitochondria via Elesclomol, contributing to mitochondrial dysfunction and evoking cuproptosis. Simultaneously, CA‐4S 2 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.