Abstract

Cancer stem cells (CSCs) have been recognized as the culprit for tumor progression, treatment resistance, metastasis, and recurrence while redox homeostasis represents the Achilles' Heel of CSCs. However, few drugs or formulations that are capable of elevating oxidative stress have achieved clinical success for eliminating CSCs. Here, we report hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanoparticles ( [email protected] NPs), which conspicuously suppress CSCs not only in vitro but also in numerous tumor models in vivo . Furthermore, [email protected] NPs effectively inhibit CSCs in fresh tumor tissues surgically excised from hepatocellular carcinoma patients. Mechanistically, we uncover that hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanocrystals via copper‑oxygen coordination interactions, thereby promoting copper-diethyldithiocarbamate colloidal stability, cellular uptake, intracellular reactive oxygen species production, and CSCs apoptosis . As all components are widely used in clinics, [email protected] NPs represent promising treatments for CSCs-rich solid malignancies and hold great clinical translational potentials. This study has critical implications for design of CSCs targeting nanomedicines .