Cuproptosis-mediated stemness inhibition by a self-assembled herbal nanoplatform overcomes chemoresistance in ovarian cancer

Abstract

Ovarian cancer remains difficult to treat due to the persistence of chemoresistant cancer stem-like cells (CSCs), which are major drivers of tumor relapse. Herein, we engineered a hyaluronic acid-functionalized nanoplatform (HS-Cu@DOX) via the assembly of a shikonin–copper (SKN-Cu) coordination complex with hyaluronic acid, followed by electrostatic loading of doxorubicin (DOX), enabling tumor-targeted co-delivery of both therapeutic agents. This nanoplatform disrupts intracellular redox homeostasis to induce cuproptosis while concurrently suppressing CSC stemness through downregulation of key pluripotency-associated transcription factors (e.g., SOX2, OCT4, and NANOG). By depleting intracellular glutathione (GSH) and impairing antioxidant defenses, HS-Cu@DOX disrupts the oxidative stress resilience of CSCs, thereby restoring their sensitivity to DOX-induced apoptosis. Consequently, this strategy enhances DOX-mediated cytotoxicity and reduces systemic toxicity while maintaining potent antitumor efficacy. Collectively, our findings demonstrate that combining cuproptosis induction with CSC stemness suppression represents a promising strategy for overcoming chemoresistance, highlighting HS-Cu@DOX as a potential therapeutic candidate for recurrent ovarian cancer.