Self‐Reliant Nanomedicine with Long‐Lasting Glutathione Depletion Ability Disrupts Adaptive Redox Homeostasis and Suppresses Cancer Stem Cells

Abstract Bulk cancer cells and cancer stem cells (CSCs) harbor efficient and adaptive redox systems to help them resist oxidative insults arising from diverse therapeutic modalities. Herein, a tumor microenvironment (TME)‐activatable nano‐modulator capable of disrupting adaptive redox homeostasis, prepared by integrating FDA‐approved xCT inhibitor sulfasalazine (SSZ) into pH‐responsive hydroxyethyl starch‐doxorubicin conjugate stabilized copper peroxide nanoparticles (HSCPs) is reported. Compared to poly(vinylpyrrolidone) (PVP)‐stabilized copper peroxide nanoparticles, HSCPs exhibit superior physiological stability, longer circulation half‐life, and higher tumor enrichment. Under an acidic TME, the active components inside HSCPs are productively released along with the disintegration of HSCPs. The specifically generated hydrogen peroxide (H₂O₂) from copper peroxide nanoparticles furnishes a constant power source for copper‐mediated hydroxyl radical (•OH) production, serving as a wealthy supplier for oxidative stress. Meanwhile, the tumor‐specific release of Cu²⁺ and SSZ can induce long‐lasting glutathione (GSH) depletion via copper‐mediated self‐cycling valence transitions and SSZ‐blocked GSH biosynthesis, thereby reducing the offsetting action of the antioxidant GSH against oxidative stress. As a result, this sustained oxidative stress potently restrains the growth of aggressive orthotopic breast tumors while suppressing pulmonary metastasis by eradicating CSC populations. The reported smart nanomedicine provides a new paradigm for redox imbalance‐triggered cancer therapy.