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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. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs), enabled to self-renew, differentiate, and initiate the bulk tumor, are recognized as the culprit of treatment resistance, metastasis, and recurrence. Simultaneously eradicating CSCs and bulk cancer cells is crucial for successful cancer therapy. Herein, we reported that doxorubicin (Dox) and erastin co -loaded hydroxyethyl starch-polycaprolactone nanoparticles (DEPH NPs) eliminated CSCs and cancer cells by regulating redox status. We found that an excellently synergistic effect existed when Dox and erastin were co-delivered by DEPH NPs. Specifically, erastin could deplete intracellular glutathione (GSH), thereby inhibiting the efflux of intracellular Dox and boosting Dox-induced reactive oxygen species (ROS) to amplify redox imbalance and oxidative stress. The high ROS levels restrained CSCs self-renewal via downregulating Hedgehog pathways, promoted CSCs differentiation, and rendered differentiated cancer cells vulnerable to apoptosis. As such, DEPH NPs significantly eliminated not only cancer cells but more importantly CSCs, contributing to suppressed tumor growth, tumor-initiating capacity, and metastasis, in various tumor models of triple negative breast cancer. This study demonstrates that the combination of Dox and erastin is potent in elimination of both cancer cells and CSCs, and that DEPH NPs represent a promising treatment against CSCs-rich solid tumors. DEPH nanoparticles eliminate cancer stem cells (CSCs) by destroying the redox equilibrium to suppress CSCs self-renewal pathway, promote differentiation and induce apoptosis. [Display omitted] • DEPH NPs simultaneously and precisely release erastin and Dox for synergistic effect. • Erastin enhances Dox tumor accumulation and aggrandizes Dox-induced oxidative stress. • DEPH NPs potently suppress both CSCs and cancer cells by regulating redox balance. • This study provides novel insights on combination therapy and anti-CSCs therapy. [ABSTRACT FROM AUTHOR]

High reactive oxygen species (ROS) levels provide a therapeutic opportunity to eradicate cancer stem cells (CSCs), a population of cells responsible for tumorigenesis, progression, metastasis, and recurrence. However, enhanced antioxidant systems in this population of cells attenuate ROS-inducing therapies. Here, we developed a nanoparticle-assisted combination therapy to eliminate CSCs by employing photodynamic therapy (PDT) to yield ROS while disrupting ROS defense with glutaminolysis inhibition. Specifically, we leveraged an oleic acid-hemicyanine conjugate (CyOA) as photosensitizer, a new entity molecule HYL001 as glutaminolysis inhibitor, and a biocompatible folic acid-hydroxyethyl starch conjugate (FA-HES) as amphiphilic surfactant to construct cellular and mitochondrial hierarchical targeting nanomedicine (COHF NPs). COHF NPs inhibited glutaminolysis to reduce intracellular ROS scavengers, including glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH), and to blunt oxidative phosphorylation (OXPHOS) for oxygen-conserved PDT. Compared to COLF NPs without glutaminolysis inhibitor, COHF NPs exhibited higher phototoxicity to breast cancer stem cells (BCSCs) both in vitro and in vivo. More importantly, we corroborated that marketed glutaminolysis inhibitors, such as CB839 and V9302, augment the clinically used photosensitizer (Hiporfin) for BCSCs elimination. This study develops a potent CSCs targeting strategy by combining glutaminolysis inhibition with PDT and provides significant implications for cancer therapy. This study reports a hierarchical targeting nanoparticle with high drug loading efficiency, consisting of an oleic acid modified photosensitizer and a glutaminolysis inhibitor, which amplifies oxidative stress by reducing intracellular ROS scavengers and enabling oxygen conserving photodynamic therapy, resulting in potent eradication of cancer stem cells. [Display omitted] • COHF NPs is a cellular and mitochondrial hierarchical targeting nano-formulation. • COHF NPs engage in two-way cross-talk to synergistically amplify oxidative stress for CSCs elimination. • This study develops a potent CSCs elimination strategy by combining glutaminolysis inhibition with photodynamic therapy. [ABSTRACT FROM AUTHOR]