One‐Stone‐Two‐Birds Carrier‐Free Nano‐Cocktail Enables Synergistic Eradication of Cancer Cells/Stem Cells in Breast Cancer Treatment

Cancer stem cells (CSCs) are widely recognized as the culprits of chemoresistance, tumor metastasis, and relapse. Moreover, most chemotherapeutic drugs not only fail to eliminate CSCs effectively, but also induce the acquisition of stemness characteristics in non-stem cancer cells. Herein, we propose a cancer cells/CSCs double-killing modality for breast cancer treatment. Specifically, a carrier-free nano-cocktail is developed through the precise co-assembly of a redox-responsive docetaxel (DTX) dimeric prodrug and salinomycin (SAL, an anti-CSCs drug). Precision combination of DTX and SAL not only shows synergistic tumor-killing activity, but also sharply reduces the proportion of CSCs in tumors. More importantly, tumor-specific prodrug activation-initiated drug release from the nano-cocktail confers high drug co-delivery efficiency and low off-target toxicity risk. As expected, such a one-stone-two-birds nanomedicine presents satisfactory performance on tumor stemness eradication, antitumor responses, and safety in both xenograft and orthotopic 4T1 breast cancer mouse models. This study advances cancer cells/CSCs double-killing nanotherapeutics towards clinical breast cancer therapy.