A Self‐Assembly Nano‐Prodrug for Combination Therapy in Triple‐Negative Breast Cancer Stem Cells

Abstract Triple‐negative breast cancer (TNBC) displays a highly aggressive nature that originates from a small subpopulation of TNBC stem cells (TNBCSCs), and these TNBCSCs give rise to chemoresistance, tumor metastasis, and recurrence. Unfortunately, traditional chemotherapy eradicates normal TNBC cells but fails to kill quiescent TNBCSCs. To explore a new strategy for eradicating TNBCSCs, a disulfide‐mediated self‐assembly nano‐prodrug that can achieve the co‐delivery of ferroptosis drug, differentiation‐inducing agent, and chemotherapeutics for simultaneous TNBCSCs and TNBC treatment, is reported. In this nano‐prodrug, the disulfide bond not only induces self‐assembly behavior of different small molecular drug but also serves as a glutathione (GSH)‐responsive trigger in controlled drug release. More importantly, the differentiation‐inducing agent can transform TNBCSCs into normal TNBC cells, and this differentiation with chemotherapeutics provides an effective approach to indirectly eradicate TNBCSCs. In addition, ferroptosis therapy is essentially different from the apoptosis‐induced cell death of differentiation or chemotherapeutic, which causes cell death to both TNBCSCs and normal TNBC cells. In different TNBC mouse models, this nano‐prodrug significantly improves anti‐tumor efficacy and effectively inhibits the tumor metastasis. This all‐in‐one strategy enables controlled drug release and reduces stemness‐related drug resistance, enhancing the chemotherapeutic sensitivity in TNBC treatment.