Targeted therapy for triple-negative breast cancer via a membrane-encased multi-active iron-sulfur nanoinducer

Triple-negative breast cancer (TNBC) is a highly malignant form of cancer, notorious for its limited treatment alternatives. Accumulating studies have revealed its susceptibility to ferroptosis, rendering ferroptosis inducers highly promising for the treatment of this cancer. This study aimed to evaluate the effect of a membrane-encased iron-sulfur nanoinducer (ISN) for the targeted treatment of TNBC. The ISN was developed with unique features combining enzyme-like activities and iron-releasing capabilities, functioning synergistically as a potent ferroptosis inducer. It exhibited dual enzymatic activities that synergistically promoted tumor cell death. The peroxidase-like activity of the ISN intensified oxidative stress in tumor cells, while its glutathione oxidase-like activity suppressed glutathione peroxidase 4 expression and depleted glutathione. Notably, the ISN demonstrated pH-responsive properties, selectively releasing Fe²⁺ in acidic conditions to further enhance the ferroptotic effects. These combined mechanisms enabled ISN to induce programmed cell death in TNBC cells through coordinated ferroptosis, autophagy, and apoptosis pathways. Furthermore, the biomimetic coating of the ISN with TNBC cell membranes improved tumor accumulation after intravenous injection and boosted antitumor efficacy in <em>in vitro</em> and <em>in vivo</em> models. These findings provide a potential approach for TNBC treatment using a multi-active ISN.