Utilization of DOX–Fe complex and RSL3 co-loaded liposomes in ferroptosis-enhanced treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer and is characterized by high invasiveness, rapid recurrence, and poor prognosis. To date, the ferroptosis-combined therapies have exerted their potential in the TNBC treatments via multi-mechanisms. Here, we reported a doxorubicin (DOX)-Fe complex and RSL3 co-loaded liposomes (DOX-Fe/RSL3@LIPs) for ferroptosis-enhanced chemotherapy on TNBC tumors. This nanoformulation performed a uniform spherical structure with a mean particle size of 126.9 nm, a zeta potential of -3.56 mV, and high colloidal stability. The pH-responsive dissociation of DOX-Fe and release of DOX were conducive to drug accumulation in the tumor microenvironment and tumor cells, meanwhile efficiently suppressed free DOX leakage in the blood circulation, potentially reducing the cardiotoxicity of DOX. <i>In vitro</i> cell and <i>in vivo</i> pharmacodynamic studies demonstrated a favorable anticancer effect of the DOX-Fe/RSL3@LIPs on 4T1 tumors by synchronously delivering biologically active DOX, Fe²⁺, and RSL3 to the tumor sites. DOX induced tumor cell death through a dual pathway of apoptosis/ferroptosis, and promoted the H₂O₂ generation. The tumor cell ferroptosis was observably enhanced via supplements of the ferrous ions and H₂O₂, and RSL3-derived GPX4 inhibition to severely destroy the oxidation balance in cells. In this paper, the DOX-Fe/RSL3@LIPs have exerted a synergistic anticancer effect on TNBC by combining ferroptosis and conventional chemotherapy, and made a meaningful exploration of new strategies for TNBC therapy.