Ferroptosis-enhanced chemotherapy for triple-negative breast cancer with magnetic composite nanoparticles

Triple-negative breast cancer (TNBC) causes great suffering to patients because of its heterogeneity, poor prognosis, and chemotherapy resistance. Ferroptosis is characterized by iron-dependent oxidative damage by accumulating intracellular lipid peroxides to lethal levels, and plays a vital role in the treatment of TNBC based on its intrinsic characteristics. To identify the relationship between chemotherapy resistance and ferroptosis in TNBC, we analyzed the single cell RNA-sequencing public dataset of GSE205551. It was found that the expression of Gpx4 in DOX-resistant TNBC cells was significantly higher than that in DOX-sensitive TNBC cells. Based on this finding, we hypothesize that inducing ferroptosis by inhibiting the expression of Gpx4 can reduce the resistance of TNBC to DOX and enhance the therapeutic effect of chemotherapy on TNBC. Herein, dihydroartemisinin (DHA)-loaded polyglutamic acid-stabilized Fe₃O₄ magnetic nanoparticles (Fe₃O₄-PGA-DHA) was combined with DOX-loaded polyaspartic acid-stabilized Fe₃O₄ magnetic nanoparticles (Fe₃O₄-PASP-DOX) for ferroptosis-enhanced chemotherapy of TNBC. Compared with Fe₃O₄-PASP-DOX, Fe₃O₄-PGA-DHA + Fe₃O₄-PASP-DOX demonstrated significantly stronger cytotoxicity against different TNBC cell lines and achieved significantly more intracellular accumulation of reactive oxygen species and lipid peroxides. Furthermore, transcriptomic analyses demonstrated that Fe₃O₄-PASP-DOX-induced apoptosis could be enhanced by Fe₃O₄-PGA-DHA-induced ferroptosis and Fe₃O₄-PGA-DHA + Fe₃O₄-PASP-DOX might trigger ferroptosis in MDA-MB-231 cells by inhibiting the PI3K/AKT/mTOR/GPX4 pathway. Fe₃O₄-PGA-DHA + Fe₃O₄-PASP-DOX showed superior anti-tumor efficacy on MDA-MB-231 tumor-bearing mice, providing great potential for improving the therapeutic effect of TNBC.