Zwitterionic polymer-coated magnetic nanoparticle induced chemotherapy and ferroptosis for triple-negative breast cancer therapy

Triple-negative breast cancer (TNBC), an aggressive cancer with a high risk of metastasis and recurrence, is resistant to conventional chemotherapy. Ferroptosis, a non-apoptotic form of cell death, is primarily caused by excessive accumulation of lipid peroxides, and is closely associated with the occurrence and development of various diseases. Mounting evidence indicates that ferroptosis is becoming a promising treatment for TNBC based on its inherent characteristics. Herein, zwitterionic polymer poly (<i>N</i>-(3-sulfopropyl)-<i>N</i>-methacryloxyethyl-<i>N</i>,<i>N</i>-dimethylammonium betaine) (PSBMA)-coated gambogenic acid (GNA)-loaded magnetic composite nanoparticles (Fe₃O₄@PSBMA-GNA) were fabricated for chemotherapy combined with ferroptosis therapy for TNBC. Fe₃O₄@PSBMA-GNA achieved significant cytotoxicity against TNBC cell lines and contributed to the disruption of intracellular redox homeostasis. Furthermore, Fe₃O₄@PSBMA-GNA could induce apoptosis through the inhibition of Bcl-2 and trigger ferroptosis by inhibiting the PI3K/AKT/mTOR/GPX4 pathway in MDA-MB-231 cells simultaneously. Given the excellent blood circulation performance, Fe₃O₄@PSBMA-GNA enhanced tumor accumulation and showed a satisfactory tumor suppression effect on MDA-MB-231 tumor-bearing mice. This strategy of chemotherapy combined with ferroptosis therapy is expected to be a feasible treatment for refractory TNBC.