Nanosecond pulsed electric field-empowered physical–chemical cascade ferroptosis therapy for triple-negative breast cancer

Bis-allylic hydrogen atoms of polyunsaturated fatty acids (PUFAs) in biological membranes are major initiation sites of ferroptosis. However, the location of PUFAs in the hydrophobic interior of the lipid bilayer makes it challenging for most ferroptosis-inducing drugs to interact with the PUFAs to promote lipid peroxidation (LPO), potentially limiting the occurrence of ferroptosis. Herein, we propose a new generalized method named physical-chemical cascade ferroptosis (PCCF) for triggering ferroptosis by disrupting the integrity of the cell membrane to expose bis-allylic hydrogen atoms that react with nanozyme MnFI under nanosecond pulsed electric field (nsPEF) assistance. <i>In vitro</i>, PCCF continuously depletes GSH and produces LPO, inducing catalytic efficiency improvement, and collaboratively ferroptosis occurs through the GSH-mediated GPX4 pathway during triple-negative breast cancer (TNBC) treatment. <i>In vivo</i>, PCCF exhibit a significant tumor growth inhibitory potential through ferroptosis and increases CD8⁺ T cell and CD4⁺ T cell infiltration and DC cell maturation in tumor tissues. At the same time, the PCCF platform inhibits TNBC lung metastasis in mice. This work provides a novel TNBC therapeutic strategy that exposes PUFAs to react with nanozymes to directly trigger LPO production with nsPEF assistance and stimulate ferroptosis-mediated anti-tumour immune efficacy.