Self-assembled nanoparticles overcoming hypoxic and acidic microenvironment to synergistically potentiate ferroptosis in triple-negative breast cancer.

Ferroptosis, a newly identified form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a promising therapeutic strategy for triple-negative breast cancer (TNBC) due to the heightened susceptibility of TNBC cells to this form of cell death. Nonetheless, the unique hypoxic and acidic tumor microenvironment confers resistance to ferroptosis, which limits the clinical efficacy of single-agent ferroptosis inducers. To overcome this, we developed a synergistically enhancing ferroptosis nanomedicine named sorafenib (SOR)-quercetin (QUE) nanoparticles (SQ NPs) by co-assembling SOR, QUE, and polyvinylpyrrolidone K30 (PVP K30). In this system, SOR facilitates ferroptosis by downregulating the expression of glutathione peroxidase 4 (GPX4). Simultaneously, QUE mitigates the hypoxic tumor microenvironment by suppressing the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and hexokinase Ⅱ (HK-Ⅱ), thereby inhibiting glycolysis, reducing LA production, and impeding GSH synthesis. This multifaceted approach culminates in enhanced ferroptosis in TNBC cells. In vivo studies on antitumor and antimetastatic effects have demonstrated the superior therapeutic efficacy and metastasis-inhibiting capabilities of SQ NPs in the context of TNBC. This report highlights the therapeutic potential of QUE in synergy with SOR under hypoxic conditions, offering a novel strategic approach for the treatment of TNBC.