Co-disruption of GPX4 and DHODH Ferroptosis Defense Systems via Excipient-Free Self-Assembled Nanoassemblies for Enhanced Ferroptosis Therapy in Triple-Negative Breast Cancer

Triple-negative breast Cancer (TNBC) remains a formidable clinical challenge due to its aggressive phenotype and limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is evolving as a highly promising approach to combat TNBC. However, tumor cells deploy redundant Ferroptosis defense systems including Glutathione Peroxidase 4 (GPX4) and Dihydroorotate Dehydrogenase (DHODH) systems to evade this lethal process. Here, doxorubicin (DOX) and teriflunomide (Tfm) were used as therapeutic building blocks for the self-assembly of tumor-targeting, excipient-free nanoassemblies (DoT) that enhance Ferroptosis induction in TNBC. After being trapped in Cancer cells, the FDA-approved antitumor drug DOX could not only disrupt the GPX4 defense system by inhibiting Nrf2 but also ignite an intracellular Reactive Oxygen Species storm to unleash a lipid peroxidation spark. Simultaneously, Tfm further devastated the intracellular Ferroptosis defense system by suppressing DHODH and crippling the radical-trapping antioxidant capacity, thus evoking robust ferroptotic cell death in TNBC cells. The work presents a synergistic co-disruption strategy against dual Ferroptosis defense systems, exhibiting significant potential for clinical applications.