Bimetallic chitosan/hyaluronic acid nanoparticles self-amplify ferroptosis/cuproptosis in triple-negative breast cancer

As a notoriously incurable tumor, triple-negative breast cancer (TNBC) exhibits significant sensitivity to ferroptosis and the glutathione (GSH) antioxidant defense system plays a crucial role in its progression. Herein, we report a bimetallic chitosan/hyaluronic acid nanoparticle (5FCN, with a Fe/Cu mass ratio of 5:5) that employs a self-amplified dual mechanism of ferroptosis and cuproptosis for TNBC therapy. Hyaluronic acid in 5FCN specifically binds to the overexpressed CD44 receptor on TNBC cells. This allows 5FCN to enter cells via receptor-mediated endocytosis, then release metal ions in acidic environments. Released Fe 3+ and Cu 2+ react with GSH in tumor cells, weakening the antioxidant system and producing Fe 2+ and Cu + . These ions trigger Fenton/Fenton-like reactions with H 2 O 2 , generating toxic hydroxyl radicals (·OH) to boost ferroptosis. Meanwhile, high-valent Cu 2+ and Fe 3+ are produced, forming a cycle for GSH depletion and ·OH generation. As H 2 O 2 depletes, the rising Cu + level in cells causes lipoylated protein aggregation, amplifying cuproptosis. In vitro and in vivo studies demonstrated that 5FCN exhibited superior cell-killing efficacy against TNBC with few side effects. Collectively, 5FCN represents a potential drug to self-amplify ferroptosis/cuproptosis in TNBC.