Hyaluronic acid-modified nanoparticles with Fe/ H2O2 supply and GSH depletion capabilities to improve breast cancer therapy via induction of ferroptosis.

Ferroptosis is an iron-dependent programmed cell death modality characterized by the massive accumulation of lipid peroxides (LPO). However, the efficiency of ferroptosis is commonly limited by insufficient supply of iron ions and endogenous hydrogen peroxide (H2O2) in the tumor cells. To overcome these drawbacks, MIL-100 NPs were synthesized via a microwave-assisted method to encapsulate β-lapachone (Lap), followed with the hyaluronic acid (HA) surface modification (designated as LMH NPs). LMH NPs exhibited GSH-responsive degradation in the tumor cells to release Lap and Fe3+. The released of Lap could generate H2O2 via catalysis by tumor-overexpressed quinone oxidoreductase 1 (NQO1), leading to increased intracellular H2O2 levels. The abundant production of H2O2 could supply substrates for Fe2+-mediated Fenton reactions to produce toxic hydroxyl radicals (·OH), thereby promoting LPO accumulation and enhancing ferroptosis. Meanwhile,  Fe3+ released from LMH NPs was reduced to Fe2+ through GSH consumption, which could diminish glutathione peroxidase 4 (GPX4) activity. In vitro and in vivo experiments confirmed that LMH NPs possessed effective targeted uptake and exhibited optimal tumor inhibition without significant toxic side effects. Overall, the integrated strategy presents a novel ferroptosis-based clinical approach for enhanced breast cancer therapy.