A MOF-Based Potent Ferroptosis Inducer for Enhanced Radiotherapy of Triple Negative Breast Cancer

Radiotherapy(RT) is one of the important clinical treatments forlocal control of triple-negative breast cancer (TNBC), but radioresistancestill exists. Ferroptosis has been recognized as a natural barrierfor cancer progression and represents a significant role of RT-mediatedanticancer effects, while the simultaneous activation of ferroptosisdefensive system during RT limits the synergistic effect between RTand ferroptosis. Herein, we engineered a tumor microenvironment (TME)degradable nanohybrid with a dual radiosensitization manner to combineferroptosis induction and high-Z effect based onmetal-organic frameworks for ferroptosis-augmented RT of TNBC.The encapsulated l-buthionine-sulfoximine (BSO) could inhibitglutathione (GSH) biosynthesis for glutathione peroxidase 4 (GPX4)inactivation to break down the ferroptosis defensive system, and thedelivered ferrous ions could act as a powerful ferroptosis executor via triggering the Fenton reaction; the combination of theminduces potent ferroptosis, which could synergize with the surfacedecorated Gold (Au) NPs-mediated radiosensitization to improve RTefficacy. In vivo antitumor results revealed thatthe nanohybrid could significantly improve the therapeutic efficacyand antimetastasis efficiency based on the combinational mechanismbetween ferroptosis and RT. This work thus demonstrated that combiningRT with efficient ferroptosis induction through nanotechnology wasa feasible and promising strategy for TNBC treatment.