Multifunctional nanozyme–phytochemical synergy induces immunogenic ferroptosis by disrupting the antioxidant defence system of tumour cells

Ferroptosis, a promising antitumour approach, is triggered by lipid peroxide (LPO) accumulation in tumour cells. However, the antioxidant defence system of tumour cells significantly restricts the efficacy of ferroptosis. Herein, we report osthole-loaded iron-based metal–organic framework nanomaterials (NH 2 -MIL-88B@Ost@PEG, NOP), a nanoenzyme, which disrupts the cellular antioxidant defence system by scavenging glutathione (GSH) and inactivating glutathione peroxidase 4 (GPX4), inducing potent immunogenic ferroptosis. In particular, NOP exhibited peroxidase-like activity, catalysing the decomposition of endogenous hydrogen peroxide (H 2 O 2 ) into bursts of highly cytotoxic hydroxyl radicals, increasing reactive oxygen species (ROS)-dependent LPO. The GSH peroxidase−like activity of NOP induced GSH conversion to oxidised glutathione in tumours, impairing the functional efficacy of GPX4. The released osthole could directly inactivate GPX4 through the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway. NOP concurrently depleted GSH and inactivated GPX4, thereby potently driving LPO accumulation and inducing robust immunogenic ferroptosis. This study offers a distinct approach to achieve efficient ferroptosis. We developed an osthole-loaded Fe-MOF nanozyme that synergistically depletes GSH and inactivates GPX4 to dismantle tumour antioxidant defenses and robustly induce immunogenic ferroptosis. Download: Download high-res image (313KB) Download: Download full-size image