A Magnetically Actuated MOF‐Based Nanozyme for Intensified Induction of Ferroptosis and Immunogenic Cell Death Via Autophagy Blockade

Abstract Nanozymes mimicking enzymes show great promise in anti‐tumor therapy but are often limited by their low catalytic activity and lack of tumor specificity in hostile tumor microenvironments. This study develops a novel nanozyme, D/P@ZUCO, utilizing metal–organic frameworks (MOFs) with glutathione oxidase, peroxidase, and catalase‐like activities. D/P@ZUCO is synthesized using ZnFe2O4 and NH2‐UiO66 (Cu/Zr) through an in situ growth method, followed by loading with doxorubicin (DOX) and primaquine (PQ), and functionalization with oxidized hyaluronic acid (OHA). It efficiently catalyzes the conversion of hydrogen peroxide (H2O2) into hydroxyl radicals (·OH) and glutathione (GSH) into glutathione disulfide (GSSH), initiating ferroptosis in cancer cells. Additionally, the conversion of excess H2O2 into oxygen (O2) enhances the apoptosis effects of DOX. Importantly, the inhibition of autophagy by D/P@ZUCO exacerbates ferroptosis and immunogenic cell death (ICD), triggering a potent anti‐tumor immune response. The targeted drug delivery of D/P@ZUCO is facilitated by magnetic guidance and interactions between OHA and CD44 receptors. D/P@ZUCO demonstrates effective cancer treatment by triggering multiple cell death pathways through a synergistic combination of enzymatic actions, serving as a paradigm for systemic activation of multiple enzymes in triple‐negative breast cancer therapy.