Breaking the ROS inflammation loop: a hierarchical nanozyme natural enzyme cascade for acetaminophen induced acute liver injury.

Acetaminophen (APAP) induced acute liver injury (ALI) is driven by a self amplifying cascade of reactive oxygen species (ROS) and lipid peroxidation, yet current therapies fail to interrupt this pathological loop. Here we engineer a liver targeted hierarchical nanozyme, SOD@ZIF-8/Mn3O4, which integrates natural superoxide dismutase (SOD) and Mn3O4 nanozymes within a ZIF‑8 nanoplatform. Unlike conventional single step scavengers, this system implements a catalytic hierarchy matching strategy. SOD rapidly converts O2·- to H2O2, while Mn3O4 simultaneously decomposes H2O2 and intercepts ·OH, thereby converting the entire ROS cascade into benign water. Density functional theory calculations reveal that the SOD-Mn3O4 interface lowers the energy barriers for catalase like and glutathione peroxidase like steps, establishing a synergistic channeling effect. In APAP injured AML-12 cells and a murine ALI model, the nanozyme not only alleviates oxidative stress and lipid peroxidation but also breaks the ROS inflammation feed forward loop by restoring the Keap1/Nrf2/HO‑1 redox switch and suppressing NF‑κB activation. Transcriptomic and functional analyses confirm that treatment rewires hepatic transcriptional programs associated with lipid metabolism and inflammatory signaling. This work establishes a modular nanozyme natural enzyme hybrid platform where the MOF acts as a spatiotemporal organizer, transforming the pathological ROS chain into a controlled detoxification pathway. The concept is readily extensible to other diseases driven by sequential ROS cascades, offering a paradigm shift from single enzyme mimicry to pathway reprogramming nanobiocatalysis.