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Breaking the ROS inflammation loop: a hierarchical nanozyme natural enzyme cascade for acetaminophen induced acute liver injury
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DOI：10.1186/s12951-026-04912-2.png)
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Abstract
En 中文
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.
Keywords:
SOD
Metal-organic frameworks
Catalytic hierarchy
ROS cascade interruption
Acute liver injury
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