Biomimetic Cascade Nanozymes: Superoxide Dismutase-Templated Ultrasmall Iron Oxide for Liver Fibrosis Therapy and MRI-Assisted Staging

Background: Liver fibrosis represents a critical pathological juncture in the progression of chronic liver disease toward irreversible cirrhosis and hepatocellular carcinoma; however, early diagnosis and effective therapeutic intervention remain significant clinical challenges. Methods: Herein, we report a biomimetic cascade nanozyme platform (termed iSOD) featuring a core–shell nanostructure for the accurate diagnosis and therapy of liver fibrosis. Synthesized via a green, one-pot coprecipitation method utilizing natural superoxide dismutase (SOD) as a structural template, the iSOD comprises an ultrasmall Fe3O4 core (approximately 4.04 nm in diameter) seamlessly enveloped by an active SOD protein shell. Results: This unique architecture provides the SOD-mediated superoxide-scavenging activity and catalase (CAT)-like activity from the ultrasmall iron oxide core. This sequential dual-enzyme cascade can eliminate deleterious reactive oxygen species (ROS) by dismutating superoxide anions and decomposing intermediate hydrogen peroxide (H2O2) into water and oxygen. In vitro evaluations demonstrate that iSOD significantly diminishes intracellular ROS in HSC-T6 cells and protects them against oxidative stress-induced injury. Relaxivity measurements revealed longitudinal (r1) and transverse (r2) relaxivities of 2.874 and 13.878 mM−1 s−1, respectively, indicating the ability of iSOD to influence both T1 and T2 relaxation. In vivo, T1-weighted MRI revealed changes in hepatic signal intensity and spatial distribution 30 min after iSOD administration, with distinct signal patterns observed among healthy, moderately fibrotic, and severely fibrotic rat livers. Histological analyses further demonstrated reduced collagen deposition and improved hepatic tissue morphology following iSOD treatment. Short-term biocompatibility evaluations revealed no obvious adverse effects under the investigated conditions. Conclusions: Collectively, these findings highlight the potential of iSOD as a multifunctional nanoplatform integrating antioxidant therapy with MRI-based assessment of liver fibrosis.