Mitochondria‐Targeting Iron–Carbon Nanozymes Combat Hepatic Ischemia–Reperfusion Injury via the Dual Mechanisms of Respiratory Chain Remodeling and Pyroptosis Inhibition With MRI Monitoring

ABSTRACT Hepatic ischemia‒reperfusion injury (HIRI) critically compromises liver surgery and transplantation outcomes. Its pathogenesis centers on mitochondrial dysfunction‐driven oxidative stress and sterile inflammation. However, current therapies lack lesion‐specific targeting, fail to suppress ROS generation at the mitochondrial source, and lack integrated theranostic capabilities such as cascade antioxidant activity, anti‐inflammatory effects, and real‐time imaging. To address these limitations, we developed FeCD‐SS31, an integrated nanoplatform composed of a mesoporous Fe 3 O 4 core conjugated with glutathione/biotin‐derived carbon dots (CDs) and linked to the mitochondrial‐targeting peptide SS31 through an ROS‐responsive bond. The system enabled hepatic mitochondrial targeting and responsive SS31 release, restoring mitochondrial complex integrity to suppress de novo ROS generation. Meanwhile, the Fe 3 O 4 /CDs core exerted cascade enzymatic activities to scavenge existing ROS, achieving dual‐axis oxidative stress inhibition. This synergy blocked the caspase‐1–GSDMD‐N pyroptosis axis and reduced neutrophil infiltration, attenuating inflammation and preserving hepatocytes. These effects alleviated HIRI and improved liver function, while Fe 3 O 4 superparamagnetism enabled magnetic resonance imaging (MRI) for lesion monitoring. Collectively, this nanoplatform synergistically mitigates HIRI via mitochondrial protection and pyroptosis inhibition, coupled with intrinsic MRI monitoring capability.