Abstract

Hepatic ischemia-reperfusion injury (IRI), driven primarily by excessive mitochondrial reactive oxygen species (ROS) generation, is a major cause of liver dysfunction, graft failure, and postoperative complications. However, no pharmacological agents have been clinically approved for its prevention or treatment, and there is an urgent need for effective therapeutic strategies. In this study, we established a nanoplatform composed of PEGylated polydopamine nanoparticles modified with the mitochondrial-targeting peptide SS-31 (PPS NPs). SS-31 peptide modification confers PPS NPs with efficient mitochondrial-targeting capability, thereby restoring mitochondrial membrane potential and reducing ROS accumulation in the hypoxia/reoxygenation model. Furthermore, treatment with PPS NPs significantly mitigates liver injury, decreases inflammatory factor levels, and inhibits neutrophil recruitment in mice subjected to IRI. Transcriptome sequencing and metabolomics analyses indicate that PPS NPs can protect the liver from ischemia-reperfusion injury by preserving mitochondrial integrity, reducing ROS generation, and regulating arachidonic acid and glutathione metabolism. By preserving mitochondrial function, maintaining cellular redox homeostasis, and suppressing inflammatory cascades, PPS NPs ultimately inhibit mitochondria-dependent apoptosis and confer protection against liver IRI, providing a practical therapeutic strategy for hepatic IRI clinical management.