Mitochondria-targeted ROS-scavenging polymer protects the hepatocytes and macrophages against hepatic...

While liver transplantation (LT) is the most effective therapeutic intervention for end-stage liver diseases, hepatic ischemia-reperfusion injury (HIRI) remains a major determinant of adverse clinical outcomes. Mitochondrial reactive oxygen species (ROS) have been implicated in HIRI pathogenesis. In this study, we conjugated the small molecule, antioxidant 4‑hydroxy‑2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) with a neutral, long-circulating, and mitochondria-targeted polymer, poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA), to obtain a conjugate containing 10 % TEMPO (OPT10). OPT10 exhibited reliable biocompatibility and efficiently mitigated mitochondrial ROS in hepatocytes; it was also readily internalized into hepatic macrophages, promoting polarization to the anti-inflammatory M2 phenotype for over 24 h. Through these effects, together with reducing oxidative stress and decreasing activation of the MAPK pathway, OPT10 could attenuate innate immune-driven inflammation and alleviate HIRI. Compared with clinically used antioxidants such as N-acetylcysteine (NAC) and glutathione (GSH), OPT10 exhibited superior efficacy in ameliorating HIRI in a mouse model and can be considered a promising candidate for clinical translation. STATEMENT OF SIGNIFICANCE: Liver transplantation remains an effective therapeutic intervention for end-stage liver diseases. Alleviating hepatic ischemia-reperfusion injury (HIRI) is crucial for enhancing graft viability and improving long-term patient outcomes. Excessive production of mitochondrial reactive oxygen species (mtROS) during HIRI not only exacerbates hepatocellular damage but also promotes macrophage M1 polarization, thereby driving hepatic inflammation and injury. In this study, we synthesized a mitochondria-targeted ROS-scavenging polymer that enabled precise delivery to both hepatocytes and macrophages, effectively alleviating liver injury and offering novel insights into therapeutic strategies for HIRI.