A Multifunctional Nanoplatform for Treating Hepatic Ischemia–Reperfusion Injury by Modulating the Nrf2 and NF-κB Pathways

Hepatic ischemia-reperfusion injury (HIRI), a critical pathological process in surgeries such as liver transplantation and hepatectomy, involves complex mechanisms, including oxidative stress, immune-inflammatory responses, and cell apoptosis. However, universally accepted clinical treatment remains lacking. In this study, an erythrocyte-membrane-coated poly(lactic-<i>co</i>-glycolic acid) (PLGA) nanoplatform was constructed to deliver edaravone (Eda) and dexamethasone (Dex), ingeniously transforming the physiological clearance of nanoparticles by the hepatic reticuloendothelial system into a targeted delivery strategy. Edaravone synergizes with the nuclear factor E2-related factor 2 (Nrf2) pathway to scavenge excessive reactive oxygen species (ROS) in damaged hepatocytes, reducing the level of oxidative stress injury during ischemia-reperfusion. Concurrently, dexamethasone regulates the nuclear factor-κB (NF-κB) signaling pathway in neutrophils, thereby suppressing the release of proinflammatory cytokines from activated neutrophils and abrogating the subsequent immune cascade, which, in turn, mitigates the associated immune-mediated liver injury. This multifunctional nanoplatform-based therapeutic strategy can concurrently address short-term oxidative stress and long-term immune damage, which offers a clinically promising approach for the treatment of HIRI.