Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a common perioperative complication occurring after liver transplantation and can lead to further problems such as early allograft dysfunction (EAD). Currently, the treatment options for HIRI are extremely limited. In this study, we used bioinformatics analysis to elucidate the critical role of neutrophil chemokines (CXC chemokines) in HIRI. By analyzing sequencing data from the hepatic tissue of posttransplant patients with EAD and the reperfused animal model, we discovered that hepatocytes and macrophages are the primary cells secreting CXC chemokines, and the activation of the nuclear factor kappa B (NF-κB) signaling pathway is the main driver of their secretion. Melatonin (MT) can protect cells from oxidative harm while also inhibiting NF-κB signaling, suggesting its potential to ameliorate HIRI. Accordingly, we designed a nanoparticle platform coated with genetically engineered macrophage membranes-called CXCR2-MM@PLGA/MT-to target the cells secreting CXC chemokines. CXCR2 overexpression on the macrophage membranes not only enhanced the targeting capacity of the nanoparticles but also prevented neutrophil infiltration via the scavenging of CXC chemokines. Meanwhile, the MT delivered to the site of injury successfully attenuated CXC chemokine release after macrophage polarization and hepatocyte necrosis by inhibiting NF-κB phosphorylation and inducing antioxidant effects. Through the synergistic effects of MT and the CXCL/CXCR axis-blocking function of the engineered nanoparticles, CXCR2-MM@PLGA/MT attenuated the aggregation of neutrophils at the site of injury, markedly reducing local inflammation and cellular damage following HIRI. This engineered cellular nanoparticle-based therapy could thus serve as a safe, effective, and cost-efficient strategy for treating HIRI.