A biomimetic nanomedicine alleviates liver transplant-related biliary injury by sequentially inhibiting oxidative stress and regulating macrophage polarization via Nrf-2/HO-1 and JNK pathways

Liver transplantation is an effective method for treating end-stage liver disease. However, 10–20 % of liver transplantation patients develop biliary injury, the main cause of which is ischemia-reperfusion injury (IRI), which consists of oxidative stress injury in the early stage and inflammatory injury in the advanced stage. Biliary injury seriously affects patient outcomes and even leads to mortality, and there are few effective treatments for IRI. Herein, nanoparticles containing quercetin (QR) and rapamycin (RP) coated with poly (lactic-co-glycolic acid) (PLGA) and encapsulated by platelet membrane (PM) were designed to treat IRI in the liver transplantation. The specific binding of ICAM-1 expressed on the PM to integrins (e.g., LFA-1 and Mac-1) in damaged vascular endothelial cells, as well as the interaction between P-selectin on the platelet surface and PSGL-1 on the macrophage surface, allows the accumulation of these biomimetic cell membrane-encapsulated nanoparticles, and subsequently, the delivery of both drugs, to ischemia-reperfusion sites in the liver. The encapsulated QR alleviated oxidative stress injury by activating the Nrf-2/HO-1 signaling pathway in the early stage in model rats with IRI and liver transplantation models. Moreover, RP alleviated inflammatory damage in the advanced stage by suppressing the JNK signaling pathway in M1 macrophages. Thus, these biomimetic nanoparticles that intervene in IRI to alleviate both the early oxidative stress and the advanced inflammatory response constitute a novel delivery system for managing biliary injury after liver transplantation. A biomimetic nanomedicine that synergistically treats early oxidative stress injury and advanced macrophage polarization via Nrf-2/HO-1 and JNK pathway in a sequential manner was designed to treat biliary injury induced by ischemia‒reperfusion during liver transplantation. • Utilizes platelet membrane targeting to enhance drug accumulation at the site of injury. • Simultaneous delivery of two drugs, targeting different stages of the injury mechanism, with the synergistic effect of the two drugs being more effective than a single drug. • Reducing oxidative stress through QR activation of Nrf-2/HO-1 pathway in early stage, and regulating macrophage polarization through RP inhibition of JNK pathway in advanced stage.