Hepatic ischemia-reperfusion injury (IRI) is an intricate and inevitable physiological event occurred in the liver transplantation (LT) and it is of paramount importance to devise novel and efficient methods to ameliorate IRI. Herein, we report a "one stone for two birds" strategy for IRI therapy. In this study, we engineered CAR-ART nanoparticles (CANPs) utilizing carvacrol (CAR) and artesunate (ART) as precursor monomers and simulated IRI in an in vivo mouse model. Our research results indicate that CANPs proficiently surmount the constraints linked with the solitary components utilized in preceding studies such as water solubility, stability, and biocompatibility. Furthermore, they exhibit a distinctive accumulation in the liver. From an immunological standpoint, CANPs have been observed to significantly impede the accumulation and activation of various immune cells such as macrophages, neutrophils, and Kupffer cells. This results in the restoration of the hepatic immune cell distribution to a state akin to that of a normal liver. Furthermore, CANPs markedly inhibit the accumulation of a multitude of pro-inflammatory cytokines. Cellularly, it has been observed that CANPs significantly hinder the onset of ferroptosis in hepatocytes. This is accomplished by inhibiting the accumulation of crucial enzymes such as long-chain-fatty-acid-CoA ligase 4 (ACSL4), as well as associated lipid oxidation intermediates like malondialdehyde (MDA), which are relevant to the process of ferroptosis. Consequently, a solitary intravenous administration of CANPs has the potential to simultaneously inhibit ferroptosis of hepatocytes and normalize proinflammatory immune cells, one stone for two birds. In conclusion, CANPs may serve as a promising multi-bioactive nanotherapeutic agent and a bioresponsive targeting delivery nanocarrier, offering a potentially effective treatment strategy for hepatic IRI.

Liver transplantation (LT), an ultimate and vital method for treating end-stage liver disease, is often accompanied by ischemia-reperfusion injury (IRI) resulting from warm or cold ischemia of the donor liver. Organ protection techniques are used to improve the quality of liver grafts (from retrieval to implantation). Reactive oxygen species (ROS) cause oxidative stress, which is considered a crucial factor in IRI after LT. Nano antioxidants capable of scavenging ROS alleviate IRI in multiple types of organs and tissues. In this study, we synthesized ceria nanoparticles (NPs) with antioxidant properties using a pyrolysis method and covered them with phospholipid-polyethylene glycol to improve their biocompatibility in vivo. We investigated the potential organ-protective effect of ceria NPs and the underlying mechanisms. Ceria NPs promoted liver function recovery after LT by attenuating IRI in liver grafts in vivo. The protective effect of ceria NPs on liver grafts was investigated by applying hypothermic oxygenated machine perfusion ex vivo. Ceria NPs attenuated hypoxia reoxygenation- or H₂O₂-induced hepatocyte injury by enhancing mitochondrial activity and ROS scavenging in vitro. These effects may be associated with the activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/heme oxygenase 1 (HO-1) signaling pathway. In conclusion, ceria NPs may serve as a promising antioxidant agent for the treatment of hepatic IRI after LT.