Targeted Delivery of Bilirubin to Pulmonary Endothelium Mitigates Paraquat-Induced Lung Injury.

Introduction: Paraquat (PQ) poisoning causes high mortality via acute lung injury (ALI) driven by excessive reactive oxygen species (ROS) in pulmonary microvascular endothelial cells. We developed BR@Lipo-CerTP, a lung-targeted nanotherapeutic using C16-ceramide-binding peptide-modified bilirubin liposomes, to enhance endothelial delivery and treat PQ-induced ALI. Methods: BR@Lipo-CerTP was characterized for physicochemical properties and cellular uptake in pulmonary microvascular endothelial cells (PMVECs). In vitro efficacy was assessed via cytotoxicity, apoptosis, ROS, antioxidant capacity, and mitochondrial function assays in PQ-exposed PMVECs. Multi-omics analysis elucidated therapeutic mechanisms. In vivo efficacy and biosafety were evaluated in a PQ-induced ALI mouse model through survival, histopathology, edema, and toxicity assessments. Results: BR@Lipo-CerTP exhibited uniform ~120 nm spherical morphology, narrow size distribution, excellent stability, and enhanced PMVEC uptake versus non-targeted liposomes. In vitro, it significantly attenuated PQ-induced cytotoxicity, apoptosis, and ROS accumulation while restoring antioxidant capacity and mitochondrial function. Multi-omics revealed it disrupts a vicious cycle of glutathione depletion, ferroptosis, and NF-κB/NLRP3-driven inflammation, resetting pathological crosstalk between redox homeostasis, regulated cell death, and immune activation. In vivo, BR@Lipo-CerTP markedly improved survival, alleviated pulmonary damage and edema, suppressed oxidative stress and inflammation, with no systemic toxicity. Discussion: Pulmonary endothelial-targeted bilirubin delivery effectively mitigates PQ-induced ALI by coordinately regulating redox balance, cell death, and inflammation. This strategy offers a promising nanotherapeutic for PQ poisoning and other ROS-driven pulmonary diseases, highlighting targeted nanomedicine's potential in toxicological emergencies.