Adaptive bilirubin nanoscavenger alleviates pulmonary oxidative stress and inflammation for acute lung injury therapy

Introduction Acute lung injury (ALI) is a life-threatening condition characterized by rapidly progressing respiratory distress and hypoxemia. Oxidative stress-induced inflammation in lung tissue plays a crucial role in the progression of ALI. Excessive generation of reactive oxygen species (ROS) in the pulmonary microenvironment activates inflammatory signaling pathways, enhancing the transcription of pro-inflammatory factors and ultimately leading to tissue necrosis. Objectives Bilirubin (BR), an exceptional endogenous antioxidant, possesses the ability to counteract elevated levels of reactive oxygen species (ROS) through direct reactions or by inducing antioxidant systems such as Nrf2/HO-1 signaling. However, its limited solubility poses a hindrance to further applications. Hence, it is imperative to develop a suitable bilirubin-based system for biological utilization. Methods In this study, we developed a bilirubin-based ROS-sensitive adaptive nanoscavenger (GP@BR) by co-assembling bilirubin-conjugated glycol chitosan (GC-BR) and bilirubin-conjugated polyethylene glycol (PEG-BR), aiming to alleviate oxidative stress for ALI treatment. Results The different conjugations endowed the bilirubin derivatives with varying sensitivity towards reacting with ROS, enabling GP@BR to exert antioxidative properties specifically in oxidative environments on demand. Besides its excellent antioxidant properties, GP@BR also demonstrated the ability to absorb excess inflammatory cytokines. Moreover, our optimized nanoscavenger facilitated bilirubin transport across the mucosal layer on pulmonary epithelial cells. In vivo studies confirmed that GP@BR significantly improved ALI symptoms and suppressed pulmonary fibrosis. Conclusion This study highlighted the potential of ROS-sensitive adaptive properties and multiple actions of this nanoscavenger in the treatment of ALI.