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.