Nebulized inhalation of novel baicalein liposome based on phospholipid complex to alleviate acute lung injury

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are high-mortality respiratory diseases manifested by excessive inflammation and oxidative stress. Current therapies for ALI are limited by uncertain efficacy, severe side effects, restricted administration routes, or inadequate targeting capacity. Baicalein, a natural flavonoid with significant anti-inflammatory and antioxidant activity, shows promise for ALI. Unfortunately, its clinical application is limited by its low solubility and bioavailability. In this study, a novel baicalein liposome (BAPC-DLP) based on a baicalein‒phospholipid complex (BAPC) was constructed for nebulized inhalation. Comparative studies demonstrated that BAPC-DLP outperformed other baicalein-loaded liposomes in colloid stability, mucus penetration ability, and <i>in vivo</i> pulmonary deposition. Further, BAPC-DLP enhanced the baicalein loading capacity and exhibited excellent aerosolization performance. Moreover, it effectively suppressed lipopolysaccharide (LPS)-induced inflammatory responses and scavenged excessive ROS in macrophages and alveolar epithelial cells. <i>Ex vivo</i> fluorescence imaging confirmed its efficient lung deposition and prolonged lung retention. In an LPS-induced ALI mouse model, inhaled BAPC-DLP exerted a superior protective effect to free baicalein by alleviating pulmonary edema, lowering the level of proinflammatory cytokines, decreasing inflammatory cell infiltration, and significantly ameliorating tissue injury. This study presents a promising preventive pharmacotherapy strategy for ALI/ARDS and a potential nebulized inhalation delivery platform for insoluble natural products, highlighting the significant potential for clinical translation.