Inhalable Lipid Nanoparticles with Mucus Clearance and ROS Scavenging Properties for Acute Lung Injury Treatment

Abstract Acute lung injury (ALI) is a severe condition marked by dysregulated inflammatory responses, compromised integrity of the alveolar‐capillary barrier, and overproduction of reactive oxygen species (ROS), all of which contribute to significant morbidity and mortality. In this study, inhalable lipid nanoparticles (Cur‐NAC Lipos) encapsulating curcumin and the FDA‐approved mucolytic agent N‐acetylcysteine (NAC) are developed for the treatment of ALI. NAC plays a crucial role in breaking disulfide bonds in mucus, thereby facilitating the clearance of the thick, viscous mucus typically observed in ALI. This mucus‐clearing effect enhances the delivery of nanoparticles, enabling them to target and penetrate inflammatory lesions in the lung epithelium more effectively. It is found that the levels of ROS and pro‐inflammatory cytokines, including IL‐1β, IL‐6, and TNF‐α, are reduced by curcumin, an antioxidant and anti‐inflammatory agent, thereby contributing to the alleviation of lung inflammation. Moreover, the inhaled Cur‐NAC Lipos significantly modulate immune responses by downregulating inflammation‐related immune cells, such as neutrophils, alveolar macrophages (AMs), and interstitial macrophages (IMs). Therefore, Cur‐NAC Lipos represent a promising, noninvasive inhalation delivery platform for the clinical management of respiratory diseases.