Inhalable Multifunctional Liposomes Disrupt the Inflammation-Oxidative Stress Cycle for Acute Lung Injury Therapy

Acute lung injury (ALI) is characterized by an uncontrolled cycle of inflammation and oxidative stress. However, conventional therapeutics are limited by physiological pulmonary barriers and poor targeted bioavailability. In this study, an inhalable multifunctional liposomal system (designated as R&I/Lip@PEG-M) was elaborately engineered to codeliver Resveratrol and IMD-0354 to disrupt the inflammation-oxidative stress cycle for ALI therapy. Upon nebulized inhalation, the negatively charged R&I/Lip@PEG-M liposomes would efficiently penetrate the mucus barrier, extensively accumulate in the pulmonary alveoli, and be specifically taken up by alveolar macrophages via mannose-mediated targeting recognition. Particularly, the internalized liposomes could exert combined therapeutic effects by scavenging intracellular reactive oxygen species (ROS) and blocking the NF-κB signaling pathway to inhibit inflammation. In the LPS-induced ALI mouse model, the designed R&I/Lip@PEG-M significantly reduced the population of inflammatory macrophages, reprogrammed the redox microenvironment, and successfully mitigated lung damage and pulmonary edema.