Inhalable ROS-Responsive Liposomes for Orchestrating Microenvironment Remodeling and Epithelial Regeneration in Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease with limited therapeutic options. Current treatments, such as nintedanib and pirfenidone, target downstream fibrosis but fail to address the upstream drivers, including persistent alveolar epithelial injury and abnormal repair. This study presents an inhalable, reactive oxygen species (ROS)-responsive liposomal system (SAB/GC-1@Lip-cRGD) that co-delivers the antioxidant salvianolic acid B (SAB) and the thyroid hormone receptor β (TRβ) agonist Sobetirome (GC-1). The liposomes are surface-modified with cRGD peptides for targeted delivery to fibrotic lesions and possess a negative surface charge to enhance mucus penetration. In the high-ROS fibrotic microenvironment, the liposomes destabilize, releasing SAB and GC-1. SAB scavenges ROS to remodel the fibrotic niche, while GC-1 reactivates TRβ signaling, driving the differentiation of stalled Krt8+ transitional epithelial cells into functional alveolar type I (AT1) cells. In a mouse model of pulmonary fibrosis, SAB/GC-1@Lip-cRGD significantly reduced pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and TGF-β1 in bronchoalveolar lavage fluid and lung homogenates. The proportion of CD206+ M2 macrophages decreased from 27.4% in the model group to 6.2% after treatment, indicating potent anti-inflammatory and anti-fibrotic effects. This synergistic strategy of microenvironment remodeling and epithelial regeneration achieved robust collagen depletion, restoration of alveolar integrity, and recovery of pulmonary function, outperforming single-drug or non-targeted formulations. The work provides a generalized paradigm for integrating microenvironment regulation with regenerative repair in pulmonary diseases.