Integrin/CD44-Targeted Liposomal Co-Delivery of Nintedanib and Dexamethasone for Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) poses a significant clinical challenge due to its high morbidity and mortality, coupled with a lack of effective targeted therapies. Here, utilizing single-cell transcriptomic analysis, we identified integrin and CD44 as markedly upregulated in injured alveolar type II cells and myofibroblasts, highlighting their potential as pathological delivery targets in AE-IPF. Based on these findings, we developed a dual-targeted liposomal nanoplatform (ND-RHL) co-encapsulating nintedanib and dexamethasone, specifically engineered to exploit integrin/CD44 overexpression for pulmonary precise drug delivery and synergistic anti-fibrotic and anti-inflammatory effects. ND-RHL exhibited favorable physicochemical characteristics, efficient dual-drug loading, and selective accumulation in integrin/CD44-high cells both in vitro and in vivo. In a murine model of AE-PF, intratracheal administration of ND-RHL markedly improved survival, mitigated lung inflammation and fibrosis, and preserved pulmonary architecture, with minimal systemic toxicity. Mechanistically, transcriptomic profiling and immune phenotyping demonstrated that ND-RHL reversed AE-induced gene expression patterns and inhibited pivotal signaling pathways, including PI3K–AKT–mTOR, Wnt/β-catenin, and NF-κB–PPARγ, thereby orchestrating the remodeling of both immune and extracellular matrix microenvironments. This study presents ND-RHL as a mechanistically informed, cell-targeted nanotherapeutic with robust therapeutic potential and translational promise for the treatment of AE-IPF and related fibrotic lung diseases.