PEGylation is commonly used to improve the pharmacokinetics and efficacy of intravenously administered drug nanocarriers; however its impact on pulmonary drug delivery remains unclear. While previous studies have focused on its role in crossing the lung mucosal barrier and stabilizing formulations for nebulization, less is known about its effects on lung surfactant corona composition, biodistribution, and therapeutic efficacy. Here, we present a multiscale study on how PEG-free and PEGylated liposomes loaded with pirfenidone interact with pulmonary barriers. PEGylation increased mucus penetration and reduced protein adsorption in the lung surfactant corona. However, statistical analysis of functional proteins showed only moderate changes in anti-inflammatory and adhesion proteins, with no apparent effect on key surfactant proteins that influence liposome fate in the lung. This correlated with similar biodistributions and retention times in both healthy and fibrotic lungs for PEG-free and PEGylated liposomes. Concerningly, PEGylated liposomes enhanced native surfactant fluidity, potentially altering lung function. In a bleomycin-induced pulmonary fibrosis model, both PEG-free and PEGylated liposomes improved the antifibrotic efficacy of pirfenidone. However, PEGylation attenuated the reduction in fibrotic biomarkers within the lung fluid. These findings suggest that, although PEGylation facilitates mucus penetration, it does not significantly enhance therapeutic outcomes and may adversely affect lung function. This study provides critical insights into the optimization of lipid-based nanocarriers for pulmonary fibrosis and other lung diseases