Inhalable stealth liposomes improve peptide delivery for pulmonary fibrosis treatment

Pulmonary fibrosis is a life-threatening lung disease with limited therapeutic options and suboptimal clinical outcomes. Peptide-based agents such as CSP7, a heptapeptide derived from caveolin-1, have shown promising antifibrotic activity with low systemic toxicity. However, effective inhaled administration of CSP7 is impeded by physiological barriers in fibrotic lungs, including alveolar edema fluid and clearance by inflammatory macrophages. Here, we report a high-loading stealth liposomal system designed to enhance pulmonary delivery of CSP7 by inhalation. CSP7 was covalently conjugated to an aliphatic lipid moiety to generate a lipidated prodrug (l-CSP7), enabling markedly improved incorporation into PEGylated stealth liposomes (l-CSP7/Lips) with about 4-fold higher encapsulation efficiency and drug loading. The optimized formulation also exhibited enhanced penetration through edematous alveolar fluid and reduced macrophage clearance. After deposition in the alveoli and uptake by myofibroblasts, intracellular enzymes cleave l-CSP7 to release active CSP7, thereby attenuating profibrotic cellular phenotypes. In bleomycin-induced idiopathic pulmonary fibrosis and silica-induced silicosis animal models, inhaled l-CSP7/Lips achieved superior alveolar delivery and therapeutic outcomes compared with free CSP7 and clinical drug nintedanib, reversing fibrotic remodeling, improving respiratory function, and reducing inflammation and collagen deposition. These results introduce a modular and translatable nanocarrier platform for inhalable peptide therapeutics and support a localized treatment strategy for pulmonary fibrosis and potentially other lung diseases. To address poor pulmonary delivery of inhaled CSP7, an antifibrotic peptide, the authors design a lipidated prodrug encapsulated in stealth liposomes, with the formulation optimized across multiple dimensions. This system penetrates edema-filled alveolar fluid and evades uptake by inflammatory macrophages, enhancing CSP7 delivery to fibrotic cells. The inhalable platform increases local drug exposure and supports peptide therapy in diseased lungs. • Lipidated CSP7 prodrug markedly enhances peptide loading in liposomal bilayers. • Inhaled formulation penetrates alveolar edema fluid and evades macrophage uptake. • l-CSP7/Lips show superior therapeutic efficacy to nintedanib across multiple models.