Nebulized inhalation of nintedanib-loaded biomimetic nano-liposomes attenuated bleomycin-induced interstitial lung fibrosis in mice

Idiopathic pulmonary fibrosis (IPF) is an irreversible interstitial lung disease with a poor prognosis. However, there are currently few drugs available for its treatment. Nintedanib is clinically effective but is associated with gastrointestinal adverse effects and weight loss. Due to drug intolerance, the overall outcomes of nintedanib therapy are substantially compromised in quite a few patients. In the present study, we synthesized nintedanib-loaded biomimetic liposomes (Nin-lipo) to improve the antifibrotic efficacy and drug tolerance of nintedanib. It was observed that nebulized inhalation of small doses of Nin-lipo (2 mg/kg) resulted in greater delivery efficiency and higher drug concentrations in lung tissue than conventional oral doses of nintedanib (60 mg/kg). Furthermore, Nin-lipo significantly inhibited bleomycin (BLM)-induced pulmonary fibrosis and improved lung function in mice. The possible molecular mechanism of anti-fibrosis by Nin-lipo was investigated. Nin-lipo was found to act mechanistically on alveolar macrophages via alveolar surfactant proteins A and D (SP-A/D) by simulating pulmonary surfactants and inhibiting the polarization of M2 macrophages. These effects thereby reduced the secretion of transforming growth factor 1 (TGF-β1) in macrophages. Moreover, Nin-lipo demonstrated significant efficacy against weight loss and liver function abnormalities in a mouse model caused by nintedanib. Therefore, nebulized Nin-lipo could greatly improve the antifibrotic efficacy of nintedanib while maintaining an excellent safety profile. Nin-lipo could potentially be developed as a new therapy for IPF.