Decoupling efficacy from toxicity: Inhalable liposomal nintedanib for safe and effective treatment of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited treatment options. Nintedanib (NDNB), a triple tyrosine kinase inhibitor, slows disease progression, but its clinical utility is constrained by the oral formulation. This formulation suffers from low oral bioavailability and dose-limiting systemic toxicities, including severe gastrointestinal disturbances and hepatotoxicity. To overcome these challenges, we developed an inhalable nintedanib liposomal suspension (NDNB-Lip) for local pulmonary delivery. The optimized NDNB-Lip exhibited a uniform nanoscale size, high encapsulation efficiency, and sustained release profile in vitro. The results of the stress testing suggested that NDNB-Lip remained relatively stable under high temperature and intense light. Pharmacokinetic studies revealed that pulmonary inhalation of NDNB-Lip achieved a remarkable enhancement in lung-targeted exposure, with a relative bioavailability in lung tissue. In a bleomycin-induced pulmonary fibrosis model, NDNB-Lip demonstrated superior anti-fibrotic efficacy, significantly attenuating histological damage and reducing key fibrotic markers. Crucially, this enhanced efficacy was coupled with a markedly improved safety profile, as inhaled NDNB-Lip effectively circumvented the gastrointestinal and hepatic injuries associated with oral administration. Our findings underscore inhaled NDNB-Lip as a promising therapeutic strategy that decouples efficacy from toxicity, offering a novel paradigm for the safe and effective long-term management of IPF.