Inhalable Albumin Nanoparticles Co-Delivering Dihydroartemisinin and Nintedanib Attenuate Pulmonary Fibrosis by Suppressing TGF-β1/Smad2/3 Signaling.

Purpose: Pulmonary fibrosis (PF) is a progressive interstitial lung disease characterized by high morbidity and limited treatment options. Current antifibrotic agents, such as pirfenidone and nintedanib (NIN), are restricted by systemic toxicity and insufficient pulmonary targeting. This study aimed to develop an inhalable human serum albumin (HSA)-based nanoparticle system co-delivering NIN and dihydroartemisinin (DHA), termed DHA/NIN@HSA, to achieve efficient lung-targeted combinational therapy against PF. Methods: DHA/NIN@HSA nanoparticles were prepared via a self-assembly strategy and characterized for morphology, particle size, and drug-loading efficiency. Pulmonary deposition and retention profiles after airway inhalation were evaluated using in vivo fluorescence imaging. The antifibrotic efficacy and safety of DHA/NIN@HSA were further assessed in a bleomycin-induced PF mouse model. Results: DHA/NIN@HSA nanoparticles exhibited uniform particle size (125 ± 5 nm) and excellent pulmonary deposition, ensuring prolonged lung retention and reduced systemic exposure. Airway administration of DHA/NIN@HSA every 48 h significantly mitigated fibrosis progression, improved survival, and restored alveolar architecture. Mechanistically, NIN inhibited fibroblast proliferation and myofibroblast differentiation, while DHA suppressed transforming growth factor-β1 (TGF-β1)/Smad2/3 signaling and inflammatory cytokines expression. Notably, DHA showed antifibrotic efficacy comparable to NIN with superior anti-inflammatory activity, highlighting its therapeutic potential in PF. Conclusion: Airway co-delivery of DHA/NIN@HSA achieved maximal antifibrotic efficacy, precise lung targeting, and favorable safety, providing a translatable nanotherapeutic platform for combinational therapy of PF.