Nintedanib (NDB) is a crucial tyrosine kinase inhibitor used in the treatment of non-small cell lung cancer (NSCLC). However, its oral administration results in limited uptake of NDB by the lungs, necessitating high and frequent dosages, which leads to severe systemic adverse effects and poor bioavailability. To address these issues, a nasal formulation of NDB-invasomes (NLI) was developed as a potential therapy for NSCLC, aiming to improve the sustainability, targeting, bioavailability, and efficacy of NDB. Utilizing design expert software, various formulations were created and optimized. Additionally, analyses were performed on the cytotoxicity, bioavailability, targeting, and toxicity of the optimized NLI formulation. The chosen formulation contained 1.723 % phospholipids, 1.5 % cineole, and 1 % ethanol. The optimized NLI formulation enhanced the sustainability and bioavailability of free NDB by 55 % and 7.93-fold, respectively. Targeting studies indicated that the NLI formulation could achieve a more localized accumulation of NDB in the lungs. Furthermore, the optimized NLI formulation demonstrated greater anticancer efficacy against A549 lung cancer cells than free NDB. Histopathological analysis of the lungs in the optimized NLI group revealed no signs of toxicity. These findings suggest that the nasal NLI formulation is a promising option for treatment of NSCLC.