Objective:The purpose of this study was the design ibuprofen (IBU)-loaded unique Eudragit(R)RS 100 (ERS) and/or octadecylamine modified PLGA nanoparticles (NPs) for cancer treatment. Significance:The rational for this approach is to bring a new approach to cancer treatment with modification of IBU-loaded PLGA NPs with ERS and/or octadecylamine by means of smaller particle size (PS), cationic surface, biocompatible nature, and investigating their selective efficacy on lung cell lines (A549 lung cancer cell and CCD-19Lu normal cell line). Methods:IBU encapsulated PLGA-based NPs were prepared and characterized for physical and solid-state analyses.In vitrorelease, MTT, and determination of apoptotic pathways were performed. Results:Considering characterizations, B, C, E, F, H, and K formulations with higher EE%, smaller PS and encouraging higher zeta potential were chosen for further experiments were intended to enhance anticancer action and apoptotic behavior. Formulations were showed biphasic release profile with extended release manner (Korsmeyer-Peppas model with a diffusion-controlled mechanism). The NPs effect on lung cancer cells with high specificity and affinity was demonstrated by MTT study. It was found that the effect of IBU was increased 4-28 times over the pure form. Annexin V-FITC/PI staining method, FITC Active Caspase-3 staining method, and mitochondrial membrane potential detection analyses was performed to determine the apoptotic pathways by flow cytometry. Conclusion:E coded NP is selected as a promising candidate with its highly specific affinity for human lung adenocarcinoma cells and could induce cell death effectively and be a potent system to treat lung cancer.