Coarse-grained molecular dynamics was used to investigate different polymers to encapsulate the siRNA for its transposition through two lung surfactant models. These models consisted of a monolayer containing either 1,2-dipalmitoylsn-glycero-3-phosphatidylcholine (DPPC) or a 70:30 mixture of DPPC and 1,2- palmitoyl-sn-glycero-3-phospho-(1 -sn-glycerol) (DPPG). The nanocarriers chosen to encapsulate the anti-TNF siRNA were polyethylene glycol (PEG) and polyethyleneimine (PEI). It is believed that the use of siRNA to genetically silence the cytokine TNF might be therapeutic to treat several inflammatory diseases, in particular, pulmonary ones. The simulations showed that the nanoparticles containing PEG promoted the lipid depletion of the lung surfactant model by forming a lipid corona. The nanoparticles containing only PEI, or both PEG and PEI showed some perturbation of the lung surfactant model, however no collapse during the nanoparticle transposition was observed. The umbrella sampling method was used to calculate the Gibbs free energy of transposition through the pure DPPC lung surfactant model. The nanoparticles containing PEG showed a decreased Gibbs free energy as compared with naked siRNA, while PEI nanoparticles have not caused any change. The implication of this finding is that siRNA encapsulated with both PEI and PEG enhances the transposition of anti-TNF siRNA through lung surfactant models at the gas-liquid interface.