Unveiling Interactions of Tumor-Targeting Nanoparticles with Lipid Bilayers Using a Titratable Martini Model.

pH-responsive nanoparticles are ideal vehicles for drug delivery and are widely used in cell imaging in targeted therapy of cancer, which usually has a weakly acidic microenvironment. In this work, we constructed a titratable molecular model for nanoparticles grafted with ligands of pH-sensitive carboxylic acids and investigated the interactions between the nanoparticles and the lipid bilayer in varying pH environments. We mainly examined the effect of the grafting density of the pH-sensitive ligands of the nanoparticles on the interactions of the nanoparticles with the lipid bilayer. The results show that the nanoparticles can penetrate the lipid bilayer only when the pH value is lower than a critical value, which can be readily modulated to the specific pH value of the tumor microenvironment by changing the ligand grafting density. This work provides some insights into modulating the interactions between the pH-sensitive nanoparticles and cellular membranes to realize targeted drug delivery to tumors based on their specific pH environment.