Nanoparticles modified with cell penetrating peptides: Assessing adsorption on membranes containing acidic lipids

Cell-penetrating peptides (CPP) are poly-cationic molecules that facilitate the cellular uptake of nano-sized cargoes. Accumulation of the cargoes on the cell surface regulates the cargoes internalization rate and constitutes a critical step prior membrane crossing. In this work, we characterize the adsorption of nanoparticles coated with CPP on membranes containing acidic lipids. We describe how the particle-membrane interactions and the extent of adsorption, depend on the size of the particles, the number of grafted CPP molecules, and the composition of the solution in contact with the membrane. Our results are obtained by applying a molecular theory that takes into account electrostatic and steric interactions, entropic effects, and the acid-base equilibrium of all titratable molecules. It also takes into account the shape, protonation state, charge distribution and conformational flexibility of the peptide-grafted particles. Adsorption free energy profiles allow to quantify the adsorption energy, and reveal that nanoparticles attachment and detachment from the membrane surface are restrained by free energy barriers. At physiological pH, the surface binding of the nanoparticles is ultimately driven by the deprotonation of acidic lipids; the adsorption free energy is more sensitive to the concentration of salt or particles in solution than to the number of grafted CPP molecules. At variance, the height of the adsorption/desorption barriers increases with the CPP load. Our results indicate that electrostatic interactions, modulated by entropic effects, provide the driving force and regulate the adsorption kinetics of CPP-coated particles on acidic membranes.