Membrane binding strength vs. pore formation cost - What drives the membrane permeation of nanoparticles coated with cell-penetrating-peptides coate?

Abstract

Cell-penetrating peptides (CPPs) enable the transport of nanoparticles through cell mem- branes. Using molecular simulations, we con- duct an in-depth investigation into the thermo- dynamic forces governing the passive translo- cation of CPP-coated nanoparticles across lipid bilayers, contrasting their behaviour with that of bare particles to dissect the peptides? con- tribution. Our analysis unveils a distinctive two-stage translocation mechanism, where the particles? adsorption energy overcomes the cost of forming a hydrophilic transmembrane pore. Properly evaluating the translocation mecha- nisms is only possible when using two reac- tion coordinates, in particular one that explic- itly includes the density of the lipids on the binding site of the particle. An analysis of ad- sorption, activation, and insertion-free energies in terms of a simple kinetic model provides a clearer understanding of the CPP-e ect. Experimental validation using non-endocytic cells con rms the superior membrane permeation of CPP-coated particles. Our ndings have impli- cations for the rational design of more e cient cell-permeating particles.