Improved Intracellular Delivery of Polyarginine Peptides with Cargoes

Complementary to endocytosis, cell-penetrating peptides (CPPs) at high concentrations can penetrate the cell membrane in a direct way, which further makes CPPs popular candidates for delivering therapeutic or diagnostic agents. Although featured as rapid uptake, the translocation efficiency and potential toxicity of the direct penetration are usually affected by cargoes, which is still unclear. Here, using coarse-grained molecular dynamics simulations, we show that the polyarginine (R8) peptides penetrate the membrane through a water pore in the membrane, and the transmembrane efficiency is improved by conjugating to small nanoparticles (NPs) with proper linkers. It can be attributed to both the extension of the lifetime of the water pore by the NPs and outward diffusion of negative lipids in the asymmetry membrane, which induces the surrounding R8–NP conjugates to the water pore before it is closed. The translocation efficiency is closely related to the length of the linkers, and it gets the maximum valu...