Structural transitions in lipid membranes: Mechanism for cell-penetrating peptides

Cell-penetrating peptides are short cationic peptides that have the ability to translocate efficiently across the plasma membranes of most eukaryotic cells. Successful intracellular delivery of many biologically active molecules has been possible using these peptides. However, the exact molecular mechanism of entry remains elusive. Many different mechanisms, including direct translocation and various endocytotic pathways, have been proposed but how a relatively short peptide facilitates these effects is unknown. Here, we review the various proposed mechanisms and note that the complete CPP behavior is not fully explained. We examine how peptides interact with lipid membranes using small-angle X-ray scattering and confocal microscopy and show that CPPs induce negative Gaussian curvature, the type of curvature observed in membrane-destabilizing processes like poration, invaginations, and protrusions. We further show how CPPs can multiplex interactions with different cellular components to facilitate cellular uptake of small proteins to large nanoparticles. © 2014 Elsevier Inc.