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Cell-penetrating peptides have been extensively used since their discovery for delivering cargoes unable to cross the cell membrane. Among other transported cargoes, they have shown very efficient delivery for oligonucleotides making cell-penetrating peptides a powerful tool for gene therapy. Numerous cell-penetrating peptides have now been discovered offering a wide library of structures and mechanisms of actions. Nevertheless, if it is known that different pathways are available for particles to be taken up, most mechanisms by which these particles enter cells are still to be characterized more precisely. Indeed it is admitted that cell-penetrating peptides are taken up either by direct translocation or by endocytosis but classes of cell-penetrating peptides are usually not related to specific entrance mechanisms. Actually, for most particles, different pathways can be detected during their uptake which makes the literature sometimes contradictory. Recent studies have nevertheless shown convergent uptake patterns for individual structures. Acetylated cell-penetrating peptides complexed with oligonucleotides have been shown to interact to scavenger receptor class A to induce caveolae-mediated endocytosis whereas antimicrobial peptides create pores in the cell membrane for direct translocation. Arginine-rich peptides have presented concentration-dependent mechanisms, being taken up either by membrane destabilization or clathrin-mediated endocytosis. Relating the structure of cell-penetrating peptides or their particles to distinct mechanisms would allow this delivery platform to become even more specific by using rational design to fit to the desired uptake pathway.

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