The growing number of reports on the effective cargo delivery by cell-penetrating peptides (CPPs) has extensively widened our knowledge about the mechanisms involved in CPP-mediated delivery. However, the data available on the internalization mode of CPP-cargo complexes are often conflicting and/or equivocal. Moreover, the intracellular trafficking of CPP-cargo complexes is, to date, relatively unexplored resulting in only minimal information about what is really happening to the complexes inside the cell. This review focuses on defining the endocytic pathways engaged in the transduction of CPP-cargo complexes and seeks to determine the extent of different endocytic routes required for effective uptake. In addition, the intracellular pathways utilized during the trafficking and sorting of CPP-cargo complexes as well as the ultimate fate of the complexes inside cells will be discussed.
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