Cell-penetrating peptide-based non-invasive topical delivery systems

Cell-penetrating peptides (CPPs) have been receiving much attention over the last few decades due to their unique ability to translocate across plasma membranes efficiently and carry the wide range of macromolecular cargoes with them. Although their intracellular delivery mechanism has not been fully elucidated, CPP-based cellular uptake, mainly mediated by direct transduction or endocytosis, depends on structural characteristics of CPPs, the type and concentration of CPPs or cargoes, and cell types being treated. To overcome the intrinsic drawbacks of CPPs including lack of cell or tissue specificity, short plasma half-life, and endosomal sequestration, various strategies have been suggested such as activatable CPPs (ACPPs), introduction of targeting moieties and fusion peptides, and topical delivery systems for clinical application. In this review, we provide an overview of up-to-date knowledge of intracellular delivery mechanisms of CPPs and introduce potential topical applications of CPPs such as transdermal, nasal and ocular delivery for non-invasive delivering the therapeutic proteins or peptides.