Activatable cell-penetrating peptides: 15 years of research

An important hurdle for the intracellular delivery of large cargo is the cellular membrane, which protects the cell from exogenous substances. Cell-penetrating peptides (CPPs) can cross this barrier but their use as drug delivery vehicles is hampered by their lack of cell type specificity. Over the past years, several approaches have been explored to control the activity of CPPs that can be primed for cellular uptake. Since the first report on such activatable CPPs (ACPPs) in 2004, various methods of activation have been developed. Here, we provide an overview of the different ACPPs strategies known to date and summarize the benefits, drawbacks, and future directions.