Nanomedicine has opened the way to the design of more efficient diagnostics and therapeutics.
Moreover, recent literature has illustrated the use of short cationic and/or amphipathic peptides,
known as cell-penetrating peptides (CPPs), for mediating advanced drug delivery. CPPs exploit their
ability to enter cells and enhance the uptake of many cargoes ranging from small molecules to proteins.
The distinctive properties of nanocarriers (NC) based systems provide unforeseen benefits over
pure drugs for biomedical applications and constitute a challenging research field particularly focused on imaging and delivery;
nonetheless, several problems have to be overcome to make them a viable option in clinic. The use of CPPs improves
significantly their delivery to specific intracellular targets and thus readily contributes to their use both for effective
tumor therapy and gene therapy. A key issue is related to their mechanism of uptake, because although classical CPPs
enhance NCs’ uptake, the entry mechanism involves the endocytic pathway, which means that the delivered material is
sequestered within vesicles and only a small amount will escape from this environment and reach the desired target. In
this review, we will summarize recent advances in the use of CPP for enhanced delivery of nanocarriers, nucleic acids, and
drugs, we will discuss their uptake mechanisms and we will describe novel approaches to improve endosomal escape of internalized
Keywords: Active targeting, cell-penetrating peptides, drug delivery, endosomal escape, gene therapy, nanocarriers, passive
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