Therapeutics are restricted from cellular internalization due to the biological barrier formed by the cell membrane.
Especially for therapeutics with high molecular weight, strategies are required to enable delivery to intracellular
targets. Cell-penetrating peptides (CPPs) represent a powerful tool to mediate the entry of large cargos such as proteins,
siRNA and nanoparticles. The high diversity of CPPs is the prerequisite to use this class of carriers for various applications.
However, therapies based on CPPs are hampered by their unfavorable pharmacokinetics, mainly dominated by their
rapid renal clearance and their lack of specificity. Rational design is required to overcome these disadvantages and thereby
exploits the actual potential of CPPs. We summarize and highlight the current state of knowledge with special emphasis
on pharmacokinetics. The unclear internalization pathways of CPPs remain one of the main obstacles and therefore have
been in the focus of research. In this review, several promising strategies such as the combination with targeting sequences,
activatable CPPs and adjustment of the molecular weight are described. In addition, new absorption pathways
such as nasal, pulmonary or transdermal uptake expand the applicability of CPPs and may be a promising prospect for
Keywords: Absorption, biodistribution, cell-penetrating peptide, internalization, pharmacokinetics, targeting, topical application.
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