cellpenetrating

Cell-penetrating describes the property of certain molecules to cross cellular membranes, a capability exploited to deliver otherwise impermeable cargos into cells. In biomedicine, this concept is most commonly linked to cell-penetrating peptides (CPPs), short peptides typically 5 to 30 amino acids long that can facilitate the uptake of diverse cargoes, including nucleic acids, proteins, nanoparticles, and imaging agents.

CPPs are often rich in basic residues such as arginine and lysine, and many are amphipathic, combining polar and hydrophobic regions. Classic examples include the TAT peptide from HIV-1, penetratin derived from the Antennapedia homeodomain, and various arginine-rich or amphipathic sequences. Cargo delivery can be achieved through covalent conjugation or noncovalent complexation, enabling transport of a wide range of molecules.

Uptake mechanisms for CPPs and their cargo are heterogeneous and can involve direct translocation across the plasma membrane or energy-dependent endocytic routes, such as macropinocytosis, clathrin-mediated endocytosis, or caveolae-mediated pathways. The exact route depends on peptide and cargo properties as well as experimental conditions. A major challenge is endosomal entrapment, which can limit cargo release into the cytosol and reduce effectiveness.

Applications of CPPs include delivery of antisense and siRNA, plasmid DNA, therapeutic proteins, and diagnostic imaging agents. They are investigated for cancer, genetic diseases, and vaccines. Limitations involve variability in in vivo performance, potential cytotoxicity, immunogenicity, and regulatory considerations related to safety and manufacturing. Several CPP-based constructs have entered clinical trials, but no CPP-based therapy has achieved broad regulatory approval as of now.