SCARA Involvement in the Uptake of Nanoparticles Formed by Cell-Penetrating Peptides

The investigation of uptake mechanisms for cell-penetrating peptides (CPPs) is and has been an ongoing project for as long as the peptides have been known, a time period that now spans over two decades. The ultimate answer is yet to be revealed and the current understanding is that no "one" mechanism will ever be found. The reason for this is that the uptake mechanism seems to be dependent on a multitude of factors that include which CPP, what cells are used, whether or not there is cargo and what the cargo is. CPPs are capable of delivering a variety of bio-macromolecules that are by themselves unable to enter into cells. Our group has reported on many different peptides in recent years, many aimed at delivering various oligonucleotide-based cargoes. These peptides have utilized the inherent positive charge of the peptides and some rationally designed modifications to non-covalently complex oligonucleotides and bring them into cells. In this chapter, we present a brief overview of the current proposals for the uptake mechanisms of CPPs and describe methods for detecting and evaluating the role of scavenger receptor class A receptors in the uptake of non-covalent cell-penetrating peptide:oligonucleotide complexes.