<p> Scavenger receptors as a target for nucleic acid delivery with peptide vectors Carmen Tali</p><p>Summary</p><p>Nucleic acids and synthetic oligonucleotides (ONs) are promising tools for regulation of gene functions and for the treatment of various diseases. However, the plasma membrane that surrounds cells provides an impermeable barrier for such big and negatively charged molecules. In order to facilitate the intracellular delivery of ONs and gain their access to target sites, various transfection methods have been developed. Among these, the cell-penetrating peptides (CPPs) have gained increased popularity. CPPs are short, usually cationic and/or amphipathic peptides that can efficiently cross the barrier of the cell plasma membrane. Due to the positive charge, CPPs form complexes with negatively charged ONs via electrostatic and hydrophobic interactions, and thereby facilitate cellular uptake of ONs. Despite extensive research in the field of CPPs, the cell entry mechanisms of CPP-ON complexes into cells are still largely unknown. Until quite recently it has been thought that positively charged CPP-ON complexes associate with negatively charged cell surface molecules, which induce the uptake of the complexes through endocytic mechanisms. Very recently, contrarily to expectation we found the nanocomplexes of CPP and ON to be negatively charged. Induction of internalization of such complexes into cells through simple electrostatic interactions with cell membrane is unlikely, and probably it occurs in a receptor-dependent manner. Identifying the specific receptors involved, and understanding the exact mechanisms of how CPPs and their complexes with ONs reveal their activity inside cells are highly essential in order to harness such complexes for medical purposes. The aim of this study was to examine the mechanisms of scavenger receptors at recognition of extracellular ONs and their complexes with CPPs. In more detail we describe the recruitment of the receptors to the plasma membrane by CPP-ON nanocomplexes, subsequent cell entry mechanisms and intracellular destination of the nanocomplexes.</p>