In 2003, Simeoni et al. [94] were the first who noncovalently complexed siRNA with the peptide MPG. At a 1:10 ratio of negative nucleic acid to positive peptide charges a decrease in luciferase activity of about 80 % was detectable in HeLa or Cos-7 cells. This effect was further enhanced to about 90 % down-regulation by a mutation in the NLS sequence of the carrier peptide (MPG NLS ), presumably due to an increased delivery to the cytoplasm, where RISC is localized. Recently, Veldhoen et al. [55] used a derivative of the MPG peptide for the delivery of siRNA, which will be described in the chapter "MPG -mediated delivery of siRNA and steric block oligonucleotides". Leng et al. [21] presented promising results with a prospect for cell-specific siRNA delivery. Different versions of a branched histidine/ lysine-polymer (H3K8b) yielded up to 80 % knockdown of the target gene in several cell types. Structure-function studies revealed an important role of the composition of the histidine-rich domain as well as its position within the peptide and the branches for siRNA delivery, whereas size and surface charge did not have any effect. Furthermore, the toxicity was much lower than for the commercial cationic lipids Oligofectamine and LF2000. Finally, the attachment of the tripeptide RGD, an integrin-ligand, slightly enhanced siRNA delivery and turned this carrier into a cell-specific system. A  Fig. (1) . Simplistic scheme of peptide-based nucleic acid delivery systems (A). Interaction of CPP and cargo is either achieved by covalent attachment or by non-covalent complexation through mainly ionic interactions. In case of non-covalent complex formation, a further assembly of cargo/carrier complexes occurs, leading to the formation of large nanoparticles (confer Fig. (2) ). In case of covalently joined molecules a similar scenario is less likely, yet cannot be excluded. Prior to the translocation process the particles attach to the cell surface by ionic interactions of positively charged CPP residues with negatively charged membrane components. Subsequently, complexes are taken up via an endocytotic pathway. Although less likely, direct penetration cannot be excluded and may occur simultaneously. Once inside the cell, the cargo has to escape from vesicular compartments, otherwise it eventually gets degraded in the lysosome. Red: negative charges, blue: positive charges, green: hydrophobic domains. Three-dimensional model of MPG /siRNA interactions (B). The model was generated by iterative rigid body docking cycles of siRNA (PDB 1R9F) and peptide using the program Hex 4.2 [201] . The PDB file of MPG was generated with the program ICM (Molsoft LLC) taking into consideration different secondary structure predictions and energy minimization protocols. Out of many docking solutions particular ones were picked for illustration purposes using the program Chimera [202] . The phosphate backbone of the siRNA is shown in red, the nucleobases in light gray. Aliphatic, aromatic and hydrophobic residues of the peptide are shown in green, positive charged residues in blue and the remaining amino acids in gray. It is assumed that formation of larger particles is driven by hydrophobic peptide/peptide interactions generating free positive charges where other siRNA molecules can interact. This eventually drives complex formation in a sandwich or mesh like assembly reaction. In principle such a scenario holds true for any given nucleic acid cargo. similar concept has very recently been used by Kumar et al. [95] for a specific delivery approach into the brain. A peptide derived from rabies virus glycoprotein (RVG) interacts specifically with the nicotinic acetylcholine receptor (AchR) on neuronal cells to enable viral entry. The authors could show that the biotinylated form of the 29-amino-acid peptide (YTIWMPENPRPGTPCDIFTNSRGKRASNG) was taken up by neuronal cells. In order to transport nucleic acids with this vehicle, R 9 was conjugated to RVG peptide. Systemic treatment of mice with siRNA in a non-covalent complex with this modified peptide promoted a highly specific cellular import of siRNA only into cells expressing AchR. Even more important, an antiviral siRNA treatment resulted in successful protection of mice against encephalitis caused by Japanese encephalitis virus (JEV). This is the first study to report on a non-toxic method to deliver siRNA across the blood brain barrier which could help to circumvent dangerous and ineffective injections into the brain. To date it presents one of the most promising tissue-specific delivery approaches which might be expandable to other in vivo applications.