Decoy oligonucleotides and short interfering RNAs (siRNA) constitute powerful biomedical tools to control protein activation and/or gene expression post-transcriptionally. (Elbashir et al., 2001; Hannon, 2002). However, the major limitation of siRNA applications, like most antisense or nucleic acid-based strategies remains their poor cellular uptake associated with the poor permeability of the cell membrane to nucleic acids. Several viral and non-viral strategies have been proposed to improve the delivery of either siRNA-expressing vectors or synthetic siRNAs both in cultured cells and in vivo (De Fougerolles et al., 2007; Juliano et al., 2008). CPP-based strategies have been developed to improve the delivery of oligonucleotides both in vitro and in vivo. Delivery of charged oligonucleotide and siRNA is more challenging as multiple anionic charges of the nucleic acid interact with CPP moiety and inhibit uptakes by steric hindrance. Delivery of charged oligonucleotide was achieved by using either peptide-based non-covalent or PNA-hybridization strategies. In the latter, CPPs are covalently linked to a PNA that is able to hybridize with a double-stranded decoy oligonucleotide containing on one strand a flanking sequence complementary to the PNA. Strategies have been applied with Transportan and TP10 CPP for the delivery of decoy oligonucleotide interacting with NFkB or Myc (Fisher et al., 2004; El-Andaloussi et al., 2005). The MPG peptide-based delivery system has been successfully applied for the delivery of various type of nucleic acid, including phosphodiester-oligonucleotide targeting the protein phosphatase cdc25C (Morris et al., 1999), phosphorothioate-oligonucleotides targeting MDR-1 promoter in human CEM leukaemia cells (Marthinet et al., 2000) and thio-phosphoramidate telomerase template antagonists in cancer cells (Asai et al., 2003; Gryaznov et al., 2003). Several CPP-based strategies have been used for the delivery of siRNA into cultured cells. siRNA covalently linked to Transportan (Muratovska and Eccles, 2004) and penetratin (Davidson et al., 2004) have been associated with a silencing response. Nevertheless, non-covalent strategies appear to be more appropriate for siRNA delivery and yield significant associated biological response (Simeoni et al., 2003; Kim et al., 2006; Veldhoen et al., 2006; Crombez et al., 2007; Kumar et al., 2007; Lundberg et al., 2007; Meade and Dowdy, 2007). MPG peptide has been reported to improve siRNA delivery into a large panel of cell lines including adherent cell lines, cells in suspension, cancer and challenging primary cell lines (Simeoni et al., 2003; Morris et al., 2004a; Nguyen et al., 2006). MPG has been applied for in vivo delivery of siRNA targeting OCT-4 into mouse blastocytes (Zeineddine et al., 2006) and of siRNA targeting an essential cell cycle protein, cyclin B1; intravenous injection of MPG/cyclin B1 siRNA particles has been shown to efficiently block tumour growth (Crombez et al., 2007). A variant of MPG (MPG-alpha) harbouring five mutations in the hydrophobic domain, in order to favour helical conformation of the peptide, has also been shown to improve siRNA delivery (Veldhoen et al., 2006). However, such modifications of MPG increase toxicity and favour endosomal cellular uptake (Deshayes et al., 2004c; Veldhoen et al., 2006). This non-covalent approach has been extended to other CPPs including polyarginine- (Kim et al., 2006; Kumar et al., 2007), penetratin- (Lundberg et al., 2007) and Tat- (Meade and Dowdy, 2007) derived peptides. Tat peptide associated with an RNA-binding motif has been reported to block in vivo epidermal growth factor (EGF) factor, cholesterol-Arg9 has been shown to enhance siRNA delivery in vivo against vascular endothelial growth factors (Kim et al., 2006) and more recently, a small peptide derived from rabies virus glycoprotein associated to polyarginine R9 has been shown to deliver siRNA in the CNS (Kumar et al., 2007).