As described above, siRNAs represent a valuable tool to inhibit the expression of a target gene in a sequence-specific manner. In the following section, selected examples of CPPmediated siRNA delivery will be presented which are summarized in Table 2 . Only a few studies describe the covalent attachment of nucleic acid cargo and peptide carrier (confer Table 2 ). In one approach, simple mixing of siRNA targeted against GFP or CDK9 and Tat peptide did not generate any measurable RNAi effect whereas cross-linked siRNA-Tat 47-57 led to a significant down-regulation of the target proteins. However, high concentrations of siRNA (about 300 nM) had to be used [88] . Both LF-and Tat 47-57 -mediated transfections resulted in a perinuclear localization of siRNA. In contrast, fluorescently labeled Tat 47-57 without cargo was mainly found in the nucleolus, suggesting that interactions with RISC influence subcellular localization. In another approach, significant uptake of siRNAs targeted against luciferase or GFP could be observed after disulfide coupling the 5'-end of the sense strand to penetratin or transportan [89] . Compared to LF2000, slightly higher levels of transfection were achieved. Interestingly, after LF2000-mediated transfection, basal luciferase activity returned to normal levels one day earlier than after CPP-mediated transfection although the same concentration of siRNA was applied. A remarkably strong RNAi effect in hard to transfect primary neuronal cells was reported by Davidson et al. [90] . Here, siRNAs directed against several endogenous proteins were coupled to penetratin via a disulfide bond. The observed down regulation of the target proteins after peptide-mediated siRNA delivery was found to be far more effective compared to LF2000. This was in part attributed to the toxicity of the lipids. As one of the first groups to report on Tat 48-60 -or penetratin-mediated siRNA delivery in vivo, Moschos et al. showed, that intratracheal administration of the conjugates did not lead to any intensification of the knockdown of the target gene p38 mitogen-activated protein kinase in mouse lungs in comparison to unmodified non-formulated siRNA [91] . Strikingly, it was found that the peptides alone triggered a detectable decrease in target gene expression and that the penetratin-conjugate induced elevated levels of the immune markers IFN-, TNF-, and IL-12p40 in lung tissue.