A variety of CPPs and derivatives have been frequently employed to facilitate the membrane translocation of siRNA, but their application in the area of pulmonary delivery of siRNA is limited. Only a few such as HIV-derived TAT trans-activator proteins and polyarginine peptides have been assessed for their suitability as a vector for pulmonary siRNA delivery. In most of the cases, CPPs are formulated with siRNA in the way of either forming nanocomplexes based on the electrostatic interaction or covalently attaching to siRNA. In addition, CPPs also could be used to modify lipid- or polymer-based siRNA delivery systems, for example, the conjugation of octa-arginine and TAT to neutral lipids to increase cellular uptake. Despite the 30%-45% gene knockdown obtained when siRNA was conjugated to cholesterol and TAT and delivered intratracheally to BALB/c mice, it was also found that the incorporation of CPP could elicit inflammatory response.35 Nevertheless, in another more recent study, CPP-siRNA complexes condensed by calcium promisingly offer high (up to 93%) target gene silencing effects in the human epithelial lung cell line (i.e., A549-luc-C8) with little to no evidence of cytotoxicity,38 suggesting it is worth putting more efforts in promoting this vector in the clinical application of siRNA.

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