Suppressive effects of sugar-modified cationic liposome/NF-kappaB decoy complexes on adenovirus vector-induced innate immune responses.

To date, no countermeasures have been developed to overcome adenovirus (Ad) vector-induced innate immune responses in gene therapies that utilize these vectors. In the present study, we attempted to suppress Ad vector-induced innate immune responses and hepatotoxicity by delivering an NF-kappaB decoy to splenic macrophages and dendritic cells, as well as to Kupffer cells in the liver, using sugar-modified cationic liposomes. Pre-injection of the sugar-modified cationic liposome/NF-kappaB decoy complexes reduced serum levels of interleukin (IL)-12, which is a typical inflammatory cytokine induced by Ad vectors, and also reduced hepatotoxicity following Ad vector injection. Electrophoretic mobility shift assay demonstrated a reduction of Ad vector-induced NF-kappaB activation by pre-injection of the sugar-modified cationic liposome/NF-kappaB decoy complexes. Two types of sugar-modified cationic liposomes, fucosylated cationic liposomes (Fuc-liposomes) and mannosylated cationic liposomes (Man-liposomes), were tested in this study. Man-liposomes, which are considered to have greater affinity than Fuc-liposomes for splenocytes, appeared to have superior suppressive effects to those of Fuc-liposomes. Pre-injection of the sugar-modified cationic liposome/NF-kappaB decoy complexes did not inhibit Ad vector-mediated transduction in the organs. This study provides important findings for overcoming Ad vector-induced innate immune responses.