Novel siRNA delivery strategy targeting multiple genes was developed using multi-siRNA conjugates that were composed of at least two different kinds of siRNA sequence. Different from previous studies designed with multiple target sequences embedded short hairpin RNAs (shRNAs) in one single virus vector or the cocktailed system of multiple siRNA complexed with a cationic carrier [1], we simply cross-linked two kinds of siRNA via a reducible disulfide bond. These dual gene targeted multi-siRNA conjugates could be easily cleaved in a reductive environment, e.g. cytoplasm, to restore native forms and underwent the subsequent RNAi mechanism without any risks of off-target effects related with Dicer digestion or immune responses induced by long double strand RNA. With using cationic polymers as nano-complexing agents, dual gene targeted multi-siRNA conjugates demonstrated that both of target genes were more efficiently suppressed than physically mixed two kinds of naked siRNAs and those of multi-siRNA conjugates composed of single gene targeted siRNA.
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