Aptamer-targeted cell-specific RNA interference

RNA interference (RNAi) refers to the sequence-specific cleavage of messenger RNA that follows the cellular introduction of complementary, small interfering (si)RNA duplexes 21 to 25 nt in length [1,2]. The development of siRNA-based therapeutics has progressed rapidly because of their specific and potent RNAi triggering activity [3,4]. Although siRNAs offer several advantages as potential new bio-drugs to treat various diseases [4-6] including cancers and HIV infection [7], the efficient delivery of siRNAs in vivo remains a crucial challenge for achieving the desired RNAi effect in clinical development [5,8,9].In particular, a targeted intracellular delivery approach for siRNAs to specific cell populations or tissues is highly desirable for the safety and efficacy of RNAi-based therapeutics. Targeted delivery of therapeutics is an area of vigorous research, and numerous recent investigations have described cell type-specific siRNA delivery using different strategies. For example, siRNAs have been covalently conjugated to a targeting ligand (cholesterol [10], α-tocopherol [11], lipophilic molecule [12,13], short peptide and antibody [14,15], agonist molecule [16] and nucleic acid-based aptamer [17-20]). Alternatively, siRNAs have also been non-covalently assembled with active recognition moieties and delivery vehicles as multifunctional targeting delivery systems, such as folate conjugated dendrimer [21], folate-conjugated phage RNAs [22-24], transferrin modified polymer/liposomes [25-28], peptide-based nanovectors [29-32], cholesterol polymers [33], antibody-mediated delivery formulations [34-48] and aptamer delivery platforms [20,49-51]. The last holds great promise for clinical translation. An ideal targeted delivery system contains two essential elements: (i) a potent therapeutic siRNA and (ii) a targeting vehicle that can selectively recognize and effectively escort cargo into a particular organ or cell. Indeed, a targeting ligand with high specificity and affi