Fig. 1.

Schematic of the mechanism of synthetic small interfering RNA (siRNA)-mediated knockdown. Synthetic mature siRNA can be effectively delivered to the cell by nanocarriers, as an siRNA conjugate or through other mechanisms (see text for details). The double-stranded siRNA comprises the ‘sense’ or ‘passenger strand’ (red) and the ‘antisense’ or ‘guide strand’ (blue). After cell entry, for example, via endocytosis and escape from the endosome, the siRNA is introduced into the RNA-induced silencing complex (RISC), which comprises several distinct proteins including Argonaute-2 (Ago-2), Dicer, and the transactivation response element RNA-binding protein (TRBP). Upon siRNA activation by removing its ‘sense’ or ‘passenger’ strand, the remaining ‘antisense’ or ‘guide’ strand directs RISC towards sequence-specific binding to the target messenger RNA (mRNA). The siRNA action relies on 100% complementarity to the target sequence, and by bringing RISC into close proximity to its target mRNA, it initiates Ago-2-mediated mRNA cleavage (black scissors). Because of this cleavage and the subsequent presence of unprotected ends, the mRNA is rapidly degraded by intracellular RNAses, leading to the efficient prevention of protein synthesis. After mRNA cleavage, the siRNA-loaded RISC can dissociate and bind to another mRNA target molecule, thus acting in a catalytical manner