Small interfering RNA nunchucks with a hydrophobic linker for efficient intracellular delivery.

The high stiffness and low spatial charge density of siRNA limit the effectiveness of the electrostatic condensation of siRNA with cationic polyelectrolytes. Here, a facile method to stabilize nanoscale siRNA/polyelectrolyte complexes by introducing a reductively cleavable alkyl chain to siRNA as a hybrophobic linker of dimeric siRNA conjugates is reported. The increased length of the hydrophobic linker increases the intracellular translocation and gene silencing activity of the dimeric siRNA conjugates when they are complexed with linear polyethylenimine (LPEI). The results suggest that the introduction of a hydrophobic linker in the dimeric siRNA conjugates can facilitate the intracellular delivery of siRNA through effective condensation with cationic polyelectrolytes.