SiRNAs with Neutral Phosphate Triester Hydrocarbon Tails ExhibitCarrier-Free Gene-Silencing Activity

Short interfering RNAs (siRNAs) show promise as gene-silencing therapeutics, but their cellular uptake remains achallenge. We have recently shown the synthesis of siRNAs bearing a single neutral phenylethyl phosphotriester linkage within thesense strand. Here, we report the synthesis of siRNAs bearing three different hydrophobic phosphate triester linkages at keypositions within the sense strand and assess their gene silencing in the absence of a transfection carrier. The best siRNAs bearinghydrophobic phosphate triester tails were not aromatic and exhibited effective gene silencing (IC50 approximate to 56-141 nM), whereas thearomatic derivative with three hydrophobic tails did not exhibit carrier-free gene silencing

Automated summary

siRNAs have shown promise as gene-silencing therapeutics, but their cellular uptake remains a challenge. Researchers synthesized siRNAs with different hydrophobic phosphate triester linkages and evaluated their gene silencing effects without a transfection carrier. The best siRNAs exhibited effective gene silencing.