Chimeric Flaviviral RNA−siRNA Molecules Resist Degradation by The Exoribonuclease Xrn1 and Trigger Gene Silencing in Mammalian Cells

Abstract

RNA is an emerging platform for drug delivery, but the susceptibility of RNA to nuclease degradation remains a major barrier to its implementation in vivo. Here, we engineered flaviviral Xrn1-resistant RNA (xrRNA) motifs to host small interfering RNA (siRNA) duplexes. The xrRNA-siRNA molecules self-assemble in vitro, resist degradation by the conserved eukaryotic 5' to 3' exoribonuclease Xrn1, and trigger gene silencing in 293T cells. The resistance of the molecules to Xrn1 does not translate to stability in blood serum. Nevertheless, our results demonstrate that flavivirus-derived xrRNA motifs can confer Xrn1 resistance on a model therapeutic payload and set the stage for further investigations into using the motifs as building blocks in RNA nanotechnology.

Progressing nanotechnology to improve targeted cancer treatment: overcoming hurdles in its clinical implementation

“…However, ensuring their stability in biological environments remains a challenge, requiring ongoing research efforts [71]. Small interfering RNAs (siRNAs) represent a different approach to targeting cancer cells at the genetic level [72]. SiRNAs, synthesized chemically or produced through recombinant technology, can silence genes responsible for cancer cell growth and survival.…”