Oral delivery of siRNA and antisense oligonucleotides.

Inhibition of gene expression with antisense oligonucleotides or RNA interference (RNAi) mediated gene silencing by small interfering RNA (siRNA) has tremendous potential to silence the expression of disease-causing genes in the clinic. A major hurdle to their widespread clinical use is the safe and efficient delivery to target cells in vivo. Delivery via the oral route is considered the holy grail for small molecule and macromolecular drug delivery as it has the advantages of ease of administration, increased patient compliance, and cost-effectiveness. However, the harsh biological milieu of the acidic stomach and enzyme-rich gastrointestinal tract make efficient delivery of oligonucleotides and siRNA via the oral route difficult. Nonetheless, the first studies on the oral delivery of siRNA in animals and antisense oligonucleotides in humans suggest that significant oral delivery of these nucleic acids can be achieved across the gut wall. This can occur either by encapsulating siRNA within biodegradable particles that protect them from degradation and target them to M cells in intestinal Peyer's patches or by using chemically stabilized antisense oligonucleotides together with a penetration enhancer. This article reviews these studies as they mark important advances in the delivery of gene silencing nucleic acids and have heralded a new wave of enthusiasm that might lead to a significant expansion of the therapeutic options available for gene silencing drugs in the clinic.