Table 3.

Challenges of RNAi molecular delivery in IBD

RNAi molecule	Physical barriers	Pathological changes in gastrointestinal tract of IBD
High molecular mass: ~13 kDa of siRNA Strong net negative charge (~40 negative phosphate charges) of siRNA leads to electrostatic repulsion with anionic cell membrane surface Short half-life in vivo Off-target effects Immunostimulation	Low pH stomach environment Endogenous nuclease in gut lumen Reticuloendothelial system uptake and aggregation with serum proteins Gradual decline in pH and hydrolytic nuclease in endosome and lysosome via clathrin-mediated endocytosis	Abnormal colon luminal pH: 2.3–5.5 Diarrhea, abnormal motility, and surgical resection of gastrointestinal tract accelerated nanoparticulate transit time Dysbiosis of microbial composition influences polysaccharide-based nanoparticle degradation Enterocyte damage enhances nanoparticulate accumulation and uptake in enterocytes and macrophages

Abbreviations: IBD, inflammatory bowel disease; RNAi, RNA interference; siRNA, short interfering RNA.