TY - JOUR
T1 - Subcellular fate and off-target effects of siRNA, shRNA, and miRNA
AU - Singh, Saurabh
AU - Narang, Ajit S.
AU - Mahato, Ram I.
N1 - Funding Information:
The National Institutes of Health (NIH) is gratefully acknowledged for financial support (RO1 DK69968), the Department of Defense (W81XWH-10-1-0969) and Kosten Foundation.
PY - 2011/12
Y1 - 2011/12
N2 - RNA interference (RNAi) strategies include double-stranded RNA (dsRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), and microRNA (miRNA). As this is a highly specific technique, efforts have been made to utilize RNAi towards potential knock down of disease-causing genes in a targeted fashion. RNAi has the potential to selectively inhibit gene expression by degrading or blocking the translation of the target mRNA. However, delivering these RNAs to specific cells presents a significant challenge. Some of these challenges result from the necessity of traversing the circulatory system while avoiding kidney filtration, degradation by endonucleases, aggregation with serum proteins, and uptake by phagocytes. Further, non-specific delivery may result in side-effects, including the activation of immune response. We discuss the challenges in the systemic delivery to target cells, cellular uptake, endosomal release and intracellular transport of RNAi drugs and recent progress in overcoming these barriers. We also discuss approaches that increase the specificity and metabolic stability and reduce the off-target effects of RNAi strategy.
AB - RNA interference (RNAi) strategies include double-stranded RNA (dsRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), and microRNA (miRNA). As this is a highly specific technique, efforts have been made to utilize RNAi towards potential knock down of disease-causing genes in a targeted fashion. RNAi has the potential to selectively inhibit gene expression by degrading or blocking the translation of the target mRNA. However, delivering these RNAs to specific cells presents a significant challenge. Some of these challenges result from the necessity of traversing the circulatory system while avoiding kidney filtration, degradation by endonucleases, aggregation with serum proteins, and uptake by phagocytes. Further, non-specific delivery may result in side-effects, including the activation of immune response. We discuss the challenges in the systemic delivery to target cells, cellular uptake, endosomal release and intracellular transport of RNAi drugs and recent progress in overcoming these barriers. We also discuss approaches that increase the specificity and metabolic stability and reduce the off-target effects of RNAi strategy.
KW - RNA interference
KW - cellular uptake
KW - intracellular trafficking
KW - miRNA
KW - shRNA
KW - siRNA
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U2 - 10.1007/s11095-011-0608-1
DO - 10.1007/s11095-011-0608-1
M3 - Review article
C2 - 22033880
AN - SCOPUS:83555166124
SN - 0724-8741
VL - 28
SP - 2996
EP - 3015
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 12
ER -