Abstract
The RNA interference (RNAi) pathway possesses immense potential in silencing any gene in human cells. Small interfering RNA (siRNA) can efficiently trigger RNAi silencing of specific genes. FDA Approval of siRNA therapeutics in recent years garnered a new hope in siRNA therapeutics. However, their therapeutic use is limited by several challenges. siRNAs, being negatively charged, are membrane-impermeable and highly unstable in the systemic circulation. In this review, we have comprehensively discussed the extracellular barriers, including enzymatic degradation of siRNAs by serum endonucleases and RNAases, rapid renal clearance, membrane impermeability, and activation of the immune system. Besides, we have thoroughly described the intracellular barriers such as endosomal trap and off-target effects of siRNAs. Moreover, we have reported most of the strategies and techniques in overcoming these barriers, followed by critical comments in translating these molecules from bench to bedside.
Highlights
In 1998, Andrew Fire and Craig Mello published a seminal paper in which they discovered the phenomenon of post-transcriptional gene silencing (PTGS) and termed it as RNA interference (RNAi) [1]
Following the successful entrance into the cytosol via endocytosis, synthetically produced Small interfering RNA (siRNA) can interact directly with cytosolic RNAi enzymes known as Dicer and Tar RNA Binding Protein (TRBP) [18]. siRNA larger than 21 bp will interact with the Dicer enzyme that cleaves and hands it off to the RNA-induced silencing complex (RISC) loading complex (RLC) [4,19]
SiRNA can silence the expression of the target proteins by interfering with the expression of target genes
Summary
In 1998, Andrew Fire and Craig Mello published a seminal paper in which they discovered the phenomenon of post-transcriptional gene silencing (PTGS) and termed it as RNA interference (RNAi) [1]. These siRNAs later kicked off a revolution in biology due to their potential to inhibit virtually all genes by a base sequence of target mRNA alone, which gives. Approval of the first siRNA-based drug patisiran (OnpattroTM) by the U.S Food and Drug Administration (FDA) in 2018 for polyneuropathy of hereditary transthyretin-mediated amyloidosis has fostered a new interest by the pharmaceutical as well as academic research groups in RNAi based drugs [6]. We attempted to describe comprehensively these barriers and the milestones achieved in addressing the obstacles commentary on innovation further reinforced the confidence in siRNA based followed products.byAcritical timeline of these events is shown and below in prospects. Products are already(RNAi) in different stages of clinical trials [8]
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