Abstract
RNAi therapeutics are designed to produce the precise silencing effects against the gene-linked diseases which were known to be untreatable in the past. The highly immunostimulatory nature of siRNA enhances the off-target effects and easily get attacked by nucleases; hence, their modulation is essentially required for accurate alterations to be made in the structures to intensify the pharmacological attributes. The phosphonate modifications act as shield against undue phosphorylation effects, and the molecular changes in ribose sugar lowers the level of immunogenicity and increases the binding efficacy. When bases are substituted with virtual/or pseudo bases, they eventually reduce the off-target effects. These changes modulate the nucleic acid sensors and control the hyper-activation of innate immune response. Various modification designs based on STC (universal pattern), ESC, ESC + (advanced patterns) and disubstrate have been explored to silence the gene expression of various diseases e.g., hepatitis, HIV, influenza, RSV, CNV and acute kidney injury. This review describes the various innovative siRNA therapeutics and their implications on the developed immune regulations to silence the disease effects. siRNA causes the silencing effects through RISC processing. The innate immune signalling is induced by both TLR-dependent and TLR-independent pathways. Modification chemistries are utilized to modulate the immune response.