siRNAbased

siRNA-based approaches harness RNA interference to silence gene expression after transcription. Small interfering RNAs are typically 21-23 nucleotides long and duplexed. When loaded onto the RNA-induced silencing complex (RISC), the guide strand directs the complex to complementary messenger RNA sequences, promoting Argonaute-catalyzed cleavage and degradation of the target transcript. Consequently, translation of the target gene is reduced.

In research, siRNA is used as a reversible, sequence-specific method to knock down genes in cells and organisms, enabling functional genomics studies and model validation. In therapeutics, siRNA is delivered using delivery vehicles such as lipid nanoparticles or GalNAc conjugates that improve cellular uptake, stability, and tissue targeting. Chemical modifications, including 2'-O-methyl and 2'-fluoro substitutions and backbone modifications, enhance nuclease resistance and limit immune activation.

Delivery and safety challenges include nuclease degradation, off-target silencing, immune stimulation, and restricted tissue distribution. Off-target effects can occur with partial complementarity to unintended transcripts. Access to extrahepatic tissues remains a major hurdle, though ongoing research aims to broaden organ targeting and dosing regimens.

Several siRNA-based medicines have reached the clinic, notably those targeting liver-expressed genes, such as patisiran, givosiran, lumasiran, and inclisiran in various jurisdictions. These products demonstrate the clinical viability of RNA interference as a therapeutic modality, while emphasizing the importance of delivery technology and careful target selection.

Future work focuses on expanding tissue reach, improving safety profiles, reducing manufacturing costs, and developing durable, repeat-dose regimens for chronic diseases.