RNA interference, or RNAi, is a natural cellular mechanism that helps regulate gene expression. Small interfering RNA, or siRNA, therapies use this pathway in a targeted way by directing cells to break down a specific messenger RNA (mRNA) before it can be translated into protein.
siRNAs are short, double-stranded RNA molecules designed to recognize a specific target mRNA. Once inside the cell, the siRNA is incorporated into
the RNA-induced silencing complex (RISC). One strand, known as the guide or antisense strand, remains within the complex and binds to a complementary sequence on the target mRNA.
RISC then cleaves the mRNA, leading to its degradation. As a result, less of the corresponding protein is produced.
An interesting feature of this mechanism is that RISC is not necessarily finished after cleaving a single mRNA molecule. Once loaded with its guide strand, the complex can act on additional copies of the same target mRNA. This contributes to the efficient gene-silencing activity of RNA interference.
Depending on the therapeutic strategy, this can directly reduce the level of a disease-associated protein. In other cases, silencing a particular gene can influence a broader biological pathway and help restore a more favorable balance.
siRNA has developed into an established therapeutic oligonucleotide modality, with approved medicines addressing both rare and more prevalent diseases.
Examples include hereditary transthyretin amyloidosis (hATTR), primary hyperoxaluria, hypercholesterolemia and hemophilia. These therapies illustrate how selectively reducing the expression of a specific gene can be used to intervene in very different disease mechanisms.
Another notable characteristic of some siRNA therapies is the duration of their effect. Chemically stabilized siRNAs can remain active within cells for extended periods, allowing gene silencing to continue even after concentrations in the bloodstream have declined. The clinical consequences can be significant. Inclisiran, for example, targets the mRNA for PCSK9 and, following its initial doses, is administered only once every six months.
Not every siRNA therapy has such a dosing schedule, but the example shows how sequence design, chemical modification and delivery can combine to produce sustained biological effects.
Efficient delivery remains a key challenge for siRNA therapeutics. Because siRNAs are relatively large and negatively charged, they do not readily cross cell membranes on their own.
Delivery technologies such as lipid nanoparticle formulations and GalNAc conjugation have helped overcome this limitation, particularly for targeting the liver. Chemical modifications can further improve siRNA stability, reduce degradation and help optimize its interaction with the immune system.
Expanding efficient delivery beyond established target tissues remains an important area of research and could broaden the range of diseases that can be addressed with siRNA therapeutics.
siRNA therapies make it possible to intervene at the RNA level, before a disease-relevant protein is produced. By combining sequence-specific recognition with the cell's own RNA interference machinery, they offer a targeted way to modulate gene expression.
At BioSpring, we support siRNA programs with manufacturing and analytical services across different stages of drug development.
A complete list of currently approved oligonucleotide therapeutics is available here:
Browse approved oligo therapeutics
For a compact summary of the landscape download our overview: