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    How RNA silencing drugs work (siRNA and antisense)

    RNA silencing drugs are short synthetic nucleic acids that find a specific messenger RNA and destroy or redirect it, reducing the protein it encodes.[1][2] Since the first RNAi approval in 2018 the class has grown to include sixteen antisense drugs approved by US and EU regulators, and RNAi medicines for heart disease.[3][4][5]

    Editor reviewedStrict sourcingUpdated mRNA and next-gen vaccinesHealth and medicineLife sciences

    Silencing instead of instructing

    An mRNA vaccine adds a message to the cell. Silencing drugs do the opposite. They are short, man-made strands that stick to one particular message, the mRNA for a harmful protein, so the cell makes less of that protein.[6][3] There are two main families, antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs).

    Both families recognise their targets by Watson-Crick base pairing. ASOs are typically single-stranded and 15-30 nucleotides long.[6] Once bound, they work by different mechanisms. RNase H1 cleavage and RISC/AGO2-mediated silencing reduce expression, while steric-blocking designs modulate splicing.[1][2][7]

    Three ways to act on RNA

    1. Cut it. Many antisense drugs pair with the target RNA, and a cell enzyme called RNase H1 then chops up the RNA.[1]
    2. Hand it to the silencing machine. siRNA drugs load into a protein complex called RISC, which finds and cuts the matching message.[2][3]
    3. Change how it is edited. Some antisense drugs change how a gene’s message is spliced. Nusinersen does this to make a working SMN protein.[7]

    RNase H-competent ASOs form DNA-RNA heteroduplexes that RNase H1 recognises, and the enzyme degrades the RNA strand.[1] Oligonucleotides acting as AGO2 substrates activate RISC, which cleaves the target mRNA or inhibits its translation.[2] Steric-blocking splice-switching ASOs such as nusinersen bind the ISS-N1 motif downstream of SMN2 exon 7 and promote exon 7 inclusion.[7]

    Chemistry that makes the drugs work

    Natural RNA and DNA strands would be destroyed in the body within minutes, so drugmakers change their chemistry. The idea is old. The first antisense strand was reported in 1978, when it blocked a virus from copying itself.[8] Most approved antisense drugs swap one oxygen atom in the strand’s backbone for sulfur and add a small chemical group to each sugar.[9]

    The most common chemistry among approved ASOs pairs a phosphorothioate (PS) backbone with 2’-O-methoxyethyl (2’MOE) sugar modifications.[9] RNase H1-recruiting drugs are typically gapmers. A central DNA “gap” forms the DNA-RNA duplex that RNase H1 recognises, and 2’-modified “wings” on each side add stability and specificity.[10][1]

    Delivery: nanoparticles and GalNAc

    The first approved RNAi drug, Onpattro, used a lipid formulation infused every three weeks.[11] Many later drugs use GalNAc instead. This sugar binds the asialoglycoprotein receptor on liver cells, giving efficient uptake from a simple injection.[12] Alnylam’s Amvuttra, for example, is injected under the skin once a quarter.[5] The antisense drug olezarsen, approved in 2024, treats severe hypertriglyceridemia in familial chylomicronemia syndrome.[13] Because lipid nanoparticles collect mainly in the liver, reaching other organs is harder.[14] Alnylam is testing mivelsiran in phase 2 trials in Alzheimer’s disease.[15]

    Drugs for one patient

    Because an oligonucleotide is defined by its sequence, it can be designed for a single person’s mutation. The first individualized splice-correcting antisense drug, milasen, was developed in 2019 for one patient with a rare form of Batten disease. It blocks a cryptic splice site in the MFSD8 gene.[16] Gene editing has since followed a similar bespoke path; see personalized-gene-editing.[17]

    Where the field stands in 2026

    • Approvals. As of February 2026, sixteen antisense drugs had approval from the FDA and the European Medicines Agency.[4] Alnylam had six approved medicines as of July 2026.[18]
    • Heart disease. In March 2025 the FDA approved Amvuttra for transthyretin amyloid cardiomyopathy, based on the phase 3 HELIOS-B trial.[5] Amvuttra sales exceeded $1 billion in the second quarter of 2026.[19]
    • Next targets. Alnylam is running ZENITH, a phase 3 trial of zilebesiran.[15]

    See also alnylam-pharmaceuticals and the field tracker.

    This page describes the science and regulatory status. It is not medical advice.

    Questions readers ask

    What was the first approved RNAi drug?

    Alnylam's Onpattro (patisiran), approved by the FDA on 10 August 2018 for hereditary ATTR amyloidosis polyneuropathy.[3]

    How many antisense drugs are approved?

    A February 2026 review counted sixteen antisense oligonucleotide drugs approved by the US FDA and the European Medicines Agency.[4]

    How do these drugs reach the liver?

    Many are attached to GalNAc, a sugar that binds the asialoglycoprotein receptor on liver cells and drives efficient uptake.[12]

    Sources

    Each numbered claim is a statement we checked against the sources listed with it. Status shows how well established it is.

    1. [1]

      Many ASOs work by forming a DNA-RNA duplex with their target, which the enzyme RNase H1 recognises and cleaves, reducing production of the encoded protein. confirmedas of 2026-02-01

    2. [2]

      Oligonucleotides can also act through the RNA-induced silencing complex (RISC), whose AGO2 enzyme cleaves or blocks translation of the matching mRNA. confirmedas of 2026-02-01

    3. [3]

      On 10 August 2018 the FDA approved Alnylam's Onpattro (patisiran), the first approved RNAi therapeutic, which silences the mRNA encoding transthyretin to treat hereditary ATTR amyloidosis polyneuropathy. confirmedas of 2018-08-10

    4. [4]

      A February 2026 review counted sixteen antisense oligonucleotide drugs approved by the US FDA and the European Medicines Agency. confirmedas of 2026-02-01

    5. [5]

      On 20 March 2025 the FDA approved Alnylam's RNAi drug Amvuttra (vutrisiran) for the cardiomyopathy of transthyretin amyloidosis (ATTR-CM), based on the phase 3 HELIOS-B trial, with quarterly subcutaneous dosing. confirmedas of 2025-03-20

    6. [6]

      Antisense oligonucleotides (ASOs) are typically single strands of 15-30 nucleotides that bind complementary RNA by Watson-Crick base pairing. confirmedas of 2026-02-01

    7. [7]

      Some ASOs change how RNA is spliced rather than destroying it; nusinersen binds a splicing motif in SMN2 so that exon 7 is included. confirmedas of 2026-02-01

    8. [8]

      Antisense oligonucleotides were first reported in 1978, when one was shown to suppress viral replication. confirmedas of 2026-02-01

    9. [9]

      The most common chemistry among approved antisense drugs is a phosphorothioate backbone, in which a sulfur atom replaces a non-bridging oxygen, combined with a 2'-O-methoxyethyl (2'MOE) sugar modification. confirmedas of 2026-02-01

    10. [10]

      RNase H1-recruiting antisense drugs are usually "gapmers", with a central DNA stretch that pairs with the target RNA flanked by chemically modified "wings" that add stability and specificity. confirmedas of 2026-02-01

    11. [11]

      Onpattro is a lipid formulation given by intravenous infusion once every three weeks. confirmedas of 2018-08-10

    12. [12]

      GalNAc is a sugar attached to oligonucleotides that binds the asialoglycoprotein receptor on liver cells and drives efficient uptake into hepatocytes. confirmedas of 2026-02-01

    13. [13]

      The antisense drug olezarsen was approved in 2024 to treat severe hypertriglyceridemia in people with familial chylomicronemia syndrome. confirmedas of 2026-02-01

    14. [14]

      Lipid nanoparticles in the blood adsorb apolipoprotein E and therefore accumulate preferentially in the liver, which limits delivery to other organs. confirmedas of 2023-03-01

    15. [15]

      As of July 2026 Alnylam was running the ZENITH phase 3 trial of zilebesiran and phase 2 trials of mivelsiran in Alzheimer's disease. confirmedas of 2026-07-30

    16. [16]

      The first individualized splice-correcting antisense drug, milasen, was developed in 2019 for a single patient with a rare form of Batten disease, by blocking a cryptic splice site in the MFSD8 gene. confirmedas of 2026-02-01

    17. [17]

      In 2025 a team at Children's Hospital of Philadelphia and Penn Medicine designed and manufactured, within about six months, a personalized base-editing therapy delivered by lipid nanoparticles to the liver for an infant with severe CPS1 deficiency, a rare urea-cycle disorder. confirmedas of 2026-10-10

    18. [18]

      As of July 2026 Alnylam had six approved medicines. confirmedas of 2026-07-30

    19. [19]

      Alnylam reported second-quarter 2026 net product revenues of about $1.17 billion, of which Amvuttra contributed about $1.01 billion. confirmedas of 2026-07-30

    Revision history (2)
    1. Page created.
    2. Corrected the antisense approval count (FDA and EMA), and added sections on oligonucleotide chemistry and individualized antisense drugs.

    Created Oct 10, 2026. Last reviewed by an editor on Oct 10, 2026. Next scheduled review: Jan 10, 2027.

    Cite this page

    "How RNA silencing drugs work (siRNA and antisense)." ContentLora, updated Oct 10, 2026. https://contentlora.com/explain/how-rna-silencing-drugs-work

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