Release date:2023/3/21 10:19:30

Nucleic acid therapeutics are a promising way to treat diseases more precisely by introducing a sequence of nucleic acids to up-regulate, down-regulate or correct the target gene. Nucleic acid therapeutics can be divided into two categories according to their compositions: DNA drugs and RNA drugs, among which RNA drugs can be divided into antisense oligonucleotides (ASOs), Small activating RNAs (saRNA), Small interfering RNA  (siRNA), microRNAs (miRNAs), mRNA and aptamers.

siRNA is a synthetic double-stranded RNA, consisting of a sense strand and an antisense strand, which form a duplex 19 to 25 bp in length with 3' dinucleotide overhangs. The antisense strand of the siRNA duplex serves as a sequence-specific guide that directs activity of an endoribonuclease function in the RNA induced silencing complex (RISC) to degrade target mRNA.

Specifically speaking, siRNA occurs in four basic steps. First, the long double-stranded RNA (dsRNA) is processed into small interfering RNA (siRNA) duplexes by the nucleic acid endonuclease Dicer protein. Subsequently, the siRNA binds to the Argonaute-2 (AGO2) protein, which is thought to be the core of a multi-protein complex called the RNA-induced silencing complex (RISC). The siRNA is then separated into two single strands: the guide strand and the passenger strand. Finally, the passenger strand is degraded and the guide strand-RISC complex binds to the complementary target mRNAs triggering their degradation.


Figure. Schematic illustrations of the working mechanisms of siRNA

FDA-Approved siRNA Drugs

The development of siRNA drugs was not smooth in the early stage. siRNA drugs are unstable in the body, easily degraded by nucleases after entering the circulation and cleared by the kidney with a short half-life. At the same time, exogenous nucleic acid molecules are immunogenic and can easily cause an immune response in the body.

However, the FDA approved the first siRNA therapeutic drug, ONPATTRO™ (Patisiran), in August 2018, and the first gene therapy drug with a non-viral vector delivery system for the treatment of transthyretin-mediated amyloidosis. This has greatly boosted confidence in the development of this field and has guided the way for other siRNA drugs.

Patisiran was developed by Alnylam, a leading RNAi therapeutic company. In fact, all six siRNA therapies approved worldwide (Table) were developed or co-developed by Alnylam, and the market for siRNA therapies is almost monopolized by Alnylam, which generates considerable financial revenue for the company.

Drug Brand Name FDA Approval Company Delivery System Indication
Patisiran Onpattro 2018 Alnylam LNP-siRNA Hereditary transthyretin-mediated amyloidosis
Givosiran Givlaari 2019 Alnylam GalNAc-siRNA Acute hepatic porphyria
Lumasiran Oxlumo 2020 Alnylam GalNAc-siRNA Primary hyperoxaluria type 1
Inclisiran Leqvio 2021 Novartis GalNAc-siRNA Primary hypercholesterolemia
Vutrisiran Amvuttra 2022 Alnylam GalNAc-siRNA Hereditary transthyretin-mediated amyloidosis
Nedosiran Rivfloza 2023 Novo Nordisk GalXC™ RNAi platform Primary hyperoxaluria type 1

Table. FDA-Approved siRNA Drugs

siRNAs in Clinical Trials

The six approved siRNA drugs are mainly in the therapeutic areas of neurology, cardiovascular system, endocrine and metabolism, such as amyloidosis, familial amyloid polyneuropathies (FAPs), hyperlipidemia and other diseases.

With the introduction of new chemical modifications and delivery systems, the success rate of siRNA drug development is expected to increase. siRNA drug development is no longer limited to rare diseases but has successfully entered the chronic disease market, with potential breakthroughs in the oncology market. Dyslipidemia and functional cure of hepatitis B are two potential segments.

Metabolic Diseases

Cemdisiran is another liver-targeted GalNAc-siRNA drug that causes knockdown of complement 5 (C5) protein. It is being developed for the treatment of rare, life-threatening complement-mediated diseases, including paroxysmal nocturnal hemoglobinuria, immunoglobulin A nephropathy, atypical hemolytic uremic syndrome, and generalized myasthenia gravis.


Hemophilia A and B are indications for fitusiran (ALN-AT3), a GalNAc-siRNA conjugate that targets SERPINC1 mRNA. By reducing antithrombin production and increasing thrombin production, fitusiran corrects coagulation imbalances and prevents bleeding phenotypes. In phase I and II trials, fitusiran resulted in a very significant dose-dependent reduction in antithrombin. phase III trials have been completed or are still ongoing.

Infectious Diseases

The siRNA drug RG6346 mediates the selective knockdown of hepatitis B surface antigen required for the hepatitis B virus life cycle in hepatocytes. Results from a phase I trial published in November 2020 showed that dosing every 4 months resulted in a substantial and durable reduction in hepatitis B surface antigen levels lasting up to 1 year after the last dose.


Mutant KRAS is the most prominent oncogenic driver in many cancers. siRNAs targeting KRAS G12D mutants have been formulated in biodegradable polymeric matrices for sustained local release (LODER; topical drug EluteR). Notably, a study currently underway in patients with locally advanced pancreatic cancer uses this siRNA in combination with established chemotherapy based on gemcitabine or nab-paclitaxel.

Ocular Diseases

Several siRNA drug developments have been investigated for ocular diseases. These include glaucoma, age-related macular degeneration (AMD), dry eye disease (dry eye syndrome), diabetic macular edema (DME), and various genetic retinal diseases.

Delivery System of siRNA

Delivery of siRNA has been a major challenge for the application of siRNA therapeutics in humans. A key challenge for delivery is the pharmacological properties of siRNA, such as relatively large molecular weight (~13 kDa), poor membrane permeability (with approximately thirty-eight to fifty phosphate groups and excessive polarity), etc. Therefore, the selection of an appropriate delivery strategy is crucial.

Alnylam has successfully solved the siRNA drug delivery challenge by developing two siRNA delivery technologies: lipid nanoparticles (LNPs) and conjugates.

Lipid Nanoparticles (LNPs)

Lipid nanoparticle (LNP)  is one of the most promising non-viral delivery systems that encapsulate siRNAs for delivery to target tissues, consisting of neutral lipids, ionizable cationic lipids, cholesterol, and PEG. En route to their destination, siRNAs encapsulated in LNPs are protected from degradation by ubiquitous nucleases.


Figure. LNPs for siRNA, source: reference [4]

Biopharma PEG provides large-scale GMP manufacture of PEG derivatives for LNPs and related PEG intermediates.

Patisiran (ONPATTRO™), an LNP formulation of siRNA targeting transthyretin (TTR), was approved as the first siRNA drug by the Food and Drug Administration (FDA) in 2018 for the treatment of TTR-type familial amyloid polyneuropathy. Systemic administration of LNPs loaded with siRNA targeting TTR suppresses the deposition of amyloid fibrils of misfolded TTR in the peripheral nerves and heart.

In order to verify the safety and tolerability of the LNP-siRNA system in vivo, Tabernero et al conducted a phase I clinical trial of the ALN-VSP, an LNP-siRNA therapeutic targeting Vascular endothelial growthfactor (VEGF) and kinesin spindleprotein (KSP), in patients with hepatocellular carcinoma. It was found that the LNP-siRNA system has a good safety and therapeutic effect, and most of the patients' disease was alleviated and controlled.


Nanocarriers have played a great role in siRNA delivery, but delivery systems represented by liposomes and LNPs have hindered the further development of siRNA drugs due to their large particle size and in vivo toxicity.

In preclinical studies, the delivery strategy of siRNAs has gradually shifted from complex lipids or NPs with multifunctional components to chemically defined siRNA bioconjugates, including N-acetylgalactosamine siRNA conjugates (GalNAc-siRNA), cell penetrating peptides (CPP)-siRNA conjugates, and so on. At present, GalNAc-siRNA conjugates are more advanced siRNA conjugate vectors.

GalNAc, or N-acetylgalactosamine, is a sugar molecule that can recognize and bind to a cell surface protein, the asialoglycoprotein receptor (ASGPR), which is abundantly expressed on liver cells (hepatocytes). The binding affinity to the receptor increases exponentially if several GalNAc units are combined into a multivalent ligand.


Figure.  Delivery of GalNAc-siRNA conjugates into hepatocytes. Source: reference [5]


siRNA drugs have opened new avenues for innovative therapies for many diseases. Although there are several significant challenges and issues, including siRNA delivery and side effects that have slowed clinical translation, several siRNA drugs have been approved for clinical use and multiple siRNAs are in late-stage clinical studies.

As a global partner, Biopharma PEG can supply commercial quantities of high-quality functionalized PEGs, which are essential for your research of siRNA drugs. 

​1.Alshaer W, Zureigat H, Al Karaki A, et al. siRNA: mechanism of action, challenges, and therapeutic approaches. Eur J Pharmacol. 2021;916:174178.
2. Friedrich, M., Aigner, A. Therapeutic siRNA: State-of-the-Art and Future Perspectives. BioDrugs 36, 549–571 (2022).
4. Kalita, T.; Dezfouli, S.A.; Pandey, L.M.; Uludag, H. siRNA Functionalized Lipid Nanoparticles (LNPs) in Management of Diseases. Pharmaceutics 2022, 14, 2520.
5. Aaron D. Springer and Steven F. Dowdy.GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics.Nucleic Acid Therapeutics.Jun 2018.109-118.

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