N-acetylgalactosamine (GalNAc) is a carbohydrate ligand with a high affinity for the asialoglycoprotein receptor (ASGPR), a receptor abundantly expressed on hepatocyte surfaces. GalNAc binds to ASGPR with high selectivity and avidity, making it an ideal targeting agent for liver drug delivery. When conjugated to small interfering RNA (siRNA), GalNAc enables receptor-mediated endocytosis, ensuring that the siRNA payload is selectively internalized by liver cells. The use of GalNAc-based delivery enables delivery without requiring lipid nanoparticles or viral vectors while streamlining the delivery process and improving tissue targeting.
Figure 1. Structure of the triantennary GalNAc-siRNA conjugate used in several drug candidates[1].
GalNAc-siRNA conjugates are typically constructed through triantennary (three-armed) GalNAc clusters that are covalently attached to the 3'-end of the sense strand of siRNA duplexes. This configuration promotes multivalent interactions with ASGPR, increasing uptake efficiency while preserving gene silencing activity. The incorporation of GalNAc also stabilizes the siRNA structure and can be synergistically combined with chemical modifications (e.g., 2'-O-methyl, 2'-fluoro, phosphorothioate linkages) to enhance nuclease resistance and minimize off-target effects.
GalNAc-siRNA conjugates exploit the endogenous clearance mechanism of ASGPR, which is responsible for removing desialylated glycoproteins from circulation. ASGPR recognizes the GalNAc ligand to trigger clathrin-mediated endocytosis, which then internalizes the conjugate into early endosomes. The low pH within endosomes promotes separation of the receptor from its ligand, which enables ASGPR to return to the membrane while siRNA stays inside the cell.
Figure 2. GalNAc-siRNA conjugate pathway[2].
A critical aspect of hepatic delivery lies in the design of GalNAc conjugates with optimal linker chemistry. The use of cleavable linkers such as disulfide or acid-labile bonds supports the release of active siRNA into the cytoplasm after endosomal escape, enabling it to participate in the RNA-induced silencing complex (RISC), which degrades complementary mRNA. This targeting approach achieves high selectivity, resulting in a lower therapeutic dose requirement while minimizing systemic exposure to improve safety profiles.
Alfa Chemistry provides custom synthesis services along with proprietary GalNAc derivatives, which allow precise management of valency, linker architecture and conjugation strategy for use in pharmaceutical and biotechnological applications.
The delivery landscape for RNA interference (RNAi)-based therapeutics has been transformed by GalNAc-siRNA conjugates, which show exceptional results for liver-associated diseases. GalNAc conjugates demonstrate multiple strong benefits over lipid nanoparticle (LNP) systems.
| Feature | GalNAc-siRNA Conjugates | Lipid Nanoparticles (LNPs) |
| Tissue specificity | High (hepatocyte-specific via ASGPR) | Broad or limited, depending on lipid composition |
| Immunogenicity | Low | Moderate to high (can activate innate immunity) |
| Formulation complexity | Low (chemical synthesis, lyophilization possible) | High (requires precise lipid ratios, microfluidics) |
| Administration route | Subcutaneous (preferred) | Intravenous (typically required) |
| Systemic toxicity | Minimal | Dose-limiting toxicities often observed |
The simplicity, reproducibility, and scalability of GalNAc-conjugation processes position this technology as a gold standard for hepatic siRNA therapeutics. Alfa Chemistry's library of GalNAc analogs and conjugation reagents supports diverse therapeutic pipelines aimed at hypercholesterolemia, hepatitis, coagulation disorders, and rare genetic diseases.
Several GalNAc-siRNA conjugates have reached regulatory approval, underscoring the clinical potential of this delivery platform. Notably:
These drugs are administered via subcutaneous injection, offering patient-friendly dosing regimens. The conjugation of GalNAc ensures liver-specific uptake, enabling long-lasting gene silencing with infrequent dosing (e.g., quarterly or biannual). Importantly, these examples validate the clinical feasibility, safety, and pharmacodynamic durability of GalNAc-siRNA therapeutics.
| Catalog | Name | Inquiry |
| ONT1834610137 | Lumasiran | Inquiry |
| ONT1639325431 | Givosiran | Inquiry |
| ONT1639324585 | Inclisiran | Inquiry |
| ONT1867157354 | Vutrisiran | Inquiry |
Figure 3. FDA-approved siRNA drugs as of 2022[3].
Despite its successes, the GalNAc-siRNA platform is limited to hepatic tissues due to the ASGPR dependency. Expanding RNAi delivery to extrahepatic targets remains a significant challenge. Efforts are underway to develop novel ligands for other tissue-specific receptors or to enhance endosomal escape mechanisms in hepatocytes to improve cytoplasmic release of siRNA.
Figure 4. siRNA chemical modification introduced in the 3' and 5' end[4].
Another frontier involves multiplexed siRNA designs or multivalent GalNAc architectures that enable dual targeting or synergistic silencing of multiple genes implicated in complex liver pathologies. Advances in chemical modifications and conjugation chemistries, such as click chemistry and strain-promoted azide-alkyne cycloaddition (SPAAC), have improved the stability and synthetic accessibility of GalNAc-siRNA conjugates.
Q1: What makes GalNAc–siRNA conjugates liver-specific?
GalNAc ligands bind selectively to the asialoglycoprotein receptor (ASGPR), which is highly expressed on hepatocytes, enabling liver-targeted delivery through receptor-mediated endocytosis.
Q2: Can GalNAc-siRNA conjugates be used for tissues outside the liver?
Currently, their use is primarily limited to the liver due to ASGPR specificity. Efforts are ongoing to develop alternative ligands for other tissue types.
Q3: Are GalNAc-siRNA drugs approved by regulatory agencies?
Yes, drugs like Givosiran, Inclisiran, and Lumasiran have been approved and are commercially available, highlighting the clinical viability of this platform.
Q4: What are the administration routes for GalNAc-siRNA therapeutics?
They are typically administered subcutaneously, which improves patient compliance compared to intravenous formulations.
Q5: How does Alfa Chemistry support GalNAc-siRNA research?
Alfa Chemistry offers GalNAc ligands, custom synthesis of modified siRNA, conjugation reagents, and analytical services to support the development and optimization of GalNAc–siRNA therapeutics.
Q6: How stable are GalNAc-siRNA conjugates in vivo?
With appropriate chemical modifications, these conjugates exhibit high stability, long circulation half-life, and durable gene silencing activity with infrequent dosing.
References
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