ArticleMolecular therapy. Nucleic acids2022
PK-modifying anchors significantly alter clearance kinetics, tissue distribution, and efficacy of therapeutics siRNAs.
Article in Molecular therapy. Nucleic acids, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
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- Population Pharmacokinetic and Pharmacodynamic Modelling and Simulation for Nedosiran Clinical Development and Dose Guidance in Pediatric Patients with Primary Hyperoxaluria Type 1.Clinical pharmacokinetics · 2025Article
- RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Targeted siRNA Delivery Using Cetuximab-Conjugated Starch for Epidermal Growth Factor Receptor-Driven Head and Neck Squamous Cell Carcinoma.Small science · 2025Article
- Clinical development prospects of siRNA drugs for tumor therapy: analysis of clinical trial registration data from 2004 to 2024.Frontiers in pharmacology · 2025Article
- Protective Effects of GalNac-Modified Red Blood Cell-Derived Extracellular Vesicles Against Liver Diseases.International journal of nanomedicine · 2025Article
- Nedosiran population pharmacokinetic and pharmacodynamic modelling and simulation to guide clinical development and dose selection in patients with primary hyperoxaluria type 1.British journal of clinical pharmacology · 2024Article
- A programmable dual-targeting siRNA scaffold supports potent two-gene modulation in the central nervous system.Nucleic acids research · 2024Article
- RNAi-based drug design: considerations and future directions.Nature reviews. Drug discovery · 2024Review
- LDLR-Mediated Targeting and Productive Uptake of siRNA-Peptide Ligand Conjugates In Vitro and In Vivo.Pharmaceutics · 2024Article
- Self-delivering, chemically modified CRISPR RNAs for AAV co-delivery and genome editing in vivo.Nucleic acids research · 2024Article
- A programmable dual-targeting di-valent siRNA scaffold supports potent multi-gene modulation in the central nervous system.bioRxiv : the preprint server for biology · 2023Article
Corrections and comments
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Authors and funding
14 authors at 1 institution in 1 country.
Funding
Abstract
Effective systemic delivery of small interfering RNAs (siRNAs) to tissues other than liver remains a challenge. siRNAs are small (∼15 kDa) and therefore rapidly cleared by the kidneys, resulting in limited blood residence times and tissue exposure. Current strategies to improve the unfavorable pharmacokinetic (PK) properties of siRNAs rely on enhancing binding to serum proteins through extensive phosphorothioate modifications or by conjugation of targeting ligands. Here, we describe an alternative strategy for enhancing blood and tissue PK based on dynamic modulation of the overall size of the siRNA. We engineered a high-affinity universal oligonucleotide anchor conjugated to a high-molecular-weight moiety, which binds to the 3' end of the guide strand of an asymmetric siRNA. Data showed a strong correlation between the size of the PK-modifying anchor and clearance kinetics. Large 40-kDa PK-modifying anchors reduced renal clearance by ∼23-fold and improved tissue exposure area under the curve (AUC) by ∼26-fold, resulting in increased extrahepatic tissue retention (∼3- to 5-fold). Furthermore, PK-modifying oligonucleotide anchors allowed for straightforward and versatile modulation of blood residence times and biodistribution of a panel of chemically distinct ligands. The effects were more pronounced for conjugates with low lipophilicity (e.g., N-Acetylgalactosamine [GalNAc]), where significant improvement in uptake by hepatocytes and dose-dependent silencing in the liver was observed.
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Registered trials
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