ArticleMolecular therapy : the journal of the American Society of Gene Therapy2021
Centyrin ligands for extrahepatic delivery of siRNA.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 45 citations in OpenAlex.
- Are RNA Therapies a Solid Foundation or a Frontier Yet to Be Conquered?International journal of molecular sciences · 2026Review
- Evaluation and forecasting of siRNA delivery technologies: An analysis of hierarchical decision model based on patent data.Molecular therapy. Nucleic acids · 2026Article
- 5'-end uridine-derived base modification for siRNAs potency reinforcement.Cell & bioscience · 2026Article
- Beyond Structure: The Dynamic Role of the Extracellular Matrix Components in Immune Evasion.Cancer communications (London, England) · 2026Review
- Potent and durable gene modulation in heart and muscle with chemically defined lipophilic siRNAs.Nucleic acids research · 2025Article
- Inverted chimeric RNAi molecules synergistically cotarget MYC and KRAS in KRAS-driven cancers.The Journal of clinical investigation · 2025Article
- Advances and challenges of targeting epicardial adipose tissue (EAT) and perivascular adipose tissue (PVAT).Cardiovascular diabetology · 2025Review
- Redesigning miR-34a: structural and chemical advances in the therapeutic development of an miRNA anti-cancer agent.Biochemical Society transactions · 2025Article
- A Therapeutic Small-Interfering RNA Potentiates Janus Kinase 1 Modulation for the Treatment of Dog Inflammatory Diseases.ACS pharmacology & translational science · 2025Article
- The Fomivirsen, Patisiran, and Givosiran Odyssey: How the Success Stories May Pave the Way for Future Clinical Translation of Nucleic Acid Drugs.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2025Review
- Development, opportunities, and challenges of siRNA nucleic acid drugs.Molecular therapy. Nucleic acids · 2025Review
- A novel CD71 Centyrin:Gys1 siRNA conjugate reduces glycogen synthesis and glycogen levels in a mouse model of Pompe disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Site-directed conjugation of single-stranded DNA to affinity proteins: quantifying the importance of conjugation strategy.Chemical science · 2024Article
- RNAi-based drug design: considerations and future directions.Nature reviews. Drug discovery · 2024Review
- Strategies for non-viral vectors targeting organs beyond the liver.Nature nanotechnology · 2024Review
- Nucleic Acid Therapeutics: Successes, Milestones, and Upcoming Innovation.Nucleic acid therapeutics · 2024Review
- Non-Coding RNA-Targeted Therapy: A State-of-the-Art Review.International journal of molecular sciences · 2024Review
- Multispecies-targeting siRNAs for the modulation of JAK1 in the skin.Molecular therapy. Nucleic acids · 2024Article
- Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy.Nature communications · 2024Article
- Lipid and Peptide-Oligonucleotide Conjugates for Therapeutic Purposes: From Simple Hybrids to Complex Multifunctional Assemblies.Pharmaceutics · 2023Review
Corrections and comments
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Authors and funding
17 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
RNA interference (RNAi) offers the potential to treat disease at the earliest onset by selectively turning off the expression of target genes, such as intracellular oncogenes that drive cancer growth. However, the development of RNAi therapeutics as anti-cancer drugs has been limited by both a lack of efficient and target cell-specific delivery systems and the necessity to overcome numerous intracellular barriers, including serum/lysosomal instability, cell membrane impermeability, and limited endosomal escape. Here, we combine two technologies to achieve posttranscriptional gene silencing in tumor cells: Centyrins, alternative scaffold proteins binding plasma membrane receptors for targeted delivery, and small interfering RNAs (siRNAs), chemically modified for high metabolic stability and potency. An EGFR Centyrin known to internalize in EGFR-positive tumor cells was site-specifically conjugated to a beta-catenin (CTNNb1) siRNA and found to drive potent and specific target knockdown by free uptake in cell culture and in mice inoculated with A431 tumor xenografts (EGFR amplified). The generalizability of this approach was further demonstrated with Centyrins targeting multiple receptors (e.g., BCMA, PSMA, and EpCAM) and siRNAs targeting multiple genes (e.g., CD68, KLKb1, and SSB1). Moreover, by installing multiple conjugation handles, two different siRNAs were fused to a single Centyrin, and the conjugate was shown to simultaneously silence two different targets. Finally, by specifically pairing EpCAM-binding Centyrins that exhibited optimized internalization profiles, we present data showing that an EpCAM Centyrin CTNNb1 siRNA conjugate suppressed tumor cell growth of a colorectal cancer cell line containing an APC mutation but not cells with normal CTNNb1 signaling. Overall, these data demonstrate the potential of Centyrin-siRNA conjugates to target cancer cells and silence oncogenes, paving the way to a new class of anticancer drugs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.