ArticleNucleic acids research2023
Simultaneous inhibition of endocytic recycling and lysosomal fusion sensitizes cells and tissues to oligonucleotide therapeutics.
Article in Nucleic acids research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 24 citations in OpenAlex.
- EPHA2/CD44-directed trafficking enhances endosomal leakiness and antisense therapy delivery.The Journal of cell biology · 2026Article
- Targeting ARF6-SUCNR1 Axis: Antisense Oligonucleotide Adjuvants for Neutrophil Immunometabolism.International journal of molecular sciences · 2026Review
- The Potential Target Value of ADP-Ribosylation Factor 6 in Insulin Secretion Regulation and the Treatment of Metabolic Disorders.Metabolites · 2026Review
- Antibody-oligonucleotide conjugates: an emerging modality for precision RNA therapeutics.Antibody therapeutics · 2026Review
- Naked antisense oligonucleotides remain endolysosomally sequestered despite induced membrane damage.bioRxiv : the preprint server for biology · 2026Article
- Endolysosomal trafficking regulator SH-BC-893 inhibits coronavirus entry in vitro and in vivo.Scientific reports · 2026Article
- Bioconjugates for improved delivery of oligonucleotide therapeutics to the central nervous system.Advanced drug delivery reviews · 2026Review
- Review
- Long Non-coding RNA Based Therapy for Cardiovascular Disease.Journal of cardiovascular translational research · 2025Review
- A genome-wide CRISPR screen unveils the endosomal maturation protein WDR91 as a promoter of productive ASO activity in melanoma.Molecular therapy. Nucleic acids · 2025Article
- Sphingosine simultaneously inhibits nuclear import and activates PP2A by binding importins and PPP2R1A.The EMBO journal · 2025Article
- Metabolic Stability and Targeted Delivery of Oligonucleotides: Advancing RNA Therapeutics Beyond The Liver.Journal of medicinal chemistry · 2025Review
- Endosomal Escape and Nuclear Localization: Critical Barriers for Therapeutic Nucleic Acids.Molecules (Basel, Switzerland) · 2024Review
- Amphiphilic Oligonucleotide Derivatives-Promising Tools for Therapeutics.Pharmaceutics · 2024Review
- Synergistic integration of mRNA-LNP with CAR-engineered immune cells: Pioneering progress in immunotherapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Review
- Comparing Cell Penetration of Biotherapeutics across Human Cell Lines.ACS chemical biology · 2024Article
- A novel transient receptor potential C3/C6 selective activator induces the cellular uptake of antisense oligonucleotides.Nucleic acids research · 2024Article
- Novel Efficient Lipid-Based Delivery Systems Enable a Delayed Uptake and Sustained Expression of mRNA in Human Cells and Mouse Tissues.Pharmaceutics · 2024Article
- Targeting Recycling Endosomes to Potentiate mRNA Lipid Nanoparticles.Nano letters · 2024Article
- Synthesis of peptide-siRNA conjugates via internal sulfonylphosphoramidate modifications and evaluation of their in vitro activity.Nucleic acids research · 2024Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
Inefficient endosomal escape remains the primary barrier to the broad application of oligonucleotide therapeutics. Liver uptake after systemic administration is sufficiently robust that a therapeutic effect can be achieved but targeting extrahepatic tissues remains challenging. Prior attempts to improve oligonucleotide activity using small molecules that increase the leakiness of endosomes have failed due to unacceptable toxicity. Here, we show that the well-tolerated and orally bioavailable synthetic sphingolipid analog, SH-BC-893, increases the activity of antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) up to 200-fold in vitro without permeabilizing endosomes. SH-BC-893 treatment trapped endocytosed oligonucleotides within extra-lysosomal compartments thought to be more permeable due to frequent membrane fission and fusion events. Simultaneous disruption of ARF6-dependent endocytic recycling and PIKfyve-dependent lysosomal fusion was necessary and sufficient for SH-BC-893 to increase non-lysosomal oligonucleotide levels and enhance their activity. In mice, oral administration of SH-BC-893 increased ASO potency in the liver by 15-fold without toxicity. More importantly, SH-BC-893 enabled target RNA knockdown in the CNS and lungs of mice treated subcutaneously with cholesterol-functionalized duplexed oligonucleotides or unmodified ASOs, respectively. Together, these results establish the feasibility of using a small molecule that disrupts endolysosomal trafficking to improve the activity of oligonucleotides in extrahepatic tissues.
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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.