ArticleThe Journal of experimental medicine2024
Nucleotide modifications enable rational design of TLR7-selective ligands by blocking RNase cleavage.
Article in The Journal of experimental medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 17 citations in OpenAlex.
- Decoding Undesirable Inflammatory Responses of Nucleic Acid-Delivering Lipid Nanoparticles.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Innate immune recognition and evasion strategies of hepatitis B virus: from DNA to RNA and viral proteins.Frontiers in immunology · 2026Review
- In Silico Prediction of Potential pTLR7/pSTING Dual-Targeting Ligands via Virtual Screening and Molecular Dynamics Simulation.International journal of molecular sciences · 2025Article
- Immunology of RNA-based vaccines: The critical interplay between inflammation and expression.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- The lysosomal catabolism of nucleic acids-critical regulators of the innate immune system.Nucleic acids research · 2025Review
- New insights into the role of IFN-α/β and TLR7/8/9 in cancer immunotherapy and systemic autoimmunity.Journal for immunotherapy of cancer · 2025Review
- Immunoengineering of a Photocaged 5´-triphosphate Oligoribonucleotide Ligand for Spatiotemporal Control of RIG-I Activation in Cancer.Angewandte Chemie (International ed. in English) · 2025Article
- Cytosolic nucleic acid sensing as driver of critical illness: mechanisms and advances in therapy.Signal transduction and targeted therapy · 2025Review
- ZUGC-RNA degradation generates immunosuppressor to evade immune responses in eukaryotes.bioRxiv : the preprint server for biology · 2025Article
- Characterization of TLR9 responsiveness in cell subsets derived fromFrontiers in immunology · 2025Article
- Toll-like receptor-mediated immune imbalance in asthma: controversies, breakthroughs, and future directions.Frontiers in immunology · 2025Review
- Ribonucleases of Mice and Men: Unveiling the Roles of the RNase A Superfamily in Host Defence.Journal of immunology research · 2025Review
- Advanced technologies for the development of infectious disease vaccines.Nature reviews. Drug discovery · 2024Review
- Bacterial RNA sensing by TLR8 requires RNase 6 processing and is inhibited by RNA 2'O-methylation.EMBO reports · 2024Article
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
Toll-like receptors 7 (TLR7) and 8 (TLR8) each sense single-stranded RNA (ssRNA), but their activation results in different immune activation profiles. Attempts to selectively target either TLR7 or TLR8 have been hindered by their high degree of homology. However, recent studies revealed that TLR7 and TLR8 bind different ligands resulting from the processing of ssRNA by endolysosomal RNases. We demonstrate that by introducing precise 2' sugar-modified bases into oligoribonucleotides (ORNs) containing known TLR7 and TLR8 binding motifs, we could prevent RNase-mediated degradation into the monomeric uridine required for TLR8 activation while preserving TLR7 activation. Furthermore, a novel, optimized protocol for CRISPR-Cas9 knockout in primary human plasmacytoid dendritic cells showed that TLR7 activation is dependent on RNase processing of ORNs and revealed a previously undescribed role for RNase 6 in degrading ORNs into TLR ligands. Finally, 2' sugar-modified ORNs demonstrated robust innate immune activation in mice. Altogether, we identified a strategy for creating tunable TLR7-selective agonists.
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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.