Chemically stabilized long antisense oligonucleotides perturb RNA exosome function.

Long, chemically stabilized antisense oligonucleotides longer than 24 nucleotides can impair RNA exosome function by binding to its catalytic subunits.

• Why it matters: Understanding how RNA drugs interact with intracellular proteins like the exosome is crucial because such interactions influence drug efficacy and toxicity, yet remain poorly characterized for emerging oligonucleotide classes.
• What they did: Using proximity biotinylation proteomics, the study examined the binding of stabilized oligonucleotides to exosome subunits DIS3 and EXOSC10, and assessed the impact on exosome activity through transcript stabilization and rRNA processing analysis.
• The result: The research shows that exosome inhibition depends on chemical modification patterns and can be mitigated by specific backbone modifications, enabling the design of oligonucleotides that retain activity while reducing exosome interference, thus informing safer RNA therapeutics.