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WDR91, an endosomal maturation protein, promotes antisense oligonucleotide activity
Journal article   Open access   Peer reviewed

WDR91, an endosomal maturation protein, promotes antisense oligonucleotide activity

Suxiang Chen, Tong Zheng and Dunhui Li
Molecular therapy. Nucleic acids, Vol.37(2), 102915
2026
DOI: https://doi.org/10.1016/j.omtn.2026.102915
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Open Access CC BY V4.0

Abstract

Antisense oligonucleotides (ASOs) have emerged as an important class of nucleic acid therapeutics that enable sequence-specific targeting of RNA. Despite substantial advances in ASO chemistry and therapeutic development, efficient intracellular delivery remains a major challenge, as only a small fraction of internalized ASOs escapes endosomal compartments to reach the cytoplasm or nucleus.1 In a recent study published in Molecular Therapy – Nucleic Acids, Menchon and colleagues used a genome-wide CRISPR screen to identify regulators of ASO activity and uncovered the endosomal maturation protein WD repeat domain 91 (WDR91) as a key promoter of ASO activity.2 Loss of WDR91 markedly reduced ASO activity, suggesting that endosomal maturation process may influence oligonucleotide activity. This finding underscores the importance of intracellular trafficking pathways in determining ASO performance and raises important questions about how endosomal maturation may regulate the release of oligonucleotides from endosomal compartments...

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