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EPHA2 and scavenger receptor-directed trafficking enhances endosomal leakiness and antisense therapy delivery

Marco Martin, S.; Walsh, P. J.; Revenko, A. S.; Thomason, P. A.; McGarry, L.; MacLeod, A. R.; Ansel, S.; Tataran, D.; Bushell, M.; Braconi, C.; Norman, J. C.

2025-02-06 cell biology
10.1101/2025.02.05.635637 bioRxiv
Show abstract

The potential for using therapeutic antisense oligonucleotides (ASOs) has been hampered by lack of understanding of how they enter cells and subsequently access their targets. Endocytosis contributes to ASO uptake, but the machinery mediating subsequent ASO trafficking to permit suppression of their target mRNAs has not been described. Here, we show that ASO engagement with a scavenger receptor (CD44) activates the ERK-RSK axis to promote serine phosphorylation of a receptor tyrosine kinase (EPHA2). Serine phosphorylation of EPHA2 permits endocytosis, trafficking, and accumulation of ASOs in nuclear-adjacent endosomes. These endosomes then become leaky, allowing ASOs to escape and effectively suppress target mRNA expression. Inhibition of stress granule-mediated repair of leaky endosomes further enhances ASO effectiveness. These data identify an endocytic route to the nucleus which may be exploited to maximise effectiveness of ASO-mediated therapies.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.