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

作者：Sergi Marco, Peter J. Walsh, Alexey S. Revenko, Peter A. Thomason, Lynn McGarry, A. Robert MacLeod, Sonam Ansel, Dina Tataran, Martin Bushell, Chiara Braconi, Jim C. Norman · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.02.05.635637 · 被引用次数：1 · 研究领域：Cell Adhesion Molecules Research、RNA and protein synthesis mechanisms、RNA Interference and Gene Delivery

Summary 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.