Antisense oligonucleotides (ASOs) have been proposed as a therapeutic approach to shut down the production of faulty proteins in a wide variety of diseases, including cancer. In a study to be published August 11 in the Journal of Cell Biology ( JCB ), researchers at the Cancer Research UK Scotland Institute and the University of Glasgow identify a pathway by which ASOs enter cells and reach their targets, suggesting new ways to enhance the effectiveness of antisense therapy.
ASOs are short strands of DNA designed to bind to specific protein-encoding messenger RNAs (mRNAs) inside cells. The resulting DNA–mRNA complexes can then be degraded by a cellular enzyme, preventing the mRNA from being used to generate a disease-causing protein. This could potentially halt the production of toxic proteins that underlie certain neurodegenerative disorders or switch off the expression of mutant proteins driving proliferation of cancer cells.
ASOs are taken up into cells via a process known as endocytosis. But exactly how this happens, and how the ASOs subsequently find their target mRNA, is unclear. “Despite the importance of endocytic trafficking for ASO efficacy, the mechanisms governing their uptake and intracellular routing remain poorly understood,” says Jim C. Norman, a professor at the Cancer Research UK Scotland Institute and University of Glasgow.
Norman and colleagues, led by postdoctoral researcher Sergi Marco and conducted in collaboration with Ionis Pharmaceuticals, studied an ASO called cET-ASO KRas (developed by Ionis) that targets mRNAs encoding mutant KRAS, a protein that drives the development of multiple human cancers. Treating pancreatic cancer cells with cET-ASO KRas reduces mutant KRAS levels and inhibits tumor growth in the lab.
The researchers found that cET-ASO KRas enters cells by binding to a receptor protein on the cell surface known as CD44. This initiates a signaling pathway that activates a second receptor protein, EPHA2, causing cET-ASO KRas to be taken into the cell inside small, membrane-bound compartments called endosomes. Crucially, EPHA2 then anchors these ASO-containing endosomes near the cell nucleus, the compartment where most mRNAs are produced. Once at the nucleus, the membrane surrounding the endosomes becomes damaged and leaky, allowing cET-ASO KRas to enter the cytoplasm and encounter its target mRNA.
Norman and colleagues found that interfering with this pathway by deleting CD44 or EPHA2 from pancreatic cancer cells, or expressing mutants of EPHA2 that cannot anchor ASO-containing endosomes to the nucleus, prevented cET-ASO KRas from reducing KRAS levels and inhibiting tumor growth.
However, the researchers discovered that cells also have their own way of limiting the pathway and reducing the effectiveness of ASOs. When endosomes near the nucleus become leaky, cells initiate the formation of structures called stress granules that plug and repair the endosome membrane. Norman and colleagues found that blocking stress granule formation with a drug called ISRIB enhanced the ability of cET-ASO Kras to suppress KRAS production.
Notably, CD44 and EPHA2 are both highly expressed in aggressive pancreatic cancers. CD44, in particular, is thought to promote tumor growth by promoting nutrient uptake and maintaining therapy-resistant cancer stem cells. “We propose that this receptor, which has been selected by pancreatic tumors for its ability to support tumor stemness and growth, could be exploited as a gatekeeper to an endocytic pathway capable of delivering therapeutic molecules like cET-ASO Kras to aggressive tumors,” says Marco.
“Our finding that chemical inhibition of the pathway that repairs endosomal membranes increases cET-ASO KRas efficacy suggests that pharmacological tools targeting this stress response could also be exploited to further enhance the delivery of these therapeutics,” says Norman.
Marco et al., 2026. <em> J. Cell Biol. </em> https://rupress.org/jcb/article-lookup/doi/10.1083/jcb.202507217?PR
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Journal of Cell Biology
Experimental study
Cells
EPHA2/CD44-directed trafficking enhances endosomal leakiness and antisense therapy delivery
11-Aug-2026
All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. A. Revenko reported “Employee and stakeholder of IONIS Pharmaceuticals.” C. Braconi reported other from AstraZeneca, personal fees from AstraZeneca, grants from Servier, personal fees from Servier, personal fees from Jazz, personal fees from Dalcath, personal fees from Tahio, grants from Medannex, grants from Avacta, and personal fees from molecular partners outside the submitted work; and “Spouse is employee of AstraZeneca.” No other disclosures were reported.