Pre-mRNA splicing requires a specialized ASO mechanism active in the nucleus . This process requires DNAbased ASOs to bind pre-mRNA in the nucleus and ultimately influence splicing into mature mRNA. This mechanism is a powerful strategy for treating genetic diseases caused by splicing defects. In contrast, general mRNA knockdown mechanisms are constrained by limited RNase H recruitment -RNase H is enriched in the nucleus, whereas mature mRNA is located in the cytoplasm. Thus, RNase H recruitment is unreliable as its expression levels vary not only with cellular localisation but also with cell and tissue type . One approach to improve target engagement-and thus the efficacy-of ASO-based gene knockdown therapies is to address this localization mismatch between the effector pathway and its molecular target. Conjugation with a nuclear importer has been shown to increase the activity of splice-switching oligonucleotides and RNase H-active ASOs 7 . However, this mechanism may not be desirable for different mRNA targets. RNase L-mediated cytoplasmic degradation of viral RNA has been achieved through the covalent modification of ASOs with endogenous RNase L ligands 8 . However, fine control over RNase L activity is key; uncontrolled activation of this potent cytoplasmic anti-viral effector pathway can lead to global translational shutdown , amplification of cellular stress responses, and cell death . This demonstrates the need to develop new methods to harness a selective cytoplasmic ASO pathway for targeted degradation of mRNA.