A critical aspect of ASO effectiveness consists in their ability to localize within the nucleus (Figure ). This is because ASOs operate primarily in the nucleus, through pre-mRNA splicing and RNase H-recruitment. Current ASO therapeutics are shuttled in and out of the nucleus: an inherently inefficient process, especially for large, negatively charged molecules like ASOs. While there is a pool of ASOs in the nucleus that exert their gene-modulating effects, the constant shuttling is suboptimal. Enhancing the nuclear import and accumulation of ASOs has been postulated to significantly improve their target engagement and, consequently, their therapeutic efficacy. Previous work to improve nuclear delivery has employed nucleic acid conjugates with small molecules 6 , aptamers , and peptides 8 . Conjugates generated with the small molecule double-stranded DNA-binding dye Hoechst 9 exhibited minimal and inconsistent improvements in gene-knockdown efficacy: targets with the same mechanism of action were knocked down to different degrees. Incorporating the nucleolin aptamer AS411 in a splice-switching oligonucleotide sequence has been shown to yield very modest splice switching improvements . Efforts utilizing ASO conjugates with nuclear localization signal (NLS) peptides have faced significant toxicity and efficacy challenges . This demonstrates the need to explore simpler and more effective alternatives for enhanced nuclear accumulation of ASOs.