In this work, we have synthesised novel covalent (+)-JQ1-ASO conjugates aimed at increasing the active nuclear import of ASOs. Our approach utilizes a single covalent (+)-JQ1 ligand modification to effect the nuclear enrichment of ASOs via interactions with BET bromodomain proteins. Our (+)-JQ1-ASO conjugates are superior to unconjugated ASOs, for both mRNA knockdown and splice-switching mechanisms (Figure ). Moreover, we demonstrated that the improved efficacy of (+)-JQ1-ASO conjugates is dependent on binding to (+)-JQ1 target proteins, as excess small molecule (+)-JQ1 could 30 outcompete them. By manipulating cellular localization through this mechanism, we pave the way for the development of more effective ASO therapeutics. The ability to actively augment the nuclear accumulation of ASOs, without increasing cellular toxicity, constitutes a significant advancement in the field. This advancement has the potential to improve therapeutic outcomes and expand the applicability of nucleic acid-based drugs.