By conjugating the small molecule ispinesib to ASOs, we developed lysosomal trafficking antisense oligonucleotides (LyTONs) that can selectively knockdown mRNA through transport to the lysosome (Figure ). These RNase H-inactive LyTONs outperformed RNase H-active gapmer ASOs for mRNA knockdown. Inhibition of lysosomal acidification, via bafilomycin, resulted in the loss of LyTON activity, demonstrating LyTON-mediated transport of mRNA to the lysosome was responsible for knockdown. To illustrate the promise of this technology, LyTONs were developed to target Menin (MEN1), a promising clinical target involved in transcriptional regulation over cellular differentiation and proliferation in leukemias . The MEN1 LyTONs resulted in a dramatic protein-level knockdown following treatment.