RNase H-active ASOs are predominantly functional in the nucleus, as this is where the highest levels of RNase H preside. However, mRNA is shuttled out of the nucleus for translation. While siRNA carry out cytoplasmic degradation of mRNA, they are even more difficult to deliver into cells than ASOs . Our approach leverages a lysosomal degradation pathway that improves target engagement, and thus, can potentially enable therapeutic targeting of more clinically-relevant genes using ASOs. Using our LyTON technology, we will be able to rethink the design of gene-silencing oligonucleotides. Without the need for incorporating DNA-containing sequences for RNase H recognition or RNA-containing sequences for RISC formation, many alternative oligonucleotide chemistries could be explored for nucleic acid drug development-allowing for ASO chemistries with higher chemical stability, higher target affinity, and improved delivery profiles for gene knockdown applications. A key future goal will be to fully characterise the binding partner of ispinesib for lysosomal trafficking . This should enable the development of improved LyTONs through rational ligand design.