By leveraging lysosomal trafficking, this approach provides a powerful mechanism for degrading mRNA without interfering with native cellular processes or triggering widespread cellular damage. The ability to degrade disease-relevant mRNAs in the lysosome will improve target engagement and enable a higher degree of knockdown, as nuclear localisation and subsequent RNase H recruitment will no longer a limiting factor. Currently, all nucleic acid-mediated gene knockdown technologies rely upon DNA (ASOs) or RNA (small interfering RNA, siRNA) backbones for enzymatic recruitment and activity . In contrast, our LyTONs can be employed with alternative oligonucleotide chemistries that offer higher potency and more favourable pharmacological profiles. Thus, we believe that LyTONs will allow for the targeting of a broader spectrum of clinically-relevant gene targets, expanding our toolkit for developing innovative nucleic acid therapeutics.