A well-established MEN1 ASO sequence was chosen and obtained with all 2'-OMe-modified sugars (Figure ). As with the NCL1 LyTONs, ispinesib was conjugated using SPAAC chemistry (SI Figure ). MEN1 transcript levels were measured after transfection of the MEN1 2'-OMe LyTON using RT-qPCR in HEK293T cells at 24 hours, comparing the knockdown to the unconjugated MEN1 2'-OMe ASO, normalised to the housekeeping gene GAPDH (Figure ). The MEN1 2'-OMe LyTON outperformed the MEN1 2'-OMe ASO at all concentrations tested. We measured 36.8%, 49.8%, 55.5%, less transcript upon treatment with the MEN1 2'-OMe LyTON conjugate compared to the unconjugated MEN1 2'-OMe ASO, at 50, 100, and 200 nM respectively. We also observed a marked reduction in Menin protein levels upon MEN1 2'-OMe LyTON treatment, in a concentration dependant manner (Figure , SI Figure ). Protein levels showed minimal changes upon treatment with the MEN1 2'-OMe ASO. The MEN1 2'-OMe LyTON also exhibited improved knockdown at both the RNA and protein levels compared to the established gapmer chemistry. This effect was observed across all tested concentrations upon transfection in HEK293T cells for 24 hours, and assessed using RT-qPCR (Figure ) and western blotting (Figure ). We then sought to again confirm the mechanism of action for the ispinesib-ASO conjugates, using bafilomycin treatment. As with the NCL1 LyTON, treatment with bafilomycin resulted in the complete loss of enhanced mRNA knockdown for the MEN1 2'-OMe LyTON (Figure ). Only steric blocking activity on par with the parent MEN1 2'-OMe ASO was observed. Furthermore, this loss of activity upon treatment with bafilomycin was also observed at the protein level (Figure , SI Figure ). We also observed little to no significant differences in the toxicity profiles of the unconjugated and ispinesib-conjugated MEN1 ASOs, as above, assessed through Cell Titer Glo (SI Figure ) and transcript levels of key housekeeping genes (SI Figure ). Discussion/Future perspectives Targeted mRNA degradation is a powerful strategy for therapeutic intervention: targeting the "undruggable", allowing for personalised medicine with "n-of-1" therapies, and, potentially, circumventing traditional small molecule drug resistance mechanisms. Currently, mRNA knockdown can only be achieved through RNase H recognition of DNA-based ASOs or RNA-induced silencing complex (RISC) formation with siRNA. Our work introduces an entirely new mechanism for targeted mRNA degradation. By conjugating ispinesib, an ATTEC warhead, to ASOs, target mRNA is trafficked to the lysosome for subsequent degradation. These lysosomal trafficking antisense oligonucleotides (LyTONs) are modular and versatile. These conjugates can be generated through simple post-synthetic modification chemistry in high yields with high purity. The therapeutic potential of LyTONs was demonstrated by targeting Menin, an exciting target in cancer medicine with effective knockdown at the protein level.