In summary, our work represents a significant advancement in the field of targeted mRNA degradation. By harnessing lysosomal trafficking through the design of a bi-functional ispinesib-ASO conjugate, we offer a powerful new strategy for selective mRNA degradation. This approach holds great promise in precision medicine, particularly in expanding the use of diverse oligonucleotide chemistries for gene silencing. With its modular design and capacity for future advancements, this technology could emerge as a powerful platform for nucleic acid-based therapeutic strategies.