Engineering antisense oligonucleotides for targeted mRNA degradation through lysosomal trafficking.

ABSTRACT: Antisense oligonucleotides (ASOs) can modulate gene expression at the mRNA level, providing the ability to tackle conventionally undruggable targets and usher in an era of personalized medicine. A key mode of action for ASOs relies upon RNase H-engagement in the nucleus, however, most mature mRNA is present in the cytoplasm. This disconnect limits the efficacy and biomedical applications of ASOs. In this paper, we have established a new mechanism of action for achieving potent and targeted mRNA knockdown by leveraging a lysosomal degradation pathway. To achieve this, we employ autophagosome-tethering compound (ATTEC) technology that utilises bifunctional small molecules for lysosomal trafficking. In this manner, to induce degradation of target mRNA located in the cytoplasm, we conjugated a

SUBMITTER: Kashyap D 

PROVIDER: S-EPMC12180356 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature