DNA-Programmable Protein Degradation: Dynamic Control of Proteolysis-Targeting Chimera Activity via DNA Hybridization and Strand Displacement.

Targeted protein degradation is a powerful therapeutic approach: expanding the druggable proteome, providing enhanced selectivity, and having the ability to overcome conventional resistance mechanisms. A major class of such molecules is proteolysis-targeting chimeras (PROTACs). PROTACs are catalytic heterobifunctional small molecules that simultaneously bind a protein of interest (POI) and an E3 ligase.

Harnessing BET-Bromodomain Assisted Nuclear Import for Targeted Subcellular Localization and Enhanced Efficacy of Antisense Oligonucleotides.

Antisense oligonucleotides (ASOs) are a promising class of therapeutics designed to modulate gene expression. Both key mechanisms of action for ASOs operate in the nucleus: splice-switching ASOs modify pre-mRNA, processed in the nucleus, and mRNA-degrading ASOs require RNase H, an enzyme predominantly active in the nucleus. Therefore, to achieve maximal therapeutic efficacy, ASOs require efficient nuclear delivery.

Engineering antisense oligonucleotides for targeted mRNA degradation through lysosomal trafficking.

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.

Nucleic Acid Conjugates: Unlocking Therapeutic Potential.

Nucleic acids have emerged as a powerful class of therapeutics. Through simple base pair complementarity, nucleic acids allow the targeting of a variety of pathologically relevant proteins and RNA molecules. However, despite the preliminary successes of nucleic acids as drugs in the clinic, limited biodistribution, inadequate delivery mechanisms, and target engagement remain key challenges in the field.