To use a dsDNA sequence that would not be biologically active itself, we used a previously developed non-targeting control ASO sequence and its complement . We chose to modify all DNA strands with phosphorothioate (PS) backbones, in order to ensure nuclease stability within cells. The 5'-VH032 OligoPROTAC strand was synthesised from a commercial 5'-hexynl-modified PS DNA with a commercially-sourced VH032-azide, through copper-catalysed click chemistry (Figure ). The (+)-JQ1 alkyne was synthesised in two steps: first, the Boc group of (+)-JQ1 was deprotected to yield the (+)-JQ1 acid ; followed by a hydroxybenzotriazole (HoBT) and (3-Dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (EDC-HCl)-mediated coupling with propargylamine, resulting in the formation of (+)-JQ1-alkyne . Both modified-DNA strands were purified using HPLC and analysed by LC-MS, with yields >90% and purity >95%. The two strands were subsequently annealed to assemble the OligoPROTAC (Figure ). Since it is widely accepted that linker length plays a critical role on the efficacy of small molecule PROTACs, we chose to optimise linker lengths in our OligoPROTAC construct in an analogous manner. To vary linker length, and thus the flexibility and spatial positioning of the VH032 and (+)-JQ1 ligands, we introduced additional non-complementary thymine bases [n=0, 1, 2, 3, 5, 10] between the ligands and the dsDNA region. These additional sequence "arms" increase the spatial separation between the ligands attached at each terminus (Figure ). These OligoPROTAC designs, with varying lengths of non-complementary arms, were transfected into HEK293T cells and the resultant BRD4 degradation was measured by western blotting at 12 hours. We observed a distance-dependant degradation of the protein target, BRD4 (Figure , SI Figure ). OligoPROTAC constructs with no arms [n = 0] exhibited minimal degradation, with degradation efficiency increasing upon introduction of non-complementary thymine arms, up until [n = 3]. The degradation observed for n = 3 arms was comparable to that observed from the original small molecule PROTAC AT1 (Figure , SI Figure ). Activity was reduced when increasing the length of the non-complementary arms further, [n = 5], due to the ligands being positioned too far apart. With [n = 10] arms, there was no observable degradation (Figure , SI Figure ).