5-Dihydroxyboryluridine enhances cytosolic penetration of antisense oligonucleotides

The most significant challenge for nucleic acid drug development is their delivery across the cell membrane. Herein, we harness the reversible binding between boronic acids and cell surface glycans to aid in the cellular delivery of synthetic oligonucleotides. We install the artificial nucleotide 5-dihydroxyboryluridine (5boU) in a site-specific manner within druglike antisense oligonucleotides and demonstrate that these boronate-containing nucleic acids have enhanced cytosolic penetration and splice-correcting activity compared to non-boronate analogs. Strategic incorporation of 5boU is a simple, modular, and potentially general means of enhancing cellular delivery of therapeutic nucleic acids. Boronic acid functionalized synthetic antisense oligonucleotides demonstrate enhanced cellular uptake and biological activity, constituting a novel approach for delivery of therapeutic oligonucleotides.