  Oligonucleotide-based agents have the potential to treat or cure almost any
disease, and are one of the key therapeutic drug classes of the future.
Bioconjugated oligonucleotides, a subset of this class, are emerging from basic
research and being successfully translated to the clinic. In this review, we
first briefly describe two approaches for inhibiting specific genes using
oligonucleotides -- antisense DNA (ASO) and RNA interference (RNAi) -- followed
by a discussion on delivery to cells. We then summarize and analyze recent
developments in bioconjugated oligonucleotides including those possessing
GalNAc, cell penetrating peptides, $\alpha$-tocopherol, aptamers, antibodies,
cholesterol, squalene, fatty acids, or nucleolipids. These novel conjugates
provide a means to enhance tissue targeting, cell internalization, endosomal
escape, target binding specificity, resistance to nucleases, and more. We next
describe those bioconjugated oligonucleotides approved for patient use or in
clinical trials. Finally, we summarize the state of the field, describe current
limitations, and discuss future prospects. Biocon-jugation chemistry is at the
centerpiece of this therapeutic oligonucleotide revolution, and significant
opportunities exist for development of new modification chemistries, for
mechanistic studies at the chemical-biology interface, and for translating such
agents to the clinic.
