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Despite much progress in the field of oligonucleotide therapeutics, delivery in general remains an important aspect for innovation. Various lipids and lipophilic small molecules have long been conjugated to many oligonucleotides in hopes of creating better, drug-like substances. A few conjugates are beginning to enter clinical development as the understanding grows of how such conjugations change the pharmacology of the conjugate relative to the unmodified oligonucleotide. The delivery of different forms of oligonucleotides, such as antisense oligonucleotides and siRNA, is often a challenging, limiting aspect to this form of therapeutics. Herein, the origins of covalent attachment of lipophilic moieties to oligonucleotides are described as well as listing a few of those lipids commonly used for lipidation. The author also describes the mechanism by which lipidation may enhance delivery and/or exposure of oligonucleotides in vitro and in vivo. The covalent attachment of lipophilic moieties is one means to enhance the delivery and exposure of oligonucleotides. Such methods may also be applicable to other oligonucleotide-based modalities as long as the lipidation does not interfere with some key interaction. Lipidation may also be useful to modulate the cell type-specific delivery within tissues. As the understanding of the effects of such covalent modification grows, more lipidated oligos are soon likely to enter clinical development.

Reality check: lipid-oligonucleotide conjugates for therapeutic applications