Targeted lipid nanoparticles for antisense oligonucleotide delivery.

Antisense oligonucleotides (AS-ODNs) are short, single-stranded DNA molecules designed to bind specifically to a target messenger RNA (mRNA) and down-regulate gene expression. Despite being a promising class of therapeutics for a variety of diseases, they face major hurdles limiting their clinical application, including low intracellular delivery and poor in vivo stability. Among strategies available to enhance delivery, lipid nanoparticles have gained considerable attention. Active targeting of carriers of AS-ODNs is likely to further enhance delivery efficiency. For that, ligands for overexpressed receptors on the cell surface can be linked to the lipid nanoparticle, facilitating intracellular uptake, resulting in improved efficacy and reduced systemic toxicity. These include cell penetrating peptides (CPPs), transferrin, folate, oligosaccharides, polysaccharides and antibodies. Although targeted-lipid nanoparticles have been shown to enhance intracellular delivery and therapeutic effect of AS-ODNs, no clinical evaluation has been conducted yet. Therefore, more efforts are needed to turn these promising tools into clinical products.