Robust interest persists in the use of lipid-conjugated oligonucleotides for translational control of gene expression. Very early in this emerging field, the criticality of reduced negative charge and increased hydrophobicity on oligo stability and improved target hybridization became widely recognized. Although the expanding families of antisense oligos (ASOs), siRNA oligos, and messenger RNA (mRNA) oligos have yielded many examples of highly specific control of gene expression in vitro, there are only a very limited number of approved therapeutic applications.
The development of oligonucleotide-based therapies remains a major hurdle significantly due to the persistent challenges of 1) in vivo delivery of therapeutic oligo to specific disease-associated tissues, cell types, and tumors, 2) facilitating passage through the targeted cell membrane, and 3) effecting drug escape from the endosome in order to interact, as intended, with the translational machinery. Lipid structures can play significant roles in reducing oligonucleotide drug elimination by the blood clearance systems, in facilitating circulatory system transport, penetrating the cell membrane, and controlling cytosolic oligo drug availability.