Tissue-Specific Delivery of Oligonucleotides.

From the initial discovery of short-interfering RNA (siRNA) and antisense oligonucleotides for specific gene knockdown at the posttranscriptional level to the current CRISPR-Cas9 system offering gene editing at the genomic level, oligonucleotides, in addition to their biological functions in storing and conveying genetic information, provide the most prominent solutions to targeted gene therapies. Nonetheless, looking into the future of curing cancer and acute diseases, researchers are only cautiously optimistic as the cellular delivery of these polyanionic biomacromolecules is still the biggest hurdle for their therapeutic realization. To overcome the delivery obstacle, oligonucleotides have been encapsulated within or conjugated with delivery vehicles for enhanced membrane penetration, improved payload, and tissue-specific delivery. Such delivery systems include but not limited to virus-based vehicles, gold-nanoparticle vehicles, formulated liposomes, and synthetic polymers. In this chapter, delivery challenges imposed by biological barriers are briefly discussed; followed by recent advances in tissue-specific oligonucleotide delivery utilizing both viral and nonviral delivery vectors, discussing their advantages, and how judicious design and formulation could improve and expand their potential as delivery vehicles.