The article provides an overview of oligonucleotide-based drug platforms and their potential therapeutic applications, highlighting recent advances in improving oligonucleotide drug delivery. Oligonucleotides can modulate gene expression through various mechanisms, including RNAi, target degradation, splicing modulation, non-coding RNA inhibition, gene activation, and programmed gene editing. Despite recent technological advancements, efficient delivery of oligonucleotides to extrahepatic tissues remains a significant challenge. The authors discuss key approaches to address this issue, including chemical modification, bioconjugation, and the use of nanocarriers. Chemical modifications such as phosphorothioate backbones and 2′-O-methyl substitutions enhance nuclease resistance and binding affinity. Bioconjugation with lipids, peptides, aptamers, antibodies, and sugars promotes intracellular uptake and targeted delivery. Nanocarrier systems, such as lipid nanoparticles and exosomes, also improve delivery efficiency. The article emphasizes the importance of overcoming delivery challenges to realize the full potential of oligonucleotide therapeutics.The article provides an overview of oligonucleotide-based drug platforms and their potential therapeutic applications, highlighting recent advances in improving oligonucleotide drug delivery. Oligonucleotides can modulate gene expression through various mechanisms, including RNAi, target degradation, splicing modulation, non-coding RNA inhibition, gene activation, and programmed gene editing. Despite recent technological advancements, efficient delivery of oligonucleotides to extrahepatic tissues remains a significant challenge. The authors discuss key approaches to address this issue, including chemical modification, bioconjugation, and the use of nanocarriers. Chemical modifications such as phosphorothioate backbones and 2′-O-methyl substitutions enhance nuclease resistance and binding affinity. Bioconjugation with lipids, peptides, aptamers, antibodies, and sugars promotes intracellular uptake and targeted delivery. Nanocarrier systems, such as lipid nanoparticles and exosomes, also improve delivery efficiency. The article emphasizes the importance of overcoming delivery challenges to realize the full potential of oligonucleotide therapeutics.