Oligonucleotides are nucleic acid polymers with potential for treating a wide range of diseases. They can modulate gene expression through various mechanisms, including RNAi, target degradation, splicing modulation, and gene activation. Despite recent advances, efficient delivery of oligonucleotides, especially to extrahepatic tissues, remains a major challenge. This review discusses key approaches to improve oligonucleotide delivery, including chemical modification, bioconjugation, and nanocarriers. Oligonucleotides can be designed to target specific genes with minimal off-target effects, enabling precision and personalized medicine. They can target patient-specific sequences, specific alleles, distinct transcript isoforms, pathogenic fusion transcripts, and viral sequences. Oligonucleotide-based platforms include antisense oligonucleotides (ASOs), which can modulate gene expression via RNase H-mediated cleavage or steric block. ASOs are used for splice modulation, gene activation, and gene silencing. siRNAs are used for gene silencing via RNAi, while miRNA inhibitors are used to modulate miRNA activity. Oligonucleotide-based therapies have been approved for various indications, including hepatitis C, Duchenne muscular dystrophy, and spinal muscular atrophy. However, challenges remain in achieving efficient delivery to target tissues, as well as in minimizing off-target effects and toxicity. Strategies to enhance delivery include chemical modification, covalent conjugation to cell-targeting moieties, and nanoparticle formulation. Recent approaches include exosome loading, spherical nucleic acids, and smart materials. Oligonucleotide delivery faces challenges such as nuclease degradation, renal clearance, and passage through the blood-brain barrier. Strategies to overcome these include chemical modifications, bioconjugation, and the use of nanocarriers. Chemical modifications such as phosphorothioate linkages improve nuclease resistance and binding to proteins. Bioconjugation involves attaching oligonucleotides to lipids, peptides, aptamers, or antibodies to enhance delivery and target specificity. Nanocarriers such as lipid nanoparticles and exosomes are being developed to improve delivery to extrahepatic tissues. The review highlights the importance of chemical modifications, bioconjugation, and nanocarriers in improving oligonucleotide delivery. These approaches aim to enhance the stability, biodistribution, and target specificity of oligonucleotide therapeutics, enabling their use in a wide range of diseases.Oligonucleotides are nucleic acid polymers with potential for treating a wide range of diseases. They can modulate gene expression through various mechanisms, including RNAi, target degradation, splicing modulation, and gene activation. Despite recent advances, efficient delivery of oligonucleotides, especially to extrahepatic tissues, remains a major challenge. This review discusses key approaches to improve oligonucleotide delivery, including chemical modification, bioconjugation, and nanocarriers. Oligonucleotides can be designed to target specific genes with minimal off-target effects, enabling precision and personalized medicine. They can target patient-specific sequences, specific alleles, distinct transcript isoforms, pathogenic fusion transcripts, and viral sequences. Oligonucleotide-based platforms include antisense oligonucleotides (ASOs), which can modulate gene expression via RNase H-mediated cleavage or steric block. ASOs are used for splice modulation, gene activation, and gene silencing. siRNAs are used for gene silencing via RNAi, while miRNA inhibitors are used to modulate miRNA activity. Oligonucleotide-based therapies have been approved for various indications, including hepatitis C, Duchenne muscular dystrophy, and spinal muscular atrophy. However, challenges remain in achieving efficient delivery to target tissues, as well as in minimizing off-target effects and toxicity. Strategies to enhance delivery include chemical modification, covalent conjugation to cell-targeting moieties, and nanoparticle formulation. Recent approaches include exosome loading, spherical nucleic acids, and smart materials. Oligonucleotide delivery faces challenges such as nuclease degradation, renal clearance, and passage through the blood-brain barrier. Strategies to overcome these include chemical modifications, bioconjugation, and the use of nanocarriers. Chemical modifications such as phosphorothioate linkages improve nuclease resistance and binding to proteins. Bioconjugation involves attaching oligonucleotides to lipids, peptides, aptamers, or antibodies to enhance delivery and target specificity. Nanocarriers such as lipid nanoparticles and exosomes are being developed to improve delivery to extrahepatic tissues. The review highlights the importance of chemical modifications, bioconjugation, and nanocarriers in improving oligonucleotide delivery. These approaches aim to enhance the stability, biodistribution, and target specificity of oligonucleotide therapeutics, enabling their use in a wide range of diseases.