The article discusses the advancements and challenges in RNAi-based drug design, focusing on the development of small interfering RNA (siRNA) therapies. It highlights the progress in siRNA delivery technologies, such as lipid nanoparticles (LNPs) and GalNAc conjugates, and their clinical applications. The review emphasizes the importance of chemical modifications in improving siRNA stability, efficacy, and specificity. Key modifications include 2′-O-methyl (2′-OMe), 2′-fluoro (2′-F), phosphorothioate (PS), and 5′-(E)-vinylphosphonate (5′-VP). The article also explores strategies for enhancing siRNA delivery to extrahepatic tissues, including the use of lipophilic conjugates, protein-antibody conjugates, and modifications to the siRNA molecule itself. Additionally, it discusses the role of informatics in predicting siRNA functionality and specificity, as well as the principles of delivery strategies, such as systemic and targeted delivery. The review concludes by outlining future directions for innovation in RNAi-based drug design, emphasizing the need for continued advancements in chemistry, informatics, and delivery methods to improve therapeutic outcomes.The article discusses the advancements and challenges in RNAi-based drug design, focusing on the development of small interfering RNA (siRNA) therapies. It highlights the progress in siRNA delivery technologies, such as lipid nanoparticles (LNPs) and GalNAc conjugates, and their clinical applications. The review emphasizes the importance of chemical modifications in improving siRNA stability, efficacy, and specificity. Key modifications include 2′-O-methyl (2′-OMe), 2′-fluoro (2′-F), phosphorothioate (PS), and 5′-(E)-vinylphosphonate (5′-VP). The article also explores strategies for enhancing siRNA delivery to extrahepatic tissues, including the use of lipophilic conjugates, protein-antibody conjugates, and modifications to the siRNA molecule itself. Additionally, it discusses the role of informatics in predicting siRNA functionality and specificity, as well as the principles of delivery strategies, such as systemic and targeted delivery. The review concludes by outlining future directions for innovation in RNAi-based drug design, emphasizing the need for continued advancements in chemistry, informatics, and delivery methods to improve therapeutic outcomes.