RNA interference (RNAi) is a natural defense mechanism against exogenous gene invasion. Small interfering RNA (siRNA) can specifically silence disease-related genes, making it a promising therapeutic modality. After two decades of development, two siRNA therapeutics, ONPATTRO (patisiran) and GIVLAARI (givosiran), have been approved by Alnylam Pharmaceuticals for treating hereditary amyloidogenic transthyretin (hATTR) amyloidosis and acute hepatic porphyria, respectively. These approvals mark a significant milestone in RNAi-based therapy. siRNA can be administered quarterly or twice-yearly, offering a more convenient treatment option compared to small molecules and antibodies. However, challenges remain in delivering siRNA efficiently and safely to target tissues and cells, as well as enhancing its stability, specificity, and reducing off-target effects. This review discusses the evolution of siRNA chemical modifications and their biomedical performance, including various delivery platforms such as GalNAc-siRNA conjugates. It also summarizes the latest progress in siRNA therapeutic development, providing a comprehensive overview and roadmap for researchers in the field. The review highlights the importance of chemical modifications, such as 2'-O-methyl (2'-OMe), 2'-fluoro (2'-F), phosphorothioate (PS), and locked nucleic acid (LNA), in improving siRNA stability, activity, and specificity. Additionally, it discusses the development of various delivery systems, including lipid nanoparticles (LNPs), dynamic polyconjugates (DPC), and GalNAc-siRNA conjugates, which have been used to achieve efficient siRNA delivery to target tissues. The review also covers the challenges in siRNA delivery, such as nuclease degradation, immune recognition, and endosomal escape, and discusses strategies to overcome these barriers. Finally, it highlights the progress in siRNA-based therapies, including the approval of ONPATTRO and GIVLAARI, and the ongoing clinical trials of other siRNA therapeutics. The review provides a comprehensive overview of the current state of siRNA therapy and its potential for future drug development.RNA interference (RNAi) is a natural defense mechanism against exogenous gene invasion. Small interfering RNA (siRNA) can specifically silence disease-related genes, making it a promising therapeutic modality. After two decades of development, two siRNA therapeutics, ONPATTRO (patisiran) and GIVLAARI (givosiran), have been approved by Alnylam Pharmaceuticals for treating hereditary amyloidogenic transthyretin (hATTR) amyloidosis and acute hepatic porphyria, respectively. These approvals mark a significant milestone in RNAi-based therapy. siRNA can be administered quarterly or twice-yearly, offering a more convenient treatment option compared to small molecules and antibodies. However, challenges remain in delivering siRNA efficiently and safely to target tissues and cells, as well as enhancing its stability, specificity, and reducing off-target effects. This review discusses the evolution of siRNA chemical modifications and their biomedical performance, including various delivery platforms such as GalNAc-siRNA conjugates. It also summarizes the latest progress in siRNA therapeutic development, providing a comprehensive overview and roadmap for researchers in the field. The review highlights the importance of chemical modifications, such as 2'-O-methyl (2'-OMe), 2'-fluoro (2'-F), phosphorothioate (PS), and locked nucleic acid (LNA), in improving siRNA stability, activity, and specificity. Additionally, it discusses the development of various delivery systems, including lipid nanoparticles (LNPs), dynamic polyconjugates (DPC), and GalNAc-siRNA conjugates, which have been used to achieve efficient siRNA delivery to target tissues. The review also covers the challenges in siRNA delivery, such as nuclease degradation, immune recognition, and endosomal escape, and discusses strategies to overcome these barriers. Finally, it highlights the progress in siRNA-based therapies, including the approval of ONPATTRO and GIVLAARI, and the ongoing clinical trials of other siRNA therapeutics. The review provides a comprehensive overview of the current state of siRNA therapy and its potential for future drug development.