Nanoparticle-based siRNA delivery and therapeutic development have become crucial in the treatment of various diseases. Five siRNA-based therapeutics have been approved by the FDA, including patisiran, givosiran, lumasiran, inclisiran, and vutrisiran. However, delivering siRNA to the target site without toxicity remains a significant challenge due to factors such as membrane impermeability, enzymatic degradation, and MPS entrapment. To overcome these barriers, various modifications and delivery systems have been developed, including lipid-based, polymer-based, and inorganic nanoparticles. These nanoparticles offer better stability, target specificity, and reduced cellular toxicity compared to naked siRNA. Patisiran, an LNP-based siRNA formulation, is used to treat hereditary transthyretin-mediated amyloidosis. Other siRNA-based drugs use ligands like GalNAc for targeted delivery. Recent advancements in nanoparticle-based delivery systems have shown promising results in improving siRNA transfection efficiency and reducing off-target effects. Clinical trials have demonstrated the effectiveness of these systems in treating various diseases, and future research aims to further enhance their therapeutic potential. The review highlights the importance of nanoparticle-based delivery systems in the development of siRNA therapeutics and their potential in treating a wide range of diseases.Nanoparticle-based siRNA delivery and therapeutic development have become crucial in the treatment of various diseases. Five siRNA-based therapeutics have been approved by the FDA, including patisiran, givosiran, lumasiran, inclisiran, and vutrisiran. However, delivering siRNA to the target site without toxicity remains a significant challenge due to factors such as membrane impermeability, enzymatic degradation, and MPS entrapment. To overcome these barriers, various modifications and delivery systems have been developed, including lipid-based, polymer-based, and inorganic nanoparticles. These nanoparticles offer better stability, target specificity, and reduced cellular toxicity compared to naked siRNA. Patisiran, an LNP-based siRNA formulation, is used to treat hereditary transthyretin-mediated amyloidosis. Other siRNA-based drugs use ligands like GalNAc for targeted delivery. Recent advancements in nanoparticle-based delivery systems have shown promising results in improving siRNA transfection efficiency and reducing off-target effects. Clinical trials have demonstrated the effectiveness of these systems in treating various diseases, and future research aims to further enhance their therapeutic potential. The review highlights the importance of nanoparticle-based delivery systems in the development of siRNA therapeutics and their potential in treating a wide range of diseases.