The landscape of nanoparticle-based siRNA delivery and therapeutic development

• Published in: Molecular therapy Vol. 32; no. 2; pp. 284 - 312
• Main Authors: Moazzam, Muhammad, Zhang, Mengjie, Hussain, Abid, Yu, Xiaotong, Huang, Jia, Huang, Yuanyu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.02.2024
• Subjects: clinical trials; inorganic carrier; lipid nanoparticle; polymer; RNA interference; siRNA; polymer; lipid nanoparticle; siRNA; clinical trials; RNA interference; inorganic carrier
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2024.01.005

Five small interfering RNA (siRNA)-based therapeutics have been approved by the Food and Drug Administration (FDA), namely patisiran, givosiran, lumasiran, inclisiran, and vutrisiran. Besides, siRNA delivery to the target site without toxicity is a big challenge for researchers, and naked-siRNA delivery possesses several challenges, including membrane impermeability, enzymatic degradation, mononuclear phagocyte system (MPS) entrapment, fast renal excretion, endosomal escape, and off-target effects. The siRNA therapeutics can silence any disease-specific gene, but their intracellular and extracellular barriers limit their clinical applications. For this purpose, several modifications have been employed to siRNA for better transfection efficiency. Still, there is a quest for better delivery systems for siRNA delivery to the target site. In recent years, nanoparticles have shown promising results in siRNA delivery with minimum toxicity and off-target effects. Patisiran is a lipid nanoparticle (LNP)-based siRNA formulation for treating hereditary transthyretin-mediated amyloidosis that ultimately warrants the use of nanoparticles from different classes, especially lipid-based nanoparticles. These nanoparticles may belong to different categories, including lipid-based, polymer-based, and inorganic nanoparticles. This review briefly discusses the lipid, polymer, and inorganic nanoparticles and their sub-types for siRNA delivery. Finally, several clinical trials related to siRNA therapeutics are addressed, followed by the future prospects and conclusions. [Display omitted] Huang and colleagues summarize the unique properties of various nanocarriers, discuss current challenges, and highlight their prospects in siRNA delivery. They also review various clinical studies as well as preclinical studies of siRNA therapeutics, which provides a comprehensive view and multidisciplinary insights regarding nanocarriers for effective siRNA delivery.