The landscape of nanoparticle-based siRNA delivery and therapeutic development

Abstract

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.

Keywords: RNA interference; clinical trials; inorganic carrier; lipid nanoparticle; polymer; siRNA.

Graphical abstract

Figure 1

Several types of nanoparticles belong to lipid, polymer, and inorganic classes FDA-approved siRNA therapeutic structures are presented. (A) Structure of patisiran. Reproduced and adapted from Torre et al. under the Creative Commons Attribution (CC BY) license. (B) Structure of givosiran. Reproduced and adapted from Torre et al. under the Creative Commons Attribution (CC BY) license. (C) Structure of lumasiran. Reproduced and adapted from Torre et al. under the Creative Commons Attribution (CC BY) license. (D) Structure of inclisiran. Reproduced and adapted from Torre et al. under the Creative Commons Attribution (CC BY) license. (E) Structure of vutrisiran.

Figure 2

Structural illustration of chemical modifications for siRNA and ASO therapeutics According to the modification site, these can be classified into three categories: phosphonate modification, ribose modification, and base modification, which is indicated in red, purple, and blue. R = H or OH. (S)-cEt-BNA, (S)-constrained ethyl bicyclic nucleic acid; PMO, phosphorodiamidate morpholino oligomer. Modified from Hu et al.

Figure 3

Several nanocarriers for the delivery of siRNA