Figure 1.

Mechanism of hepatic delivery and RNA interference of siRNAs. All the siRNAs discussed in the text exert their action within the liver, but they use different delivery mechanisms. Inclisiran, olpasiran, lepodisiran, ARO-APOC3, and zilebesiran are administered subcutaneously, covalently linked to a GalNAc “trident” that binds with high affinity to the ASGPR on the hepatocyte surface. Hence, they gain endosomal entry into the cell and dissociate from GalNAc and ASGPR inside the endosome. Patisiran is administered intravenously, and it is formulated as an encapsulated lipid nanoparticle consisting of a largely hydrophobic core with inverted micelles of lipids and an outer coating of PEG lipids and cholesterol-acquiring ApoE from circulating VLDL and IDL. Patisiran nanoparticle coated by ApoE binds to the LDLR on the hepatocyte surface, and internalization by endocytosis ensues. Once inside the cell, siRNAs bind a specific protein complex and form the RISC, where they are separated into two strands: one of these strands (the “guide” strand) binds its target, a specific mRNA sequence, and leads to its degradation, preventing RNA translation and inhibiting corresponding protein synthesis. The specific targets are the following: PCSK9 for inclisiran, Lp(a) for olpasiran (and lepodisiran), APOC3 for ARO-APOC3, TTR for patisiran (and vutrisiran), and AGT for zilebesiran. AGT: angiotensinogen; APOC3: apolipoprotein C-III; ApoE: apolipoprotein E; ASGPR: asialoglycoprotein receptor; GalNAc: N-acetyl-galactosamine; IDL: intermediate-density lipoprotein; LDLR: low-density lipoprotein receptor; Lp(a): lipoprotein(a); PCSK9: proprotein convertase subtilisin/kexin type 9; PEG: polyethylene glycol; RISC: RNA-induced silencing complex; siRNA: small interfering RNA; TTR: transthyretin; VLDL: very low-density lipoprotein.