Difference in the lipid nanoparticle technology employed in three approved siRNA (Patisiran) and mRNA (COVID-19 vaccine) drugs

Abstract

Nucleic acid therapeutics are developing into precise medicines that can manipulate specific genes. However, the development of safe and effective delivery system for the target cells has remained a challenge. Lipid nanoparticles (LNPs) have provided a revolutionary delivery system that can ensure multiple clinical translation of RNA-based candidates. In 2018, Patisiran (Onpattro) was first approved as an LNP-based siRNA drug. In 2020, during the coronavirus disease 2019 (COVID-19) outbreak, LNPs have enabled the development of two SARS-CoV-2 mRNA vaccines, Tozinameran (Comirnaty or Pfizer-BioNTech COVID-19 vaccine) and Elasomeran (Spikevax or COVID-19 vaccine Moderna) for conditional approval. Here, we reviewed the state-of-the-art LNP technology employed in three approved drugs (one siRNA-based and two mRNA-based drugs) and discussed the differences in their mode of action, formulation design, and biodistribution.

Keywords: COVID-19; COVID-19 vaccine moderna; Elasomeran; Ionizable lipid; LNP; Lipid nanoparticles; Patisiran; SARS-CoV-2; Tozinameran; mRNA vaccine.

Fig. 1

Structure of the drugs. For both mRNA designs, S–2P spike proteins were modified by 2 proline substitutions to produce prefusion-stabilized SARS-CoV-2 spike proteins. UTR, untranslated region; ORF, open reading frame.

Fig. 2

Delivery mechanism of lipid nanoparticles. First, full encapsulation by lipid nanoparticles (LNP) protects RNA from nuclease digestion. LNPs are neutral in physiological pH due to the ionizable lipid and PEG-lipid, thereby reducing non-specific interactions with serum proteins. Second, following dissociation of the PEG-lipid, cells take up LNPs via apolipoprotein E (ApoE)-dependent and/or ApoE-independent pathways. Finally, protonated LNPs, upon acidification in the endosome, induce hexagonal phase structures, disrupt the membranes, and release RNA molecules into the cytoplasm.

Fig. 3

Chemical structure of lipids in lipid nanoparticles. ALC-0159 has PEG₂₀₀₀. All 3 ionizable lipids have tertiary amine groups, namely Dlin-MC3-DMA (MC3), pKa 6.44 [12] or pKa 6.35 [11]; ALC-0315, pKa 6.09 [44]; and SM-102, pKa 6.68 [11]. The related patents are as follows: Dlin-MC3-DMA, WO/2010/144740; ALC-0315, WO/2017/075531 (Lipid No. 3); and SM-102, WO/2017/049245 (Compound 25).

Fig. 4

Biodegradable design in ionizable lipid. Pink circle in each chemical structure shows the hydrolysis site. Hydrolysis of ester linkage facilitates rapid elimination and improved tolerability. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)