Lipid Nanoparticle Delivery Systems to Enable mRNA-Based Therapeutics

Abstract

The world raced to develop vaccines to protect against the rapid spread of SARS-CoV-2 infection upon the recognition of COVID-19 as a global pandemic. A broad spectrum of candidates was evaluated, with mRNA-based vaccines emerging as leaders due to how quickly they were available for emergency use while providing a high level of efficacy. As a modular technology, the mRNA-based vaccines benefitted from decades of advancements in both mRNA and delivery technology prior to the current global pandemic. The fundamental lessons of the utility of mRNA as a therapeutic were pioneered by Dr. Katalin Kariko and her colleagues, perhaps most notably in collaboration with Drew Weissman at University of Pennsylvania, and this foundational work paved the way for the development of the first ever mRNA-based therapeutic authorized for human use, COMIRNATY^®. In this Special Issue of Pharmaceutics, we will be honoring Dr. Kariko for her great contributions to the mRNA technology to treat diseases with unmet needs. In this review article, we will focus on the delivery platform, the lipid nanoparticle (LNP) carrier, which allowed the potential of mRNA therapeutics to be realized. Similar to the mRNA technology, the development of LNP systems has been ongoing for decades before culminating in the success of the first clinically approved siRNA-LNP product, ONPATTRO^®, a treatment for an otherwise fatal genetic disease called transthyretin amyloidosis. Lessons learned from the siRNA-LNP experience enabled the translation into the mRNA platform with the eventual authorization and approval of the mRNA-LNP vaccines against COVID-19. This marks the beginning of mRNA-LNP as a pharmaceutical option to treat genetic diseases.

Keywords: gene editing; lipid nanoparticles; mRNA-LNP; mRNA-based therapeutics; prophylactic vaccines; siRNA-LNP.

Figure 1

Novel lipid screening model. In vivo activity of novel ionizable lipids using a reporter gene firefly luciferase encoded in a mRNA are evaluated by intravenous administration in murine model.

Figure 2

Lipid components in approved mRNA-LNP vaccines. BNT162b2 consisted of ALC-0315 ((4 hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), ALC-0159 (2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide) and two naturally-occurring lipids DSPC 1,2-distearoyl-sn-glycero-3-phosphocholine and cholesterol (https://www.ema.europa.eu/en/documents/assessment-report/comirnaty-epar-public-assessment-report_en.pdf (accessed on 25 November 2021)) while mRNA-1273 used SM102 9-Heptadecanyl 8-{(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino}octanoate, PEG2000-DMG 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000, DSPC and cholesterol (https://www.ema.europa.eu/en/documents/assessment-report/spikevax-previously-covid-19-vaccine-moderna-epar-public-assessment-report_en.pdf (accessed on 25 November 2021)). The ionizable Nitrogen that drives the pKa of ALC-0315 and SM-102 are circled in yellow. BNT162 trials were based on three different modalities: unmodified mRNA (BNT162a), modified mRNA (BNT162b), and saRNA (BNT162c) while mRNA-1273 relied on modified mRNA.

Figure 3

Manufacturing mRNA-LNP vaccines for COVID-19: From procurement of critical raw materials to LNP manufacturing and aseptic filling, expansion of manufacturing capacity, and distribution for administration.