Biodegradable Polymer-Lipid Nanoparticles for Effective In Vivo mRNA Delivery

Abstract

Currently, only 2 mRNA Covid-19 vaccines from Moderna and Pfizer-BioNtech have been approved by the US FDA for human use. Both vaccines utilize SARS-CoV-2 mRNA as the antigen and lipids as the carrier. The lipids consist of 3 different types of lipids (PEG-lipid conjugate, ionizable lipid and helper lipid) and cholesterol. The ionizable lipid condenses mRNA into lipid nanoparticles (LNPs) through electrostatic interaction and self-assembly. The mRNA-loaded LNPs stimulate the immune cells for prophylactic response against the SARS-CoV-2 virus. The use of PEG-lipid (ALC-0159) makes the LNPs unstable, leading to delivery of mRNA primarily to the liver after injection of mRNA LNPs. In this study, we synthesize amphiphilic block copolymers of PEG and biodegradable polycarbonate with varying chain length and urea moiety to replace PEG-lipid conjugate. Urea functional groups are used to form hydrogen-bonding interactions within the LNPs to further increase the stability of LNPs. Luciferase-encoded mRNA is loaded into lipid nanoparticles by using a microfluidic device. Use of amphiphilic polycarbonate block copolymers enhances the stability of mRNA-loaded nanoparticles in serum-containing medium while yielding high transfection efficiency of mRNA in mice. The introduction of polycarbonates alters their biodistribution <i>in vivo</i>. The polymer-lipid nanoparticles with enhanced stability may be used to deliver mRNA to T cells for cancer therapy.