Biodegradable Polymer-Lipid Nanoparticles for Effective In Vivo mRNA Delivery

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 <i>in vivo</i>, leading to delivery of mRNA primarily to the liver after <i>i.v.</i> 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.