PEG immunogenicity-free LNPs targeting antigen-presenting cells enabling potent and safe H5N1 mRNA vaccination

Lipid nanoparticles (LNPs) are an effective mRNA delivery platform underpinning the success of novel vaccines against infectious diseases such as COVID-19. However, the immunogenicity of conventional poly(ethylene glycol) (PEG) lipids induces anti-PEG antibody responses, compromising both safety and efficacy. In addition, PEGylated LNPs preferably accumulate in the liver after administration. To overcome these limitations, we synthesize a series of mannose- and/or oligo(ethylene glycol) (OEG)-functionalized biodegradable polycarbonate (PCM) lipids as PEG-lipid replacements. These lipids are employed to formulate LNPs for mRNA vaccine delivery. The introduction of mannose and OEG groups impart hydrophilicity on polycarbonate and facilitate active targeting of mannose receptors on antigen-presenting cells (APCs), including dendritic cells and macrophages. PCM-engineered LNPs exhibit enhanced mRNA delivery efficiency and cellular activation in APCs in vitro. More importantly, in vivo studies have demonstrated efficient mRNA delivery with reduced liver accumulation, thereby mitigating potential hepatic toxicity. In a highly pathogenic avian influenza A(H5N1) mRNA vaccine model in mice, PCM-engineered LNPs have shown to elicit stronger humoral and cellular immune responses compared to commercial PEGylated LNPs formulated using ALC-0159. Notably, repeated administration of PCM-engineered LNPs does not induce anti-PEG antibodies, and only minimal, transient PCM lipid-specific antibody responses are observed. Overall, these findings demonstrate that PCM-engineered LNPs represent a promising, safer and more effective mRNA vaccine delivery platform that addresses immunogenicity and safety challenges associated with PEGylated systems.