Delivering mRNA with non-immunogenic lipid nanoparticles

Lipid nanoparticles (LNPs) have great potential for generating new classes of nucleic acid-based therapeutics, however their immunogenicity is a significant problem. Lowering the immunogenicity of LNPs has been challenging because LNP immunogenicity is primarily caused by the positively charged head-group of their ionizable lipid, which is also essential for delivering nucleic acids. In this report, we present the first example of a non-immunogenic LNP that can deliver mRNA efficiently, termed switchable-nanoparticles (SNPs). SNPs switch their charged state between the pHs of 4.0 and 7.4. We have been able to demonstrate that SNPs can deliver mRNA as efficiently as traditional LNPs after an intravenous injection and are orders of magnitude less immunogenic than traditional LNPs in human PBMCs, mice pre-treated with LPS and mice treated with DNA in LNPs. In addition, SNPs were significantly more effective at treating LPS-induced acute lung injury than traditional LNPs in a therapeutic setting, because they do not exacerbate pre-existing inflammation. Collectively, these results demonstrate that SNPs have great potential for lowering the toxicity of LNP/mRNA complexes.

Learning Objectives:

1. Describe the challenges associated with immunogenicity in traditional lipid nanoparticles (LNPs).

2. Explain the mechanism by which switchable nanoparticles (SNPs) alter their charge state between different pH conditions.

3. Compare the efficiency and immunogenicity of SNPs and traditional LNPs in delivering mRNA.