The immunogenicity of lipid nanoparticles (LNPs) used to deliver nucleoside-modified mRNA limits the expression level and duration of proteins encoded by mRNA, which is not conducive to the therapeutic effect of LNP-mRNA therapy.
Recently, researchers from the University of Science and Technology of China published a research paper titled "Mannich reaction-based combinatorial libraries identify antioxidant ionizable lipids for mRNA delivery with reduced immunogenicity" in Nature Biomedical Engineering, a subsidiary of Nature. Based on the combinatorial library of the Mannich reaction, this study screened out antioxidant ionizable lipids for mRNA delivery with reduced immunogenicity, C-a16. When C-a16-LNP delivers mRNA, it reduces the generation of intracellular reactive oxygen species (ROS), reduces inflammatory responses, and prolongs the duration of protein expression, providing a promising new type of ionizable lipid for the application of mRNA therapy and vaccines.
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In this latest study, the research team used the Mannich reaction to synthesize ionizable lipids. They also screened the six synthetic lipid combinatorial libraries in vitro and in vivo. They reported the discovery of an ionizable lipid C-a16 with antioxidant properties, which has significantly reduced immunogenicity.
Figure 1. Systemic mRNA delivery using C-a16 LNPs. (Gong N, et al., 2025)
When incorporated into lipid nanoparticles (LNPs) for mRNA delivery, C-a16 mitigated the generation of intracellular reactive oxygen species (ROS), thereby prolonging the duration of protein expression.
In vivo experiments in mice, incorporating C-a16 into LNPs to deliver Cas9 mRNA and gRNA simultaneously to edit the transthyretin gene increased editing efficiency by 2.8 times compared to other lipid nanoparticles (LNPs). Delivery of FGF21 mRNA increased the expression of the protein by 3.6 times. When delivering mRNA encoding tumor neoantigens or SARS-CoV-2 S protein, a stronger antigen-specific immune response was successfully induced.
Overall, this study synthesized an ionizable lipid C-a16 with antioxidant properties, which has significantly reduced immunogenicity and can be used as a promising ionizable lipid for delivering mRNA in therapeutic applications.
Reference
Gong N, et al. Mannich reaction-based combinatorial libraries identify antioxidant ionizable lipids for mRNA delivery with reduced immunogenicity. Nature Biomedical Engineering, 2025: 1-15.