PEG‐Free Monosialoganglioside Lipid Nanoparticles with Spleen‐Selective mRNA Delivery for Cancer Immunotherapy

Abstract Lipid nanoparticles (LNPs) are critical for the success of mRNA therapeutics and vaccines. Polyethylene glycol (PEG) lipids are widely utilized in LNPs. Nonetheless, they can trigger anti‐PEG antibodies, leading to adverse reactions and reduced therapeutic effects. Hence, there is an immense demand to explore alternatives to PEG. This study introduces a novel PEG‐free LNP formulation. It is demonstrated that PEG‐lipids can be completely replaced by naturally occurring monosialogangliosides glycolipids (GM‐lipids) in the FDA‐approved SM‐102 and MC3‐based LNPs. LNPs formulated with 1.5% GM‐lipids (GMLNPs) show low immunogenicity and induce neither anti‐PEG nor anti‐GM‐lipids antibodies. GMLNPs maintain constant protein expression during repeated administrations and showcase improved efficiency and safety compared to PEG‐LNPs. Furthermore, GMLNPs exhibit enhanced mRNA transfection efficacy in spleen‐targeted delivery in vivo. GMLNPs encapsulating tumor‐associated antigen mRNA markedly decrease tumor occurrence and elicit a strong immune response in murine models, outperforming PEG‐LNPs. This highlights their potential for cancer immunotherapy, providing a promising foundation for future mRNA therapeutics and vaccines.