Glycolipids Substitute PEG lipids in Lipid Nanoparticles for mRNA Delivery.

Lipid nanoparticles (LNPs) have become a pivotal platform for mRNA drug delivery, yet the immunogenicity of poly(ethylene glycol) (PEG) lipids compromises efficacy upon repeated administration, making it necessary to develop PEG-free LNP formulations. Carbohydrates share the highly hydrophilic properties of PEG, making them good alternatives. Here we report a chemically driven strategy to replace PEG lipids with rationally designed glycolipids synthesized via a one-pot Borch reductive amination reaction. This method enabled conjugation of maltoheptaose (G7) to alkyl diamines, forming glycolipids that self-assemble into stable LNPs. Structural optimization revealed that G7-based glycolipids with C14 tails (G7B2) exhibited favorable physicochemical properties. Crucially, in vivo studies revealed that G7B2 LNPs significantly enhanced splenic accumulation, while minimizing anti-PEG antibody production. Furthermore, G7B2 LNPs maintained a consistent delivery efficiency over repeated administrations, a notable advantage over conventional PEGylated LNPs. As a proof of concept, G7B2-OVA mRNA achieved robust antitumor efficacy in a B16F10-OVA melanoma model. These results establish glycolipids as chemically tunable and immunogenically inert alternatives to the PEG lipids, offering a promising strategy for next-generation LNP formulations.