Glycan Chemical Structures Dictate Organ- and Cell-Specific Tropism and Immunomodulation of Lipid Nanoparticles

Although glycan motifs are known to mediate biological recognition, how their structural features regulate lipid nanoparticle (LNP) biodistribution and immune responses remains poorly understood. Here, we systematically examine how glycan structure influences the biodistribution of lipid nanoparticles and immune responses under a controlled commercial formulation background. By screening four classes of glycan-modified LNPs, we identify distinct structure–function relationships linking glycan identity to organ distribution, cell-type tropism, and immunological outcomes. We found that some glycans previously reported to engage immune cells did not confer secondary lymphoid organ (SLO) tropism, whereas some SLO-targeting glycans failed to efficiently transfect antigen-presenting cells (APCs). Notably, GM3- and GD1A-containing LNPs achieve efficient transfection of antigen-presenting cells in SLOs while preserving favorable physicochemical properties. Functionally, they elicit potent activation of both CD8+ and CD4+ T cells, the latter being a critical yet rarely achieved response in standard LNP formulations. A head-to-head comparison showed that intravenous (IV) administration of our glycan-LNP vaccines resulted in improved tumor control compared with the benchmark intramuscular (IM) formulation. Moreover, they induce minimal cytokine release in human peripheral blood mononuclear cells, underscoring their translational potential. Together, these findings establish glycan chemistry as a tunable and generalizable design parameter for controlling mRNA nanoparticle biodistribution and immune engagement, providing a framework for the rational engineering of targeted mRNA delivery systems.