(647g) Glycan-Modified Lipid Nanoparticle Enhances Cell-Specific mRNA Delivery

mRNA-lipid nanoparticle (LNP) technology has become an invaluable solution for vaccine and cell therapy due to its transient and tunable protein expression. Targeted delivery of mRNA into specific immune cells is critical for many applications, including chimeric-antigen-receptor (CAR) cell engineering, gene editing, and autoimmune treatment. Current efforts to optimize cell-targeting LNPs generally rely on the screening of a combinatorial lipid library, as well as the manipulation of surface charge that can compromise transfection efficiency. In this work, we achieved the targeted delivery of mRNA to immune cells utilizing the cell-cell communication pathway via the binding of sialic-acid binding immunoglobulin-like lectins (Siglecs). Siglecs are highly expressed on immune cells and used to interact with glycans on cancer cells and viruses. Therefore, we incorporated a Siglecs-binding glycan lipid into our LNP formulation. Our results proved that the glycan-LNP exhibited most mRNA expression in lymph nodes and the spleen where most immune cells reside as compared to the liver. We tested different variants of the glycan-lipid and screened for top-performing formulation that shows selective and efficient mRNA transfection using luciferase expression assay. This glycan-LNP was further validated in a Cre-mediated editing experiment using an Ai14 mouse model to induce selective mRNA expression in immune cells. Finally, through in vivo administration of glycan-LNP encapsulating CAR-mRNA, we successfully engineered the immune cells with CAR, which obtained significant killing capability towards antigen overexpressing cancer cells. Overall, we revealed the great potential of glycan-LNPs as a promising platform for immunotherapy.