Targeting Lipid Nanoparticles (LNPs) to Antigen-Presenting Cells Through Siglecs to Improve Vaccine Response and Durability

Vaccines can provide both short-term and long-term protection from deadly pathogens. This was demonstrated during the COVID19 pandemic, which saw the rapid production of lipid nanoparticle (LNP) mRNA vaccines. LNP-based mRNA vaccines are easy to produce in large quantities with a great degree of quality control on a relatively short time scale. These vaccines generally rely on passive uptake by antigen-presenting cells (APCs) to initiate priming of B and T cells, which are both required for a robust humoral (antibody) response. While LNP-based mRNA vaccines induce robust antibody responses, there are still questions about the durability of the immunological memory induced by these vaccines. Such a factor is a critical feature of a vaccine that keeps people protected over the course of years to decades. In contrast, many pathogens and viruses are actively taken up by glycan-binding proteins expressed on our immune cells that recognize host-derived glycans. Therefore, passive uptake of LNP-based mRNA vaccines misses out on this natural route of uptake. We hypothesize that targeting LNPs to immune cells, particularly APCs, may help improve the efficacy of vaccines. To do so, we will target sialic acid binding immunoglobulin-type lectins (Siglecs) that are carbohydrate-binding cell surface receptors found on immune cells. Siglecs are an ideal target for delivery because of their endocytic properties, their selective expression on immune cell subsets, and the availability of high affinity and selective glycan ligands for targeting. Here, we propose three aims to test this main hypothesis. In Aim 1, we will synthesize next-generation carbohydrate-based Siglec ligands for improved targeting. In Aim 2, we will formulate LNPs with ligands targeting Siglec-1, Siglec-3 (CD33), or Siglec-7/E to direct LNPs to macrophages, monocytes, and dendritic cells, respectively. Successful targeting will result in enhanced uptake of LNPs and increased expression of encapsulated mRNA in the cell type of interest. In Aim 3, we will examine the ability of Siglec-targeted LNPs to induce robust primary antibody responses directed at the spike protein of SARS-CoV-2, as well as memory responses following a boost. In summary, this project will develop Siglec-targeted LNPs to enhance immune responses as an improved vaccination approach.