DEC205-Targeting mRNA Cancer Vaccines for Enhanced Antigen Presentation in Dendritic and Tumor Cells

Abstract

Introduction: Genetic alterations in cancer produce neoantigens that can elicit robust anticancer immune responses when effectively presented to T cells. However, the immunosuppressive tumor microenvironment often hampers antigen presentation, contributing to immune evasion. Although lipid nanoparticle (LNP)-based mRNA cancer vaccines have shown promise in delivering neoantigen-encoded mRNA, their tendency to accumulate in the liver diminishes tumor-specific antigen presentation and antitumor efficacy. To overcome this limitation, the current study employs a novel “Grab Antibody” (GrAb) approach, where apolipoprotein A1 is fused to the Fc domain of a DEC-205 antibody (NLDC145). DEC-205, known to be highly expressed on both dendritic cells (DCs) and various cancers, facilitates receptor-mediated delivery of mRNA to these crucial cell populations. By simply mixing GrAb and LNPs, the apolipoprotein moiety anchors the antibody on the LNP surface, enabling dual targeting while circumventing conventional chemical conjugation pitfalls.

Results: DEC-205-functionalized LNPs (dLNPs) retained a spherical morphology similar to control LNPs (cLNPs) (Fig. 1B). In DEC-205-expressing MutuDC1940 DCs, dLNPs prompted receptor-mediated endocytosis, evidenced by a dose-dependent reduction in surface DEC-205 (Fig. 1C). Flow cytometry and confocal microscopy confirmed that dLNPs significantly enhanced mRNA (FLuc) uptake and translation in both DCs and MC38 colorectal cancer cells, effects abrogated by DEC-205 pre-blocking (Fig. 1D？F). In vivo, dLNPs administered to MC38 tumor-bearing mice exhibited stronger tumor and tumor-draining lymph node localization compared to cLNPs or isotype-control LNPs (iLNPs), while reducing liver accumulation (Fig. 1G？I). Using CpG plus ovalbumin (OVA) mRNA as a model vaccine, dLNP-treated cells displayed increased MHC class I presentation of OVA peptides (Fig. 1J), leading to robust antitumor effects in MC38 tumor-bearing mice (Fig. 1K). Immune profiling revealed elevated DC maturation, effector memory CD8+ T cell expansion, and higher infiltration of DCs, macrophages, and cytotoxic T cells in tumors (Fig. 1L？N). Notably, IFNγ production was also enhanced, indicating a potent T cell response (Fig. 1O). Although cLNPs induced liver toxicity (Fig. 1Q), dLNPs demonstrated no significant toxicity, as confirmed by normal blood chemistry (Fig. 1P). These findings highlight the potential of DEC-205-targeting GrAb LNPs for dual delivery of mRNA to DCs and tumor cells, resulting in improved antigen presentation, enhanced immune activation, and reduced off-target effects.