Dual-Targeting mRNA Cancer Vaccines for Simultaneous Antigen Presentation in Dendritic and Tumor Cells

Abstract

Numerous clinical trials have evaluated mRNA-based cancer vaccines owing to their safety and scalability. Most approaches use lipid nanoparticles (LNPs) to deliver antigen-encoding mRNA to dendritic cells (DCs), thereby promoting antigen-specific T cell responses. However, tumors exhibit high genetic variability, which leads to heterogeneous antigen expression. Consequently, vaccines that target only DCs with specific neoantigens may not cover all tumor cell clones, allowing some to escape immune detection. To overcome these challenges, we proposed a strategy that utilizes dual-targeted LNPs designed to simultaneously enhance antigen presentation in both DCs and tumor cells. For precise targeting, the LNPs were functionalized with DEC-205-targeting antibodies (dLNPs), which specifically bind to the DEC-205 receptor, a protein highly expressed in DCs and various tumor types. To simplify the antibody functionalization step, we fused the Fc domain of the DEC-205 antibody with apolipoprotein A1 (ApoA1), which binds naturally to lipids. Following intravenous administration, dLNPs selectively accumulated in lymph nodes and tumors. Co-delivery of antigen-encoding mRNA and toll-like receptor (TLR) agonists significantly enhanced antigen presentation in both cell types, leading to robust CD8+ T cell responses. This dual-targeting strategy elicited potent antitumor effects without systemic toxicity, demonstrating its potential in overcoming immune escape and improving mRNA vaccine efficacy.