mRNA-based cancer vaccines are gaining traction due to their safety profile and ease of manufacturing, leading to numerous ongoing clinical trials. These vaccines typically use lipid nanoparticles (LNPs) to deliver antigen-encoded mRNA to dendritic cells (DCs), inducing strong and durable antigen-specific T cell responses. However, the high genetic diversity of tumors results in heterogeneous antigen expression, allowing some tumor cells to evade immune detection. Consequently, targeting only DCs may be insufficient for comprehensive tumor eradication.
To address this, we developed a dual-targeting strategy using DEC-205 antibody-functionalized LNPs to enhance antigen presentation in both DCs and tumor cells. DEC-205 is highly expressed on DCs and various tumor cells, making it an ideal target. We simplified the antibody functionalization by fusing the Fc domain of the DEC-205 antibody with apolipoprotein A1, which naturally binds to lipids. This approach enabled the antibodies to spontaneously and uniformly display on the LNP surface without requiring complex chemical conjugation. After intravenous
administration, dLNPs selectively accumulated in lymph nodes and tumor sites. Co-delivery of antigen-encoded mRNA and toll-like receptor (TLR) agonists with dLNPs enhanced antigen presentation in both matured DCs and tumor cells, inducing potent antigen-specific CD8+ T cell responses. This dual-targeting approach effectively stimulated antitumor immunity without systemic toxicity, highlighting its potential to overcome tumor heterogeneity and immune escape. Our findings demonstrate that DEC-205-mediated dual targeting significantly enhances the efficacy of mRNA cancer vaccines by simultaneously engaging both immune and tumor cells, providing a promising strategy for improving cancer immunotherapy