Development of a Novel mRNA Cancer Vaccine for Precise Lymph Node Targeting

Lymph nodes are the primary sites where adaptive immune responses are initiated. However, most mRNA cancer vaccines have low delivery efficiency to lymph nodes and instead tend to accumulate in organs such as the liver, which limits therapeutic efficacy and increases systemic toxicity.

Recently, researchers published a study online in Nature Biomedical Engineering titled “Polymer–mRNA complexes for monocyte-trafficked, lymph node-targeted cancer vaccination”. The study reports a novel polymer carrier named TRAP, which can efficiently deliver mRNA vaccines to lymph nodes and demonstrated significant therapeutic effects in mouse models of melanoma and cervical cancer.

Messenger RNA technology has revolutionized the development of preventive and therapeutic vaccines, offering broad applications against diseases such as viral infections and cancer. Despite recent clinical progress, currently available vaccines still face challenges, including suboptimal delivery to lymph nodes, the main sites of immune activation, and off-target accumulation in organs such as the liver. These issues greatly reduce vaccine efficacy and raise concerns about systemic toxicity.

To address this challenge, multiple strategies have been explored, including the development of novel lipid nanoparticle formulations, exosome-based carriers, ionizable amphiphilic Janus dendrimers, and ligand-equipped lipid nanoparticles. However, these engineered delivery systems still tend to accumulate in non-lymphoid tissues, and none have entered clinical evaluation. This highlights the urgent need for new lymph node-specific mRNA delivery approaches.

In this study, the researchers developed a polyethyleneimine-based polycomplex that binds to the transferrin receptor and named it TRAP. It was designed for lymph node-specific delivery of mRNA cancer vaccines. The study showed that dithiolane-modified TRAP enters cells by binding to TfR1 on the cell membrane, promoting efficient mRNA expression in multiple cell types and outperforming the positive control Lipofectamine 200. After subcutaneous administration, mRNA expression was found to be extremely low in organs such as the liver, while showing high specificity in lymph nodes.

Figure 1. Schematic illustration of the mechanism. (Ren Q, et al., 2026)

In addition, TRAP recruits inflammatory monocytes to the injection site through STING activation. The cyclic disulfide groups anchored on the surface of TRAP-mRNA nanoparticles strongly adhere to Ly6C⁺ monocytes, which subsequently migrate to the lymph nodes. Targeted delivery of mRNA encoding tumor antigens and the cytokine interleukin-12 significantly enhanced lymph node-specific immune responses, activated CD8⁺ T cells, and effectively inhibited tumor progression in melanoma models. When combined with anti-PD-1 antibodies, the complete remission rate in the tumor model reached 60%. Furthermore, vaccination with Survivin mRNA significantly prolonged survival in mice with the B16F10 metastatic model, highlighting the potential of this platform to achieve durable and lymph node-targeted vaccine delivery through a monocyte-driven mechanism.