Polymer-mRNA complexes for monocyte-trafficked, lymph node-targeted cancer vaccination

Area of Science:

• Biotechnology
• Immunology
• Oncology

Background:

• Lymph nodes are crucial for adaptive immunity initiation.
• Current messenger RNA (mRNA) cancer vaccines show inefficient lymph node delivery, leading to liver accumulation, reduced efficacy, and increased toxicity.

Purpose of the Study:

• To develop a novel polyplex system for enhanced lymph node targeting of mRNA cancer vaccines.
• To improve the stability and targeting of mRNA vaccines via transferrin receptor engagement.
• To reduce off-target accumulation in the liver and minimize systemic toxicity.

Main Methods:

• Developed a transferrin receptor-associating polyplex using modified low-molecular-weight polyethylenimine and mRNA.
• Utilized cyclic disulfide monomers for enhanced nucleic acid binding and thiol-based transferrin receptor engagement.
• Administered polyplexes subcutaneously and tracked monocyte recruitment and trafficking to lymph nodes.

Main Results:

• Polyplexes activated innate immunity and recruited monocytes expressing high transferrin receptor levels.
• Monocytes facilitated vaccine transport to draining lymph nodes, enabling mRNA translation and antigen presentation.
• Delivery of ovalbumin and interleukin 12 mRNA induced strong cytotoxic T cell responses, inhibiting melanoma progression and metastasis.

Conclusions:

• A monocyte-driven lymph node-targeting strategy effectively delivers mRNA cancer vaccines.
• The developed polyplex system enhances vaccine potency and selectivity.
• Demonstrated broad applicability using different antigens and tumor models, including Survivin and human papillomavirus antigens.