Dendritic cell-targeting virus-like particles as mRNA carriers induce Th1-skewed humoral and cellular immunity

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Abstract
Messenger RNA (mRNA) vaccines have emerged as a powerful vaccination platform, yet efficient and targeted delivery of mRNA to professional antigen-presenting cells (APCs) remains a major challenge. Here, we developed a dendritic cell (DC)-targeting virus-like particle (DVLP) platform for mRNA delivery by combining human immunodeficiency virus (HIV) Gag fused with the bacteriophage MS2 coat protein, which recognizes mRNA bearing MS2 stem-loop sequences and an engineered Sindbis virus glycoprotein mutant (SV-Gmt) that preferentially targets dendritic cells. African swine fever virus (ASFV) P30 was employed as a model antigen to evaluate platform performance. In vitro , SV-Gmt-pseudotyped VLPs encapsulating P30 mRNA (DVLP-P30) preferentially delivered antigen mRNA to dendritic cells compared with broad-tropic vesicular stomatitis virus G protein (VSV-G)-pseudotyped VLPs encapsulating P30 mRNA (VSV-G VLP-P30). In mice, vaccination with DVLP-P30 induced significantly higher P30-specific antibody responses than VSV-G VLP-P30. Enhanced humoral immunity was accompanied by increased frequencies of CD4 + and CD8 + effector memory T cells, indicating improved generation of antigen-specific immune memory. Notably, DC-targeted mRNA delivery promoted stronger interferon-γ responses and increased IgG2a production, consistent with a Type 1 helper T cell (Th1)-skewed immune profile. Together, these findings demonstrate that DC-targeting VLPs function as effective mRNA carriers and enhance both the magnitude and quality of vaccine-induced immunity. This work establishes a versatile platform for targeted mRNA delivery and supports further development of DVLPs for prophylactic and therapeutic vaccination.
Funding Information
  • National Cancer Institute

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