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Background <p>While mRNA vaccines represent a transformative platform for infectious disease control, their efficacy in antigen-presenting cells (APCs) remains vulnerable to endogenous regulatory networks, particularly microRNA (miR)-mediated translational suppression. This study addresses a critical gap in current vaccine design paradigms by systematically investigating host miR interference – an understudied barrier to robust antigen production.</p> Main text <p>APCs express cell-type-specific miR repertoires capable of binding vaccine mRNAs through conserved seed sequences, as evidenced by synthesis of experimental data from 67 studies demonstrating miR-mediated repression of exogenous transcripts. To decode these inhibitory interactions, the commentary proposes an integrated multi-omics framework combining Argonaute immunoprecipitation with crosslinking-based miR-mRNA interactome sequencing, enabling precise mapping of miR-vaccine mRNA binding events in vaccine-transfected APCs. Furthermore, the commentary suggests two actionable strategies for evading miR interference: (1) Synonymous codon optimization at seed-match regions, achieving binding energy reduction while preserving antigenicity through degeneracy of genetic coding; (2) Targeted co-delivery of miR inhibitors. By bridging host RNA biology and vaccine engineering, this work provides a blueprint for developing miR-resistant mRNA vaccines for public health interventions.</p> Conclusions <p>miRs may inhibit mRNA vaccine translation in APCs, potentially reducing antigen production and weakening the resulting immune response. To address this, next-generation mRNA vaccines should incorporate “miR-proofing” strategies during design to avoid miR interference.</p> Graphical Abstract <p></p>

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Mitigating host microRNA interference to enhance mRNA vaccine efficacy in public health interventions

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月27日

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  • Tielong Xu,
  • Ziqi Lin,
  • Yicheng Yu,
  • Muhammad Irfan,
  • Munir Ahmed,
  • Maya Septriana,
  • Twinky Zebrina Cysta Sumantri,
  • Anindini Winda Amalia,
  • Bin Zheng

摘要

Background

While mRNA vaccines represent a transformative platform for infectious disease control, their efficacy in antigen-presenting cells (APCs) remains vulnerable to endogenous regulatory networks, particularly microRNA (miR)-mediated translational suppression. This study addresses a critical gap in current vaccine design paradigms by systematically investigating host miR interference – an understudied barrier to robust antigen production.

Main text

APCs express cell-type-specific miR repertoires capable of binding vaccine mRNAs through conserved seed sequences, as evidenced by synthesis of experimental data from 67 studies demonstrating miR-mediated repression of exogenous transcripts. To decode these inhibitory interactions, the commentary proposes an integrated multi-omics framework combining Argonaute immunoprecipitation with crosslinking-based miR-mRNA interactome sequencing, enabling precise mapping of miR-vaccine mRNA binding events in vaccine-transfected APCs. Furthermore, the commentary suggests two actionable strategies for evading miR interference: (1) Synonymous codon optimization at seed-match regions, achieving binding energy reduction while preserving antigenicity through degeneracy of genetic coding; (2) Targeted co-delivery of miR inhibitors. By bridging host RNA biology and vaccine engineering, this work provides a blueprint for developing miR-resistant mRNA vaccines for public health interventions.

Conclusions

miRs may inhibit mRNA vaccine translation in APCs, potentially reducing antigen production and weakening the resulting immune response. To address this, next-generation mRNA vaccines should incorporate “miR-proofing” strategies during design to avoid miR interference.

Graphical Abstract