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.
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.
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.

© 2025. The Author(s).