Molecular therapy. Nucleic acidsOct 6, 2026

Segmented mRNA tail regions with microRNA sites allow tissue-specific control for mRNA therapies

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 7, 2026

Abstract

Insertion of miR-122 or miR-142 target sites at various positions within the poly(A) tail suppressed luciferase expression in non-target cells.

Segmented poly(A) tail variants can serve as gene-specific regulatory elements for synthetic mRNAs.
The effectiveness of miR target sites for gene regulation depends on their position within the poly(A) tail.
Incorporating multiple miR target sites can achieve selective silencing in non-target cells while preserving expression in intended cells.
The order of miR target sites is important for achieving optimal silencing effects, a factor not seen in constructs with only two target sites.
These findings suggest that the poly(A) tail can be engineered for precise, cell-type-selective regulation in mRNA therapies.

Simplified

Targeted delivery and controlled expression of mRNA encapsulated by lipid nanoparticles (mRNA-LNPs) are critical for the development of safe and effective mRNA medicines. However, efficient post-delivery regulation of mRNA-LNP expression remains challenging, and conventional approaches largely rely on modifying the 3' UTR at the expense of other regulatory elements. In this study, we engineered segmented poly(A) tail variants that function as gene-specific regulatory elements for synthetic mRNAs, providing an alternative regulatory module that preserves UTR integrity. Insertion of miR-122 or miR-142 target sites (MTSs) at various positions within the poly(A) tail suppressed luciferase expression in non-target cells in vitro and in vivo in a position-dependent manner. Furthermore, by incorporating triple-MTS sequences for miR-142, miR-126, and miR-148a in all possible combinations at the 5' end of the poly(A) tail, we identified specific arrangements that simultaneously reduced luciferase activity in three non-target hepatic cell types while preserving robust expression in hepatocytes. MTS insertion order proved critical for optimal silencing, highlighting a design parameter not observed in dual-MTS constructs. These findings establish the poly(A) tail as a programmable platform for cell-type-selective regulation, complementing tissue-tropic LNPs and expanding the toolbox for mRNA therapeutic design.