Segmented poly(A) tails with microRNA target sites confer tissue-specific regulation for mRNA therapeutics.

Segmented poly(A) tails with microRNA target sites enable tissue-specific regulation of mRNA expression, with suppression observed in non-target cells in vitro and in vivo.

• Why it matters: Controlling mRNA expression after delivery is essential for safe and effective mRNA therapeutics, but current methods often compromise regulatory elements within the UTRs.
• What they did: Researchers engineered poly(A) tail variants containing microRNA target sites (MTSs), testing different arrangements and combinations of miR-122, miR-142, miR-126, and miR-148a MTSs in vitro and in vivo.
• The result: Optimal MTS arrangements reduced luciferase activity in three non-target hepatic cell types while maintaining strong expression in hepatocytes, demonstrating the poly(A) tail as a programmable platform for cell-specific regulation.