Nature nanotechnologyMar 2, 2026

Using stable mRNA structures to improve cell processing and protein production

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 28, 2026

Abstract

Essence

Metal-assisted rigid mRNA folding in lipid nanoparticles boosted intracellular processing, protein output, and downstream gene editing.

Evidence

Preclinical mRNA-LNP platform experiments found specific metals increased protein expression by up to 7.3-fold versus control mRNA and enabled durable single-dose Pcsk9 editing after intravenous delivery.

Caveat

This is preclinical delivery-platform evidence rather than human therapeutic outcome data.

Simplified

The application of messenger RNA (mRNA) beyond infectious diseases is challenged by inefficient protein production. Whereas the engineering of secondary mRNA structures has been shown to increase mRNA half-life, it remains unclear whether tertiary mRNA structures influence therapeutic efficacy. Here we develop a metal-ion-assisted RNA folding (MARF) strategy and show that, when delivered with lipid nanoparticles (LNPs), specific metals promote mRNA folding architectures that result in the amplification of protein expression by up to 7.3-fold compared with control mRNA. This effect is due to altered mechanical interactions between the mRNA LNPs and the surrounding biosystem, resulting in enhanced intracellular processing and prolonged retention of delivered mRNA in targeted cells. Administered intravenously, MARF LNPs achieved effective and durable genome editing of the clinically relevant Pcsk9 gene through treatment with a single dose. Overall, this work provides a new MARF technology for more effective mRNA therapy and highlights the potential of mechanical cues in designing nanoparticles for improved mRNA delivery.