Nature biomedical engineeringNov 3, 2025

A lab model for testing fat-based mRNA delivery predicts how well it works in the heart

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

A human cardiac microphysiological system identified acid-degradable PEG-LNPs that improved heart mRNA transfection and reduced liver uptake in mice.

Evidence

This platform-screening experiment used human induced pluripotent stem cell cardiomyocyte 3D micromuscles with Cre-reporter readouts, then validated luciferase and CRE mRNA LNP delivery in Ai6 mice.

Caveat

The evidence supports screening and delivery performance for tested LNP-mRNA complexes, not therapeutic benefit in cardiac disease.

Simplified

Gene transfection via lipid nanoparticle (LNP)-mRNA complexes have tremendous potential for treating cardiac diseases. However, the transfection efficiency is poor and there is a lack of in vitro screening systems that predict transfection efficacy. Here we demonstrate a method for identifying LNP-mRNA complexes that diffuse efficiently within 3D cardiac micromuscles and transfect cardiomyocytes with high efficiency, using a phenotypic cardiac microphysiological system (MPS) constructed from a human induced pluripotent stem cell cardiomyocytes Cre-reporter line. LNP formulations containing an acid-degradable PEG-lipid had enhanced diffusion and gene editing efficiency in the cardiac MPS. The in vivo delivery of LNP-mRNA complexes, including luciferase and CRE mRNA, into Ai6 mice confirmed the cardiac MPS screening outcomes. Acid-degradable PEG-LNPs achieved notably superior transfection in the heart with reduced off-target liver uptake compared with standard LNP formulations. The cardiac MPS showed strong LNP transfection in vitro and pinpointed a promising formulation for in vivo mRNA delivery to the heart.