A microphysiological system for screening lipid nanoparticle-mRNA complexes predicts in vivo heart transfection efficacy.
basic_science · Level V
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- Record sourced from PubMed, PMID 41184608.
- Also identified by DOI 10.1038/s41551-025-01523-4.
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Abstract
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.