Bioresorbable, Injectable In Situ-Formed Electroactive mRNA-Delivering Device for Precision Gene Therapy after Myocardial Infarction

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Abstract
Myocardial infarction (MI) causes irreversible cardiomyocyte loss and triggers inflammatory and fibrotic remodeling that promote the progression to heart failure. Although regenerative gene therapy offers a promising route to cardiac repair, clinical translation has been limited because of the lack of targeted, minimally invasive, and clinically scalable delivery strategies. Here we report an injectable, bioresorbable in situ-formed electroactive device that enables local mRNA delivery through the pericardial space, a clinically established route of access. Following administration, the formulation self-assembles into a transient conductive mRNA-carrying drape electrode over the injured heart, enabling in vivo electrotransfection, and is then bioresorbed, eliminating the need for retrieval. In animal models, the formulation was well tolerated, did not disrupt cardiac contractile activity, and enabled targeted mRNA transfer. In a mouse model of MI, localized delivery of vascular endothelial growth factor (VEGF-A) mRNA attenuated adverse remodeling, improved cardiac function (e.g., stroke volume and ejection fraction were fully recovered), and established a minimally invasive strategy for localized regenerative gene delivery to the injured heart.
Funding Information
  • Stiftelsen Anna-Lisa Rosenbergs fond för neurologisk forskning
  • Deutsche Forschungsgemeinschaft (507881424)

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