A minimal invasive modified mRNA delivery platform for targeting and protecting cardiomyocytes after ischemic heart or cardiotoxic agent injury

A major consequence of myocardial infarction (MI) induced ischemia or treatment with cardiotoxic agent is the permanent loss of functional cardiomyocytes (CMs). Therefore, there is an urgent need for therapeutics that will protect CM and prevent their irreversible destruction post injury. Recently, modified mRNA (modRNA) has emerged as a promising technology for cardiac therapeutic, but major obstacles concerning direct delivery to the heart and short-term expression have impeded progress. Here, we describe a novel platform allowing for durable and specific modRNA delivery directly to CM. Using modRNA design, CRISPR technology, and positively charged nanoparticles (PCNP), we created a CM-specific modRNA translational system, called CM SMRTs. We show that CM SMRTs translate exclusively in CMs within minutes after intravenous (IV) injection. Expression lasts for up to three days and can be replenished with repeated delivery for durable protein expression. IV injection of AC CM SMRTs 2.0 immediately reduces cell death and inflammation, decreases cardiac remodeling, and improves contractility after MI and prevent cardiac damage of Doxorobixin, a known cardiotoxic agent. Altogether, we describe a minimally invasive modRNA platform that enables repetitive, controlled, and cell-specific modRNA delivery exclusively to CMs, without the need for open chest surgery. The CM SMRT system can be used as a platform to identify novel therapeutic targets, evaluate gene function, and induce gene correction.