Nanomicelle-delivered multi-mRNA cocktail promotes cardiac repair and survival after myocardial infarction

Myocardial infarction (MI) leads to complex pathological remodeling, involving reactive oxygen species (ROS), inflammation, and profibrotic signaling, which single-drug therapies often fail to address effectively. This results in adverse ventricular remodeling and progressive heart failure. There's a critical need for combinatorial strategies that offer both mechanical support and sustained tissue repair. Synthetic mRNAs provide design flexibility for delivering multiple therapeutic genes simultaneously to tackle these multifaceted challenges.

Researchers selected five genes (Hgf, Igf1, Pdgfb, Cxcl12, Tgfβ1) previously identified from human iPSC-derived cardiomyocyte extracellular vesicles. Synthetic mRNAs encoding these genes were encapsulated in polyplex nanomicelles. This multi-mRNA cocktail was delivered by direct myocardial administration in mice with MI-induced heart failure. Nanomicelles were chosen for their stable encapsulation, enhanced local expression, and prolonged persistence, aiming for multifaceted cardiac repair.

The nanomicelle-based multi-mRNA treatment yielded multifaceted benefits in MI-induced heart failure mice. It significantly promoted angiogenesis via the PI3K-Akt-ETV4 axis. Fibrosis was suppressed through inhibition of the JNK/FOXO3 pathway, and cardiac repair was enhanced by activating ERK signaling. These combined effects led to tissue regeneration, improved contractility, and extended survival in the treated animals. The study establishes the therapeutic potential of multigene mRNA cocktail therapy for post-MI heart failure. > These findings mark an important step toward developing new interventions for diseases characterized by complex remodeling.