Nanomicelle‐Based Multi‐mRNA Delivery Promotes Cardiac Repair After Myocardial Infarction

Pathological remodeling after myocardial infarction (MI) involves multifactorial mechanisms, highlighting the need for combinatorial therapeutic strategies. Synthetic mRNAs offer design flexibility and represent a modality particularly suitable for such approaches. To investigate this, five genes ( Hgf , Igf1 , Pdgfb , Cxcl12 , and Tgfβ1 ) were selected from a model in which extracellular vesicles secreted by human iPSC‐derived cardiomyocytes restored cardiac function. Synthetic mRNAs encoding these genes were delivered via polyplex nanomicelles by direct myocardial administration in mice with MI‐induced heart failure. Nanomicelles have been shown to provide stable encapsulation, enhanced local expression, and prolonged persistence. This treatment promoted angiogenesis via the PI3K–Akt–ETV4 axis, suppressed fibrosis via inhibition of the JNK/FOXO3 pathway, and enhanced repair by activating ERK signaling, together yielding multifaceted benefits, including tissue regeneration, improved contractility, and extended survival. These findings establish the therapeutic potential of multigene mRNA cocktail therapy for post‐MI heart failure and mark an important step toward developing new interventions for diseases characterized by complex remodeling.