A Systemic Selective Modified mRNA Delivery Platform for Preventing Chemotherapy‐Induced Cardiotoxicity

ABSTRACT Doxorubicin (Dox) is a widely employed chemotherapeutic agent, but its use is clinically limited by dose‐accumulative cardiotoxicity. More specifically, Dox induces oxidative stress and causes pro‐apoptotic ceramide accumulation in cardiomyocytes (CMs). Acid ceramidase (AC) modified mRNA (modRNA) has been shown to reduce ceramide levels and protect the heart following ischemic injury; however, therapeutic modRNA applications have been hindered by the need for invasive delivery. Here, we present a platform for minimally intrusive transmission of modRNA to the heart. This CM‐selective modRNA translational system (cmSMRTs) is encapsulated in lipid nanoparticles for intravenous (IV) delivery to enable systemic administration with high cardiac selectivity via microRNA‐guided translational control (miR143 and miR122) to suppress off‐target expression in other tissues, including tumors. In vitro, AC treatment preserved sarcomere structure, calcium handling, and mitochondrial function in Dox‐treated human induced pluripotent stem cell (iPSC)‐derived CMs. Moreover, weekly IV delivery of this modRNA prevented cardiac dysfunction, fibrosis, and atrophy in chronic Dox‐induced cardiotoxicity models. Notably, this cardioprotection is achieved without either compromising Dox's anti‐tumor efficacy or producing overall toxicity. These findings establish cmSMRTs 143‐122 as a minimally invasive, cardiac‐selective mRNA therapy platform with strong potential to prevent chemotherapy‐induced cardiotoxicity.