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

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.