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More specifically, Dox induces oxidative stress and causes pro\u2010apoptotic 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\u2010selective modRNA translational system (cmSMRTs) is encapsulated in lipid nanoparticles for intravenous (IV) delivery to enable systemic administration with high cardiac selectivity via microRNA\u2010guided translational control (miR143 and miR122) to suppress off\u2010target expression in other tissues, including tumors. In vitro, AC treatment preserved sarcomere structure, calcium handling, and mitochondrial function in Dox\u2010treated human induced pluripotent stem cell (iPSC)\u2010derived CMs. Moreover, weekly IV delivery of this modRNA prevented cardiac dysfunction, fibrosis, and atrophy in chronic Dox\u2010induced cardiotoxicity models. Notably, this cardioprotection is achieved without either compromising Dox's anti\u2010tumor efficacy or producing overall toxicity. These findings establish cmSMRTs 143\u2010122 as a minimally invasive, cardiac\u2010selective mRNA therapy platform with strong potential to prevent chemotherapy\u2010induced cardiotoxicity.<\/jats:p>","DOI":"10.1002\/advs.202510543","type":"journal-article","created":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T01:00:23Z","timestamp":1768611623000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Systemic Selective Modified mRNA Delivery Platform for Preventing Chemotherapy\u2010Induced Cardiotoxicity"],"prefix":"10.1002","volume":"13","author":[{"given":"Jimeen","family":"Yoo","sequence":"first","affiliation":[{"name":"Cardiovascular Research Institute Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Black Family Stem Cell Institute Icahn School of Medicine at 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