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

## TL;DR

This paper introduces a new method to deliver modified mRNA to the heart to prevent heart damage caused by chemotherapy, without affecting the cancer treatment's effectiveness.

## Contribution

A minimally invasive, cardiac-selective modRNA delivery platform using lipid nanoparticles and microRNA-guided control is developed.

## Key findings

- AC modRNA delivery preserved heart cell structure and function in Dox-treated cells.
- Weekly IV modRNA delivery prevented heart dysfunction and damage in chronic Dox models.
- Cardioprotection was achieved without reducing Dox's anti-tumor effects or causing toxicity.

## 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.

In Yoo and Mainkar et al., we present a minimally invasive, CM‐selective modRNA delivery system encapsulated in lipid nanoparticles for intravenous (IV) administration. This platform enables selective cardiac translation of therapeutic modRNA but suppresses expression in off‐target tissues, including tumors. We show that our platform can prevent Dox‐induced cardiotoxicity without either compromising Dox's anti‐tumor efficacy or producing overall toxicity.