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

Area of Science:

• Cardiology
• Oncology
• Biotechnology

Background:

• Doxorubicin (Dox) chemotherapy causes dose-dependent cardiotoxicity, limiting its clinical use.
• Doxorubicin-induced cardiotoxicity involves oxidative stress and ceramide accumulation in cardiomyocytes.
• Current mRNA therapies require invasive delivery, hindering widespread application.

Purpose of the Study:

• To develop a minimally invasive, cardiac-selective mRNA delivery system for preventing Doxorubicin-induced cardiotoxicity.
• To evaluate the efficacy of acid ceramidase (AC) modified mRNA (modRNA) delivered via a novel platform in preclinical models.

Main Methods:

• Developed a cardiac-selective mRNA translational system (cmSMRTs) using lipid nanoparticles for intravenous delivery.
• Utilized microRNA-guided translational control (miR143 and miR122) for enhanced cardiac targeting and reduced off-target expression.
• Assessed AC modRNA efficacy in vitro using Doxorubicin-treated human induced pluripotent stem cell-derived cardiomyocytes.
• Evaluated cmSMRTs 143-122 in chronic Doxorubicin-induced cardiotoxicity mouse models.

Main Results:

• In vitro, AC treatment preserved cardiomyocyte structure, calcium handling, and mitochondrial function.
• Intravenous delivery of AC modRNA via cmSMRTs prevented cardiac dysfunction, fibrosis, and atrophy in Doxorubicin-treated mice.
• The therapy demonstrated cardiac selectivity, with no compromise to Doxorubicin's anti-tumor efficacy or overall toxicity.

Conclusions:

• cmSMRTs 143-122 represents a promising, minimally invasive mRNA therapy platform for preventing chemotherapy-induced cardiotoxicity.
• This approach offers a potential strategy to improve the safety and tolerability of Doxorubicin treatment.
• The study highlights the potential of targeted mRNA delivery for managing treatment-related toxicities in cancer patients.