Optimization of Strategy for Modified mRNA Inducing Cardiac-Specific Expression in Mice

Area of Science:

• Biotechnology
• Molecular Biology
• Cardiovascular Research

Background:

• Lipid nanoparticle (LNP)-modified RNA (modRNA) enhances modRNA stability but often leads to liver accumulation.
• Optimizing modRNA delivery for targeted cardiac expression is crucial for therapeutic applications.
• Current strategies require refinement to balance cardiac efficacy and minimize off-target organ accumulation.

Purpose of the Study:

• To optimize strategies for enhancing cardiac expression efficiency of modRNA.
• To evaluate the biodistribution and cardiac specificity of modRNA delivered via different methods.
• To develop a liver-silencing modRNA to improve cardiac targeting.

Main Methods:

• Synthesis of Luciferase (Luc)-modRNA and a liver-silencing variant (122Luc modRNA).
• Administration of naked modRNA and modRNA-LNP formulations via intramyocardial injection.
• Bioluminescence imaging to quantify modRNA expression in the heart and liver.

Main Results:

• Intramyocardial injection of naked Luc modRNA resulted in high cardiac but low liver expression.
• Luc modRNA-LNP significantly increased cardiac (5-fold) and liver (15,000-fold) expression compared to naked modRNA.
• 122Luc-modRNA-LNP reduced liver signal to 0.17% with only a slight drop in cardiac signal.

Conclusions:

• Intramyocardial injection of naked modRNA achieves effective cardiac-specific expression.
• Liver-silencing modRNA (122modRNA-LNP) enhances cardiac expression specificity by reducing liver accumulation.
• This strategy offers a promising approach for targeted cardiac gene delivery using modRNA-LNP.