In vivo immune engineering via mRNA therapeutics: reprogramming the post-infarction cardiac microenvironment

Area of Science:

• Cardiovascular Immunology
• Nucleic Acid Therapeutics
• Biotechnology

Background:

• Myocardial infarction (MI) triggers a biphasic immune response critical for cardiac repair or fibrosis.
• Current therapies lack precise temporal and spatial control over this immune response.
• Nucleoside-modified messenger RNA (mRNA) encapsulated in lipid nanoparticles (LNPs) presents a novel platform for transient cardiac immune modulation.

Purpose of the Study:

• To explore interdisciplinary advancements in mRNA technology and cardiac immunology for treating myocardial infarction.
• To review strategies for mRNA design, immune cell reprogramming, LNP delivery optimization, and clinical translation.
• To propose a framework for personalized cardiac immune reprogramming.

Main Methods:

• Review of mRNA design strategies including nucleoside modifications and purification.
• Investigation of trained immunity and epigenetic reprogramming in myeloid progenitor cells.
• Examination of immune cell reprogramming (myeloid and lymphoid lineages) and cardiomyocyte signaling.
• Discussion of lipid nanoparticle (LNP) delivery optimization, targeting, and immunogenicity.
• Outline of clinical translation standards, dosing strategies, and biomarker use.

Main Results:

• mRNA-LNP technology enables transient, non-integrating, and repeatable immune modulation in the injured heart.
• Strategies are being developed to circumvent innate immune sensing and reprogram immune cells.
• Optimization of LNP delivery and next-generation RNA payloads are advancing therapeutic potential.
• Clinical pipelines like AZD8601 and mRNA-0184 demonstrate translational progress.

Conclusions:

• mRNA-LNP technology holds significant promise for precise immune modulation post-myocardial infarction.
• Integrating spatial transcriptomics, gender-stratified dosing, and multi-mRNA formulations can enable personalized cardiac immune reprogramming.
• This approach offers a viable pathway to improve outcomes after cardiac injury.