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

Myocardial infarction (MI) initiates a biphasic immune response, which plays a critical role in determining whether the heart undergoes adaptive repair or progresses to pathological fibrosis. Traditional drug and gene therapy delivery systems have been insufficient in precisely modulating this intricate sequence of events in both temporal and spatial dimensions. In recent years, nucleoside-modified messenger RNA (mRNA) technology, encapsulated within lipid nanoparticles (LNPs), has emerged as a novel platform for delivering transient, non-integrating, and repeatable immune modulation to the injured heart. This article will explore recent interdisciplinary advancements in mRNA technology and cardiac immunology from five distinct perspectives. (i) Strategies for mRNA design, encompassing nucleoside modifications and purification techniques, are primarily aimed at circumventing detection by innate immune sensors within inflamed myocardial tissue; (ii) The concept of trained immunity is investigated, focusing on how transient expression of mRNA encoding epigenetic editors may potentially erase pathological epigenetic imprints in myeloid progenitor cells; (iii) Immune cell reprogramming is examined, addressing the myeloid lineage through macrophage polarization and the degradation of neutrophil extracellular traps via metabolic and transcriptional reprogramming, as well as the lymphoid lineage through transient CAR-T cells, in situ-induced regulatory T cells, and regulatory B cells, with an emphasis on the role of cardiomyocytes as paracrine signaling hubs; (iv) The optimization of lipid nanoparticle (LNP) delivery technology is discussed, including SORT-based organ-targeting strategies and the immunogenicity challenges faced by lipid carriers in ischemic tissues, alongside the development of next-generation self-amplifying RNA payloads; (v) Standards for clinical translation are outlined, involving representative pipelines such as AZD8601 and mRNA-0184, strategies for repeated dosing from an immunological perspective, and the use of biomarkers to guide precision dosing timing. In conclusion, we propose an innovative framework that integrates spatial transcriptomics, gender-stratified dosing strategies, and multi-mRNA formulation technology, with the objective of establishing a viable pathway for personalized cardiac immune reprogramming.