Cell-Specific mRNA Therapeutics for Cardiovascular Diseases and Regeneration

Abstract

Cardiovascular diseases (CVDs) represent a significant global health burden, demanding innovative therapeutic approaches. In recent years, mRNA therapeutics have emerged as a promising strategy to combat CVDs effectively. Unlike conventional small-molecule drugs, mRNA therapeutics enable the direct modulation of cellular functions by delivering specific mRNA molecules to target cells. This approach offers unprecedented advantages, including the ability to harness endogenous cellular machinery for protein synthesis, thus allowing precise control over gene expression without insertion into the genome. This review summarizes the current status of the potential of cell-specific mRNA therapeutics in the context of cardiovascular diseases. First, it outlines the challenges associated with traditional CVD treatments and emphasizes the need for targeted therapies. Subsequently, it elucidates the underlying principles of mRNA therapeutics and the development of advanced delivery systems to ensure cell-specificity and enhanced efficacy. Notably, innovative delivery methods such as lipid nanoparticles and exosomes have shown promise in improving the targeted delivery of mRNA to cardiac cells, activated fibroblasts, and other relevant cell types. Furthermore, the review highlights the diverse applications of cell-specific mRNA therapeutics in addressing various aspects of cardiovascular diseases, including atherosclerosis, myocardial infarction, heart failure, and arrhythmias. By modulating key regulatory genes involved in cardiomyocyte proliferation, inflammation, angiogenesis, tissue repair, and cell survival, mRNA therapeutics hold the potential to intervene at multiple stages of CVD pathogenesis. Despite its immense potential, this abstract acknowledges the challenges in translating cell-specific mRNA therapeutics from preclinical studies to clinical applications like off-target effects and delivery. In conclusion, cell-specific mRNA therapeutics have emerged as a revolutionary gene therapy approach for CVD, offering targeted interventions with the potential to significantly improve patient outcomes.

Keywords: AAV vectors; cardiovascular disease; exosomes; gene therapy; heart failure; lipid nanoparticles; mRNA therapeutics; modRNA.

Figure 1

Cardiomyocyte-specific expression of modRNA. (A) CM-specific modRNA expression regulatory constructs. (B) Representative image of CM-specific Cre modRNA delivery and GFP expression or mT to mG switch in CMs.

Figure 2

Cell-specific modRNA delivery platforms in the heart. SMRTs platform to target cardiomyocytes or noncardiomyocytes (direct injection in myocardium) and in vivo CAR T-cell therapy to target activated fibroblasts in CVD (intravenous injections).