Transcatheter intracoronary delivery of LNP encapsulating VEGF mRNA efficiently attenuates ischemia-reperfusion-injured cardiac dysfunction

Abstract Background Myocardial infarction is the leading cause of death worldwide. Despite reperfusion therapy, long-term heart failure due to ischemia-reperfusion (I/R)-injured cardiac dysfucntion remains a critical challenge. Advances in mRNA technology offer significant potential for novel therapeutic strategies in heart failure treatment, with lipid nanoparticles (LNPs) being the most promising drug delivery systems. Intravenous (IV) administration of mRNA-LNPs has poor delivery efficiency to the heart, whereas intramuscular (IM) administration requires thoracotomy and has limited access to direct injection sites. Intracoronary (IC) administration presents a less invasive and potentially effective clinical delivery method, but its efficacy remains unclear. Purpose This study aimed to investigate whether IC administration efficiently delivers mRNA-LNPs to the heart, and whether this method attenuates cardiac dysfunction caused by I/R injury. Methods White rabbits underwent left thoracotomy followed by left coronary artery ligation and subsequent reperfusion after one hour to establish an I/R injury model. Firefly luciferase (FLuc) mRNA-LNPs (25 µg/kg) were administered via IV, IC, or IM methods, and hearts were harvested after four hours. mRNA expression and distribution were evaluated using IVIS and immunohistochemistry. To investigate the role of distribution differences in attenuating I/R injury, VEGF mRNA-LNPs (25 µg/kg) were administered via IV, IC, or IM methods, and cardiac function was evaluated after two weeks. Results When FLuc mRNA-LNPs were administered to I/R model rabbits (Fig. 1A), IC administration resulted in significantly higher FLuc expression than IV administration and was comparable to IM administration (Fig. 1B). Histological analysis further revealed that IC administration resulted in substantial FLuc expression not only in the infarcted area but also in the remote area (Fig. 1C). When VEGF mRNA-LNPs were administered to the I/R model rabbits (Fig. 2A), both IV and IM administration slightly attenuated cardiac dysfunction compared to the saline group, but IC administration demonstrated significant cardioprotective effects (Fig. 2B). Histological analysis showed that IC administration not only reduced the total infarct size, including the border area, but also significantly attenuated fibrosis in the remote area, which was not effectively suppressed by IV and IM administrations (Fig. 2C). Angiogenesis in the border area increased with all administration methods, but in the remote area, significant angiogenesis was observed only with IC administration (Fig. 2D). Conclusion IC administration of mRNA-LNPs effectively delivered mRNA not only to the infarcted area but also to the remote area, leading to superior attenuation of I/R-injured cardiac dysfunction compared to IV and IM administration. Clinically, this minimally invasive IC approach may serve as a promising strategy for targeted delivery of mRNA-LNPs to the heart.Figure 1:FLuc-mRNA experiment Figure 2:VEGF-mRNA experiment