Osaka University Graduate School of Medicine Suita, Osaka, Japan
Abstract: The application of messenger RNA (mRNA) has great potential for the treatment of heart failure. While lipid nanoparticles (LNPs) have proven to be effective vehicles for mRNA delivery, optimal administration methods for targeting the heart remain poorly understood. Here, we investigated the efficacy of transcatheter intracoronary (IC) administration compared to intravenous (IV) and intramyocardial (IM) administration as a method to deliver mRNA-LNPs to the heart. We evaluated these administration methods in both healthy and ischemia-reperfusion (I/R) rabbit hearts using fluorescence (ATTO 700)-labeled LNPs encapsulating Firefly Luciferase (FLuc) mRNA to confirm in vivo distribution. LNP accumulation and FLuc expression in the heart were analyzed by in vivo imaging system (IVIS) 4 hours after administration and followed by immunohistochemical analysis. In the healthy hearts, IVIS spectrum data revealed the highest LNP accumulation in the IM group, followed by the IC and IV groups, respectively. On the other hand, FLuc expression was significantly higher in the IC group than in the IV group and it was comparable to the IM group. Notably, the IC group showed widespread FLuc expression throughout the heart, while the IV group had no expression and the IM group showed strong expression only at the injection sites. Histological analysis revealed that FLuc-expressing cells were observed in cardiomyocytes, endothelial cells, smooth muscle cells, and fibroblasts. In the I/R hearts, IVIS spectrum data showed high FLuc expression in the remote area only in the IC group, although all administration methods resulted in robust LNP accumulation and FLuc expression within the infarcted area. Histological analysis revealed that a large number of cardiomyocytes in the infarcted area expressed FLuc in all administration groups, but only the IC group showed the high FLuc expression in the remote area. These findings demonstrate that transcatheter IC administration effectively delivered mRNA-LNPs not only to the damaged area but also to the non-damaged area in the diseased heart, suggesting that IC administration is a clinically safe and useful method for mRNA-LNPs delivery to a wider range of cardiac tissue.
Funding Source: Japan Society for the Promotion of Science KAKENHI Grant Numbers JP23K08252
