Effective transcatheter intracoronary delivery of mRNA-lipid nanoparticles targeting the heart

• Published in: Journal of controlled release Vol. 381; p. 113623
• Main Authors: Handa, Kazuma, Kawamura, Masashi, Sasai, Masao, Matsuzaki, Takashi, Harada, Akima, Fujimura, Lisa, Whitehouse, Julia, Saito, Shunsuke, Komukai, Sho, Kitamura, Tetsuhisa, Fujishiro, Anri, Hirano, Kunio, Miki, Kenji, Miyagawa, Shigeru
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.05.2025
• Subjects: Animals; Cardiac tropism; Drug delivery system; Gene therapy; Heart failure; Intracoronary administration; Ischemia-reperfusion injury; Lipid nanoparticle; Lipids - administration & dosage; Lipids - chemistry; Liposomes; Luciferases, Firefly - genetics; Male; mRNA; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - therapy; Myocardium - metabolism; Myocardium - pathology; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Rabbits; RNA, Messenger - administration & dosage; Heart failure; Ischemia-reperfusion injury; Cardiac tropism; mRNA; Gene therapy; Drug delivery system; Intracoronary administration; Lipid nanoparticle
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2025.113623

Messenger RNA (mRNA) has great potential to provide innovative medical solutions in the treatment of heart failure. Although lipid nanoparticles (LNPs) are an established mRNA delivery system, effectively delivering LNPs to the heart remains a significant challenge. Here, we evaluated the efficacy of transcatheter intracoronary (IC) administration compared to intravenous (IV) and intramyocardial (IM) administration in normal and ischemia-reperfusion (I/R) model rabbit hearts using LNPs encapsulating Firefly Luciferase (FLuc) mRNA. In the normal model, IVIS spectrum data showed that FLuc expression was widespread throughout the heart in the IC group and was significantly higher than in the IV group, and comparable to the IM group, where it was highly expressed 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 model, FLuc expression was also significantly higher in the IC group than the IV group, and comparable to the IM group. Although FLuc expression was strongly observed in the infarct area in all three delivery groups, the IC group demonstrated the most widespread FLuc expression in the remote area. Histological analysis revealed significantly higher FLuc-expressing cells in the remote area in the IC group than in the other groups. IC administration effectively delivered mRNA-LNPs not only to the infarct area (damaged area) but also to the remote area (non-damaged area) in the diseased heart. Moreover, VEGF mRNA-LNP administration via the IC method to I/R model rabbit hearts significantly reduced the infarct area and attenuated the impairment of cardiac function caused by I/R injury compared to the other methods. Considering the invasiveness and clinically limited applications of IM administration, our study suggests that less invasive IC administration is a clinically safe and useful method for mRNA-LNP delivery to a wider range of myocardial tissue in the heart. [Display omitted] •mRNA-encapsulated lipid nanoparticles are a novel modality for heart failure therapy.•The efficacy of intracoronary (IC) administration to the heart remains unknown.•IC administration delivered mRNA to both the infarct area and the non-infarct area.•Widespread mRNA delivery significantly attenuated ischemia-reperfusion injury.