A novel mRNA Lipid Nanoparticle Therapy Improves Heart Failure Phenotype and Suppresses Endothelial-Mesenchymal Transition In Vitro

Abstract

ObjectivesTo evaluate the therapeutic potential of BMP-7 mRNA-lipid nanoparticle formulation in attenuating cardiac fibrosis and improving function in non-ischemic heart failure, and to assess its impact on endothelial phenotype and function under pro endothelial-to-mesenchymal transition (EndMT) conditions. BackgroundDespite advances in neurohormonal blockade, heart failure (HF) progression remains driven in part by fibrotic remodeling. Endothelial-to-mesenchymal transition (EndMT) has emerged as a contributor to myocardial fibrosis, while recent work suggests endothelial phenotypic plasticity may also participate in myocardial recovery. Bone morphogenetic protein-7 (BMP-7) is a known anti-fibrotic regulator, but effective therapeutic delivery strategies remain limited. MethodsA patent pending, custom-designed BMP-7 mRNA formulated in lipid nanoparticles (AET-1978) was administered subcutaneously in a murine model of non-ischemic HF induced by L-NAME and angiotensin II. Cardiac function and fibrosis were assessed by echocardiography and histology. In an invitro EndMT model, human umbilical vascular endothelial cells (HUVECs) were treated with BMP-7 mRNA and endothelial and mesenchymal morphology, and markers were assessed along with endothelial functional tests. ResultsAET-1978 therapy significantly improved left ventricular systolic and diastolic function and reduced myocardial fibrosis compared with untreated HF mice, without evidence of renal or hepatic toxicity. In vitro, BMP-7 mRNA delivery restored endothelial morphology, suppressed EndMT-associated mesenchymal and profibrotic marker expression while preserving nitric oxide production, lipoprotein uptake, and angiogenic capacity of the HUVECs. ConclusionsA novel formulation of BMP-7-mRNA-LNP called AET-1978 represents a novel, transient, non-integrating strategy to attenuate fibrotic remodeling and improve cardiac function in heart failure, with supportive evidence of being anti endothelial to mesenchymal transition. HighlightsO_LIA novel BMP-7 mRNA-lipid nanoparticle formulation delivered as a subcutaneous injection attenuated myocardial fibrosis and improved systolic and diastolic function in a murine model of non-ischemic heart failure. C_LIO_LIBMP-7 mRNA therapy preserved endothelial phenotype and suppressed endothelial-to-mesenchymal transition in an in vitro platform of human umbilical vascular endothelial cells. C_LIO_LIBMP-7 mRNA therapy preserved endothelial function including restoration of nitric oxide production, lipoprotein uptake, and angiogenic capacity in vitro. C_LIO_LIThis study introduces AET-1978, a transient, non-integrating mRNA therapeutic platform, as a novel approach to target residual fibrotic pathways in heart failure using a clinically scalable delivery route. C_LI