Abstract Body: Background: Cardiac hypertrophy is a major pathological response to cardiovascular stress and is closely associated with the development of atrial fibrillation (AF) and arrhythmias. Consequently, it continues to have a significant global impact through cardiac remodeling processes. Long noncoding RNAs (lncRNAs) are increasingly implicated in cardiac remodeling; however, identifying functional lncRNAs and developing heart-specific delivery strategies remain major challenges.

Aims: This study aims to identify functional lncRNAs in AF and evaluate the therapeutic efficacy of cardiac-targeted magnetic nanovesicle-mediated silencing in hypertrophic remodeling.

Methods: Angiotensin II (Ang II)-treated AC16 cardiomyocytes and mice were used as in vitro and in vivo models of cardiac hypertrophy, respectively. MNV-siLINC00657 was constructed by electroporating siRNA targeting LINC00657 (siLINC00657) into mesenchymal stem cell-derived nanovesicles, which were subsequently conjugated to CD63/MLC3 antibody-functionalized iron oxide nanoparticles via click chemistry.

Results: GEO analysis suggested that LINC00657 is associated with cardiac hypertrophy and AF. LINC00657 expression was significantly increased in right atrial tissues from patients with AF (P<0.05), as well as in Ang II-treated AC16 cardiomyocytes (P<0.0001) and mouse hearts (P<0.0001). Regulation of LINC00657 expression via MNV-siLINC00657 markedly modulated cellular hypertrophy and altered miR-125a-3p levels, thereby influencing RhoA expression and supporting a role of the miR-125a-3p/RhoA axis in hypertrophy. In vivo cardiac delivery of MNV-siLINC00657 reduced hypertrophy (HW/BW ratio, P<0.01) and fibrosis (fibrosis area, P<0.0001), indicating its potential as a therapeutic strategy.

Conclusions: Our study identifies LINC00657 as a novel regulator of cardiac hypertrophy and supports cardiac-targeted magnetic nanovesicle-mediated LINC00657 silencing as a therapeutic strategy for AF.