Targeted intervention in obesity-associated atrial fibrosis using nanoparticle-loaded fusion protein

The association between obesity and atrial fibrillation (AF) has garnered increasing attention. Obesity is a significant risk factor for cardiovascular diseases and promotes the occurrence of AF through multiple mechanisms. This study aims to explore the molecular mechanisms of obesity-induced AF using GLP-1R/GIPR dual-target agonist fusion protein (Fc) loaded into adipose-derived mesenchymal stem cell (ADSC) exosome-liposome hybrid nanoparticles (LE@Fc NPs). We successfully constructed and purified the Fc, verifying its purity and functional activity through SDS-PAGE and UV absorption spectroscopy. The fusion protein was then loaded into nanovesicles, and their morphology, size, and stability were assessed using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and dynamic light scattering (DLS). In vitro experiments demonstrated that LE@Fc NPs exhibit high fusion efficiency and targeted delivery capability. In vivo experimental results show that LE@Fc NPs significantly inhibit Ferroptosis in the epicardial adipose tissue (EAT) of obese mice (iron content: 3.69 ± 0.36 vs. 0.88 ± 0.09), by restoring GSH levels (0.45 ± 0.08 vs. 0.87 ± 0.08) and Gpx4 expression (0.32 ± 0.06 vs. 1.01 ± 0.16), and reducing ROS (12.01 ± 0.95 vs. 2.68 ± 0.17), MDA (3.17 ± 0.29 vs. 0.95 ± 0.09), and 4-HNE (3.74 ± 0.51 vs. 0.91 ± 0.09) levels. Furthermore, LE@Fc NPs treatment significantly improved the inflammatory response (IL-1β: 44.08 ± 3.74 vs. 12.07 ± 0.65, IL-6: 515.59 ± 47.70 vs. 288.43 ± 16.81, MCP-1: 1401.04 ± 194.88 vs. 600.28 ± 45.54, TNF-α: 39.96 ± 2.48 vs. 18.01 ± 0.85). LE@Fc NPs also reduced atrial fibrosis, thereby effectively lowering the incidence of AF. Echocardiography and electrocardiogram monitoring revealed that LE@Fc NPs treatment significantly improved atrial remodeling and reduced the occurrence of AF in obese mice. In addition, LE@Fc NPs significantly improved obesity-induced systemic inflammation and metabolic disorders. In conclusion, LE@Fc NPs show great potential for the treatment of obesity-related AF.

Atrial fibrillation; Exosome-liposome hybrid nanovesicles; Ferroptosis; GLP-1R/GIPR dual-target agonist; Inflammatory response; Obesity.