Abstract Body: Introduction: Inflammation and fibrosis following cardiac injury drive the progression of heart failure (HF) progression, yet effective therapies remain limited. Adipocyte Enhancer-Binding Protein 1 (AEBP1) is upregulated in HF patients and associated with adverse cardiac remodeling. Apoptotic mesenchymal stem cell-derived nanovesicles (ANV) possess anti-inflammatory properties and serve as efficient drug delivery platforms. However, whether combining ANV with AEBP1-targeting strategies confers synergistic therapeutic benefits remains unknown.
Hypothesis: We hypothesize that targeted delivery of AEBP1-silencing siRNA via engineered nanovesicles will selectively accumulate in injured cardiomyocytes, suppress inflammation and fibrosis, and improve cardiac function.
Methods: ANV were conjugated with iron oxide magnetic particles and anti-myosin light chain 3 (MLC3) antibody for delivery to the injured myocardium, then loaded with AEBP1-targeting siRNA, producing ANVP-siAEBP1. Angiotensin II (Ang II)-treated iPSC-derived atrial cardiomyocytes (iPSC-aCMs) and Ang II pump-implanted mice were used as in vitro and in vivo cardiac injury models. Cardiac function, biodistribution, and molecular remodeling were evaluated following treatment.
Results: MLC3 expression was elevated in HF patient tissues (p < 0.01) and Ang II-treated iPSC-aCMs (p < 0.0001), confirming its utility as an injury-targeting marker. AEBP1 expression was upregulated in HF tissues (p < 0.001) and in both in vitro and in vivo models (p < 0.01), accompanied by increased fibrosis markers (p < 0.01). ANVP-siAEBP1 reduced intracellular AEBP1 expression in vitro (p < 0.01) and demonstrated enhanced cardiac accumulation in vivo, as confirmed by ex vivo imaging (p < 0.05). Treatment significantly reduced pro-inflammatory cytokines (IL-1β, TNF-α, and iNOS; p < 0.001), attenuated fibrosis (p < 0.01), and improved ejection fraction (p < 0.0001).
Conclusion: ANVP-siAEBP1 effectively targets injured cardiomyocytes to suppress inflammation and fibrosis and restore cardiac function, establishing a promising next-generation therapeutic platform for cardiac injury.