Magnetically guided apoptotic mesenchymal stem cell-derived nanovesicles for the modulation of pathological...

Inflammation and fibrosis can arise as consequences of cardiac injury and further contribute to the progression of heart failure (HF) and arrhythmias. Despite ongoing therapeutic advancements, effective treatments to modulate these pathological processes remain limited. To overcome these limitations, we developed a multifunctional nanotherapeutic system using apoptotic mesenchymal stem cell-derived nanovesicles (ANV) as biocompatible and immunomodulatory delivery platforms for small interfering RNA (siRNA) targeting the adipocyte enhancer binding protein 1 (AEBP1). ANV are constructed via an extrusion method and loaded with AEBP1-targeting siRNA (siAEBP1) through electroporation to form ANV-siAEBP1. The vesicles are then incubated with antibody-conjugated iron oxide magnetic nanoparticles (MNP), forming the ANVP-siAEBP1 complex. For targeted delivery to the injured myocardium, an anti-myosin light chain 3 (MLC3) antibody is incorporated, based on injury-associated MLC3 exposure for localized accumulation of ANVP-siAEBP1 at the injury site. Upon localization, intracellular release of siAEBP1 silences AEBP1 expression, downregulates pro-fibrotic signaling, and mitigates cardiac fibrosis. Simultaneously, the intrinsic anti-inflammatory effects of ANV prevent excessive inflammatory responses. This dual mechanism of action results in synergistic therapeutic effects, significantly attenuating both inflammation and fibrosis with enhanced targeting efficiency. Collectively, this engineered four-in-one nanovesicle platform offers a promising strategy for next-generation precision therapeutics in cardiac injury. STATEMENT OF SIGNIFICANCE: Cardiac injury often leads to heart failure, yet current therapies lack precise targeting and long-term effectiveness. Here, we develop a multifunctional nanocarrier system that enables targeted delivery of siRNA to injured cardiac tissue. This system combines nanoscale engineering with biological functionality, allowing gene regulation that reduces inflammation and fibrosis. By silencing adipocyte enhancer-binding protein 1 (AEBP1) via siRNA, our platform suppresses fibrosis and improves cardiac function in vivo, further supported by the inflammation-regulating properties of the nanovesicle. This work demonstrates how engineered biomaterials can be designed to control cellular responses and disease progression, offering a promising strategy for targeted gene therapy and cardiac repair.