Engineered Extracellular Vesicle-Based Therapies for Valvular Heart Disease.

Introduction: Valvular heart disease represents a significant burden to the healthcare system, with approximately 5 million cases diagnosed annually in the US. Among these cases, calcific aortic stenosis (CAS) stands out as the most prevalent form of valvular heart disease in the aging population.  CAS is characterized by the progressive calcification of the aortic valve leaflets, leading to valve stiffening. While aortic valve replacement is the standard of care for CAS patients, the long-term durability of prosthetic devices is poor, calling for innovative strategies to halt  or reverse disease progression. Here, we explor the potential use of novel extracellular vesicle (EV)-based nanocarriers for delivering molecular payloads to the affected valve tissue. This approach aims to reduce inflammation and potentially promote resorption of the calcified tissue.

Methods: Engineered EVs loaded with the reprogramming myeloid transcription factors, CEBPA and Spi1, known to mediate the transdifferentiation of committed endothelial cells into macrophages. We evaluated the ability of these engineered EVs to deliver DNA and transcripts encoding CEBPA and Spil into calcified aortic valve tissue obtained from patients undergoing valve replacement due to aortic stenosis. We also investigated whether these EVs could induce the transdifferentiation of endothelial cells into macrophage-like cells.

Results: Engineered EVs loaded with CEBPA + Spi1 were successfully derived from human dermal fibroblasts. Peak EV loading was found to be at 4 h after nanotransfection of donor cells.  These CEBPA + Spi1 loaded EVs effectively transfected aortic valve cells, resulting in the successful induction of transdifferentiation, both in vitro with  endothelial cells and ex vivo with valvular endothelial cells, leading to the development of anti-inflammatory macrophage-like cells.

Conclusions: Our findings highlight the potential of engineered EVs as a next generation nanocarrier to target aberrant calcifications on diseased heart valves. This development holds promise as a novel therapy for high-risk patients who may not be suitable candidates for valve replacement surgery.

Supplementary information: The online version contains supplementary material available at 10.1007/s12195-023-00783-x.