# Extracellular Vesicles in Calcific Aortic Valve Disease: From Biomarkers to Drug Delivery Applications

## TL;DR

Extracellular vesicles (EVs) can detect and monitor calcific aortic valve disease early and may deliver therapies to reduce disease progression.

## Contribution

This review explores EVs as both biomarkers and therapeutic delivery tools for calcific aortic valve disease.

## Key findings

- EVs carry disease-specific signatures like osteogenic proteins and inflammatory miRNAs, reflecting early CAVD processes.
- EVs in blood, urine, or saliva offer non-invasive diagnosis and long-term monitoring due to their stability.
- Engineered EVs delivering anti-calcific miRNAs reduced calcification in preclinical models.

## Abstract

Calcific aortic valve disease (CAVD) is a progressive disorder where molecular alterations occur long before visible calcification, making early biomarkers essential. Extracellular vesicles (EVs) have gained attention as stable biomarkers due to their lipid bilayer, which protects proteins, lipids, and RNAs, ensuring reliable detection even in archived samples. This review highlights the role of EVs as biomarkers and delivery tools in CAVD. EVs derived from valvular endothelial, interstitial, and immune cells carry disease-specific signatures, including osteogenic proteins (BMP-2, Annexins), inflammatory miRNAs (miR-30b, miR-122-5p), and lipid mediators. These reflect early pathogenic processes before macroscopic calcification develops. Their presence in minimally invasive samples such as blood, urine, or saliva facilitates diagnosis, while their stability supports long-term monitoring of disease progression and therapeutic response. Advances in purification and single-EV analysis increase specificity, though challenges remain in standardizing methods and distinguishing CAVD-derived EVs from those in atherosclerosis. Beyond diagnostics, engineered EVs show promise as therapeutic carriers. Delivery of anti-calcific miRNAs or combined RNA cargos has reduced calcification and inflammation in preclinical models. Overall, EVs act as molecular mirrors of CAVD, enabling early diagnosis, risk stratification, and novel therapeutic strategies. Yet, clinical translation requires technical refinement and validation of the disease-specific signatures.