Circulating small extracellular vesicles in chronic kidney disease and vascular calcification: "Tiny packages with big biological mission".

Chronic kidney disease (CKD), a condition affecting over 850 million people worldwide, is a major global health issue. CKD leads to multimorbidities and disease complexity, expediting the aging process and increasing mortality rates-a phenomenon sometimes referred to as "renal senescence." The leading cause of death in patients with CKD is cardiovascular disease (CVD), accounting for one-third to one-half of all deaths, in stark contrast to cancer, which is the primary cause of death in the general population. While previous studies on kidney disease have focused extensively on urinary extracellular vesicles due to their potential as non-invasive diagnostic tools and their origin from kidney cells, our research highlighs the significance of circulating small extracellular vesicles (cEVs). We demonstrated that cEVs act as key mediators in the pathological intercellular and inter-organ communication between the kidneys and vascular smooth muscle cells (VSMCs). However, the biogenesis, cargo, and biological functions of cEVs remain incompletely understood under physiological and pathological conditions, including CKD. We identified microRNA (miRNA) transcriptomic signatures encapsulated in cEVs from CKD animal models, which were validated in human CKD samples. Notably, the depletion of specific miRNAs in CKD-derived cEVs promoted osteogenic differentiation of VSMCs and the deposition of calcium-phosphate crystals in vessels. In contrast, miRNAs enriched in cEVs from healthy individuals suppress these pathological processes, acting as a safeguard. These findings and future research could pave the way for the development of diagnostic and therapeutic platforms leveraging cEVs in nephrology.