DNA in extracellular vesicles: biological and clinical aspects

Abstract

The study of extracellular vesicles (EVs), especially in the liquid biopsy field, has rapidly evolved in recent years. However, most EV studies have focused on RNA or protein content and DNA in EVs (EV-DNA) has largely been unnoticed. In this review, we compile current evidence regarding EV-DNA and provide an extensive discussion on EV-DNA biology. We look into EV-DNA biogenesis and mechanisms of DNA loading into EVs, as well as describe the particularly significant function of DNA-carrying EVs in the maintenance of cellular homeostasis, intracellular communication, and immune response modulation. We also examine the current role of EV-DNA in the clinical setting, specifically in cancer, infections, pregnancy, and prenatal diagnosis.

Trial registration: ClinicalTrials.gov NCT03217266.

Keywords: EV-DNA; cancer; cell-free DNA; extracellular vesicles; infection; liquid biopsies.

Fig. 1

Extracellular vesicle biogenesis and possible mechanisms of DNA uptake. Microvesicles and exosomes are prevalent types of extracellular vesicles in biofluids. Microvesicles are generated via direct outward plasma membrane budding, during which components of cytoplasm can be incorporated into vesicles (including DNA). Exosomes biogenesis includes inward invagination of plasma membrane and formation of early endosomes, which subsequently mature into late endosomes and eventually form multivesicular bodies containing intraluminal vesicles (ultimately released as exosomes). Formation of intraluminal vesicles involves sequestering of molecular cargo including cytoplasmic DNA, both genomic and mitochondrial. DNA damage caused by cellular stress can lead to its leakage from nucleus or mitochondrium, exposing DNA to cytoplasm and facilitating its shuttle to intraluminal vesicles or integration into microvesicles.