[Progress on the physiological functions and clinical applications of red blood cell-derived extracellular vesicles]

Red blood cell-derived extracellular vesicles (RBC-EVs) are one of the most abundant types of extracellular vesicles (EVs) in the blood, playing a crucial role in intercellular communication, disease progression, and medical applications. The structure of RBC-EVs differs from that of red blood cells (RBCs), characterized by phosphatidylserine externalization, reduced membrane proteins, and encapsulation of bioactive molecules such as hemoglobin and miRNAs. RBC-EVs primarily exist as microvesicles and exosomes, which are generated through membrane budding and the multivesicular bodies pathway, respectively. Their clearance in vivo mainly relies on phagocytosis by hepatic Kupffer cells. Physiologically, RBC-EVs maintain the normal physiological functions of RBCs by removing damaged and senescent signals from the RBC membrane, regulate organismal homeostasis through participation in nitric oxide balance and anticoagulant processes, and also engage in immune regulation and exert certain antiviral effects. Additionally, they serve as intercellular information carriers to function in various diseases. Endowed with advantages such as high biocompatibility and low immunogenicity, RBC-EVs have demonstrated enormous clinical application potential as carriers for small-molecule drugs (e.g., nucleic acids) in fields including hematological diseases, liver diseases, and cancer. This review systematically summarizes the composition and structure, biogenesis and clearance mechanisms, main physiological functions, clinical applications, and future prospects of RBC-EVs.