Roles and Applications of Red Blood Cell-Derived Extracellular Vesicles in Health and Diseases

Abstract

Red blood cell-derived extracellular vesicles (RBCEVs) are vesicles naturally produced by red blood cells and play multiple roles such as acting as cell-to-cell communication messengers in both normal physiological and diseased states. RBCEVs are highly promising delivery vehicles for therapeutic agents such as biomolecules and nucleic acids as they are easy to source, safe, and versatile. RBCEVs autonomously target the liver and pass the blood–brain barrier into the brain, which is highly valuable for the treatment of liver and brain diseases. RBCEVs can be modified by various functional units, including various functional molecules and nanoparticles, to improve their active targeting capabilities for tumors or other sites. Moreover, the RBCEV level is significantly shifted in many diseased states; hence, they can also serve as important biomarkers for disease diagnoses. It is clear that RBCEVs have considerable potential in multiple medical applications. In this review, we briefly introduce the biological roles of RBCEVs, presented interesting advances in RBCEV applications, and discuss several challenges that need to be addressed for their clinical translation.

Extracellular Vesicles as New Players in Drug Delivery: A Focus on Red Blood Cells-Derived EVs

“…Indeed, EVs produced from RBCs are reported to be different when produced naturally in vivo, released ex vivo during blood bag storage, or produced in vitro by chemical treatments [ 156 ]. According to Yang et al, RBCEVs lack cytoskeletal components such as spectrin and actin, whereas they are relatively enriched in connexins and lipid raft markers [ 157 ]. Thangaraju et al compared about 30 papers reporting the composition of RBCEVs obtained after different procedures of isolation/production and in different physiological/pathological conditions [ 4 ]; while Chiangjong et al made a deep comparison of the components of the parental cells (RBCs) and those of the derived vesicles (RBCEVs) [ 150 ].…”

“…RBCEVs are naturally produced during the RBC’s life and are released into circulation, where they can interact with numerous tissues and/or cells to influence their functions. RBCEVs can play roles both in physiological and pathological conditions, but if the RBCEV level in healthy states is assumed to be normal, their level is supposed to be raised with aging or under other diseased or stressed conditions [ 157 ].…”

Surface-enhanced Raman scattering (SERS) and tip-enhanced Raman scattering (TERS) in label-free characterization of erythrocyte membranes and extracellular vesicles at the nano-scale and molecular level

“…14 REVs are derived from RBCs, but the composition of their membranes is not identical. According to Yang et al, 15 in REVs, cytoskeletal proteins such as spectrin, actin, and bands 4.1, 4.2, and 4.9 are partially or even completely absent, but glycosylphosphatidylinositol (GPI) connexins and lipid raft markers such as ganglioside M1 or stomata are relatively enriched. REVs carry a variety of proteins, as well as metabolites, cytokines, and growth factors that influence cellular function and signalling.…”

“…The CD47 protein enables REVs to escape macrophage clearance. REVs' cytosol contains heat shock proteins (HSP70, HSP90) attached to antibodies involved in antigen anchoring, multivesicular body (MVB) formation proteins (Alix, TSG101) engaged in exosomal release 15 and specific proteins such as denaturated hemoglobin or enzymes (carbonic anhydrase, acetylcholinesterase 16 ) (Fig. 1A).…”

“…Similar to RBC membranes, REVs' membranes contain membrane-associated proteins (stomatin, flotillin), glycoproteins (glycophorin, Gp) and anion transport proteins (Band 3). 15 Amino acids (AAs), the building blocks of proteins, are also a crucial component of extracellular vesicles. 16 Modern proteomic techniques such as mass spectrometry have been instrumental in identifying many membrane proteins in EVs, shedding light on their molecular composition and function.…”