Red Blood Cell Extracellular Vesicle-Based Drug Delivery: Challenges and Opportunities

Abstract

Recently, red blood cell-derived extracellular vesicles (RBCEVs) have attracted attention for clinical applications because of their safety and biocompatibility. RBCEVs can escape macrophages through the binding of CD47 to inhibitory receptor signal regulatory protein α. Furthermore, genetic materials such as siRNA, miRNA, mRNA, or single-stranded RNA can be encapsulated within RBCEVs and then released into target cells for precise treatment. However, their side effects, half-lives, target cell specificity, and limited large-scale production under good manufacturing practice remain challenging. In this review, we summarized the biogenesis and composition of RBCEVs, discussed the advantages and disadvantages of RBCEVs for drug delivery compared with synthetic nanovesicles and non-red blood cell-derived EVs, and provided perspectives for overcoming current limitations to the use of RBCEVs for clinical applications.

Keywords: RBCEVs; cancer; clinical application; exosome; extracellular vesicles; microvesicles; therapeutic drug delivery.

Figure 1

RBCEV production and cargo packaging for drug delivery. RBCs produce extracellular vesicles in response to increasing intracellular Ca²⁺ concentrations. Molecular therapeutic cargo (e.g., compounds, RNA, DNA) can be packaged into RBCEVs via electroporation for drug delivery. ATP, Adenosine triphosphate; PMA, Phorbol 12-myristate 13-acetate; RBCEVs, red blood cell-derived extracellular vesicles; RBCs, red blood cells.

Figure 2

A proposed strategy of drug-loaded RBCEV therapy. RBCs can be collected from a single patient in order to produce autologous RBCEVs and administration back after drug loading to the same patient when required. Alternatively, RBCEVs can be produced in a large scale from the blood group-matched packed red cell units released from the blood bank for the allogenic RBCEV therapy.