Engineering red cells across scales: Red Blood Cells (RBCs) and RBC-derived extracellular vesicles

Red-cell therapeutics are often discussed as a single class, but current products use erythroid biology in distinct ways. Intact red blood cells (RBCs) are long-lived, deformable cells, circulating for about 120 days in humans and roughly 40-60 days in mice, and repeatedly contact immune, endothelial, and reticuloendothelial cells. They are best suited to applications that benefit from intravascular persistence and repeated surface interactions, including enzyme carriage, durable ligand or antigen display, immune modulation, and hitchhiking designs. RBC-derived extracellular vesicles (RBC-EVs) share erythroid membrane lineage at a smaller scale but operate by a different logic. Rather than relying on prolonged circulation, RBC-EVs derive their value from hours-scale routing to recipient cells, cargo protection, uptake, endolysosomal release, antigen processing, and functional intracellular cargo activity after entry. This review argues that red-cell therapeutics are best understood by engineering strategy rather than disease indication alone. For intact RBCs, the central task is to add therapeutic function while preserving deformability, membrane organization, antigen integrity, immune compatibility, and acceptable clearance. Major strategies include covalent conjugation, affinity anchoring, lipid insertion, enzymatic ligation, genetic or precursor-cell engineering, and hitchhiking-based surface association, each balancing functional gain against biological burden. For RBC-EVs, the design problem shifts to vesicle generation, cargo loading and retention, surface functionalization, targeting, intracellular delivery, storage stability, potency, and batch reproducibility. Future progress will require engineering routes that increase efficacy while reducing perturbation and manufacturing complexity, supported by scalable erythroid sources, standardized downstream processing, and release criteria matched to each platform.