Editors' ChoiceDrug Delivery

RBCs: Repurposed and Refurbished

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Science Translational Medicine  16 Jul 2014:
Vol. 6, Issue 245, pp. 245ec122
DOI: 10.1126/scitranslmed.3009807

Red blood cells (RBCs) are nature’s delivery vehicle. Having evolved to distribute oxygen throughout the body, they are abundant, possess a large surface area for transferring payload, and have a circulating lifespan of 120 days in humans. Despite such favorable qualities, attempts to usurp RBCs to deliver exogenous agents have been limited, yielding constructs that are fragile, short-lived, unable to target specific tissues, and restricted in the types of cargo they can carry. By genetically modifying RBC progenitors (the cells that ultimately become RBCs), Shi et al. now demonstrate a way to engineer stable, surface-modified RBCs capable of incorporating various payloads, circulating for prolonged durations, and targeting specific sites in the body.

Bacterial sortases are transpeptidases that recognize and modify specific peptide motifs, making them reactive with other residues on a linking peptide—a process known as “sortagging.” By engineering mouse RBC precursors that express membrane proteins capped with one of these peptide motifs and using molecules tagged with the reacting sequence, a wide range of agents, protein or otherwise, can be covalently attached to RBCs in a stable, nondamaging way. In a mouse model, the authors show that this sequence can be carried out in a manner that does not adversely affect cell differentiation or maturation, with sortagged RBCs continuing to circulate in transfused mice for nearly the same amount of time as that of native cells. Different sortases were used to tag various compounds to the same RBC in parallel, and antibodies added to the RBC surface made the cells targeted. Shi et al. further showed translational potential by sortagging human CD34+ peripheral blood stem cells. As in vitro differentiation technologies continue to advance, such repurposed RBCs—refurbished with therapeutic molecules, diagnostic probes, and/or targeting moieties—could find use in a variety of clinical applications.

J. Shi et al., Engineered red blood cells as carriers for systemic delivery of a wide array of functional probes. Proc. Natl. Acad. Sci. U.S.A. 10.1073/pnas.1409861111 (2014). [Abstract]

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