Erythrocytes as Carriers for Drug Delivery in Blood Transfusion and Beyond

•Red blood cells (RBCs) are promising carriers for biotherapeutics to enhance their pharmacokinetics and control their site and mechanism of action.•RBC drug carriers include those loaded internally or externally and may be prepared ex vivo or in vivo from allogeneic or autologous units.•Surface coupling onto membrane antigens offers a biocompatible, flexible platform for loading of drugs.•The optimal epitopes for coupling onto RBCs remain to be definitively characterized.•Drug loading onto RBCs may alter immune responses, including potential induction of tolerance.

Red blood cells (RBCs) are innate carriers that can also be engineered to improve the pharmacokinetics and pharmacodynamics of many drugs, particularly biotherapeutics. Successful loading of drugs, both internally and on the external surface of RBCs, has been demonstrated for many drugs including anti-inflammatory, antimicrobial, and antithrombotic agents. Methods for internal loading of drugs within RBCs are now entering clinical use. Although internal loading can result in membrane disruption that may compromise biocompatibility, surface loading using either affinity or chemical ligands offers a diverse set of approaches for the production of RBC drug carriers. A wide range of surface determinants is potentially available for this approach, although there remains a need to characterize the effects of coupling agents to these surface proteins. Somewhat surprisingly, recent data also suggest that red cell-mediated delivery may confer tolerogenic immune effects. Questions remaining before widespread application of these technologies include determining the optimal loading protocol, source of RBCs, and production logistics, as well as addressing regulatory hurdles. Red blood cell drug carriers, after many decades of progress, are now poised to enter the clinic and broaden the potential application of RBCs in blood transfusion.