Several research groups have tried to harness red blood cells to carry medicine either by using enzymes or osmosis to stuff the cells with compounds or by using bioaffinity ligands to target proteins to their surfaces. But Hidde Ploegh, Harvey Lodish, and their teams at MIT have put a new spin on this strategy by using sortase, a bacterial enzyme that attaches proteins to the cell walls of gram-positive bacteria (1).
“The question was, could you hitch an interesting biological to a red blood cell and have its half-life determined not by that of the biological itself but rather by the half-life of the red blood cell,” said Ploegh. In fact, the group found that engineered red blood cells, including those conjugated with biotin, lasted 28 days or longer in normal recipient mice.
“As an experimental approach, it is elegant; and as a therapeutic approach it may be relevant in situations where the benefit of permanent conjugation warrants the complexity of the transgenic approach,” noted Jeffrey Hubbell of the Ecole Polytechnique Fédérale de Lausanne in Switzerland, who was not involved with the research.
Ploegh envisions a range of applications for the new cells. For example, attaching antibodies or antibody fragments to the red blood cells may enable them to scoop up and dispose of toxic proteins, such as those used in chemical warfare.
For use in humans, the process would involve isolating red blood cell precursors from fetal cord blood or from the circulation of a normal individual and then modifying them in the lab. But before this goal can be realized, the group must first determine whether the small modifications they introduce are capable of eliciting an immune response.
“The cool thing about red blood cells is that when they mature, they kick out their nucleus, so mature cells have no DNA,” said Ploegh. That helps minimize the modifications to the red blood cell, and ensures that it carries no foreign DNA, leading the group to suspect that immune responses will be minimal.
1. Shia J et al. Engineered red blood cells as carriers for systemic delivery of a wide array of functional probes, Proceedings of the National Academy of Sciences. 2014 111:10131-10136.
2. Mao H, Hart SA, Schink A, Pollok BA. J Am Chem Soc. Sortase-mediated protein ligation: a new method for protein engineering. 2004 126:2670-2671.