Red Blood Cell Engineering: From Traditional Carriers to Armored Modification

Red blood cells (RBCs) possess unique biological attributes─including long circulation, high deformability, and intrinsic immune evasion─that make them attractive candidates for use as cellular carriers in transfusion medicine, organ perfusion, and cell-based therapies. However, native RBCs offer limited capacity for functionalization and are highly sensitive to mechanical, chemical, and oxidative stresses, constraining their performance under demanding clinical conditions. In response, recent advances have shifted RBC engineering from discrete membrane modifications toward armored RBCs, in which continuous exoskeletal shells are constructed outside the plasma membrane to enhance functionality, stability, and environmental tolerance. This review systematically examines armored RBC strategies, including metal–organic framework exoskeletons, silicified nanoshells, and polymeric or hybrid soft armor, with a focus on how exoskeleton material parameters─such as thickness, modulus, surface charge, and roughness─interact with native RBC mechanics to govern in vivo fate. By establishing a baseline rooted in RBC biomechanics, hemorheology, and splenic filtration, we propose a mechanics–chemistry design window to guide rational armor design. Finally, we discuss emerging directions toward dynamic, stimuli-responsive, and AI-assisted armor optimization and outline opportunities for integrating materials engineering with synthetic biology. Collectively, armored RBCs represent a promising bridge between nanomedicine and living-cell therapies, enabling multifunctional, programmable carriers for next-generation biomedical applications.