Red blood cells in biology and translational medicine: natural vehicle inspires new biomedical applications

Abstract

Red blood cells (RBCs) are the most abundant cell type in the blood, and play a critical role in oxygen transport. With the development of nanobiotechnology and synthetic biology, scientists have found multiple ways to take advantage of the characteristics of RBCs, such as their long circulation time, to construct universal RBCs, develop drug delivery systems, and transform cell therapies for cancer and other diseases. This article reviews the component and aging mystery of RBCs, the methods for the applied universal RBCs, and the application prospects of RBCs, such as the engineering modification of RBCs used in cytopharmaceuticals for drug delivery and immunotherapy. Finally, we summarize some perspectives on the biological features of RBCs and provide further insights into translational medicine.

Keywords: cell surface engineering; cell therapy; drug delivery; red blood cells; universal blood.

Figure 1

A schematic representation of a red cell membrane. The plasma membrane is a composite structure composed of amphiphilic lipid molecules. A two-dimensional elastic network of skeletal proteins is embedded in the lipid bilayer through tethering sites (transmembrane proteins).

Figure 2

A schematic view of the structure of sialic acid (Neu) and its derivatives Neu5Ac, Neu5Gc, and KDN.

Figure 3

The applications of engineered RBCs for drug delivery include different aspects, such as lack of blood in cancer patients, immunological disease, large physical trauma, kinds of anemia, and clearance of blood toxication.

Figure 4

Common means to obtain universal RBCs for transfusion. (A) Preparation of enzyme-converted group O (ECO) blood cells by enzyme digestion. (B) Shielding antigens of the membrane surface from donors. (C). Inducing RBCs from iPS cells, gene editing, and adjusting the culture procedure to control the blood types.

Figure 5

The relations of H, A, and B antigens and the basic structure of the ABO blood group. (A) The original ABO blood group is a precursor substance composed of glucose, galactose, and N-acetyl-galactosamine, and the H antigen (the precursor H oligosaccharide antigen) is the basic unit in the A and B antigens . (B) The antigens and related antibodies of the ABO blood group, which make the type O group the natural universal donor.

Figure 6

How to shield the original antigens and produce universal RBCs. (A) Layer-by-layer (LbL) assembly to mask antigens on RBCs. (B) Shielding of the original antigens of RBCs by modifying antigens on the membrane surface of RBCs, such as PEG and dopamine. (C) Surface-anchored hydrogel framework for generating RhD epitope stealth RBCs.

Figure 7

Sketch illumination of RBCs as a drug delivery platform precedent hitchhiking. RBCs can be used for drug delivery in two ways: taking drugs inside or binding on the surface. Electric pulsing, hypotonic hemolysis, and endocytosis are common means to invade the bilayer membrane of RBCs and absorb nanoparticles or other forms of drugs in (A), and another means is linked antibodies, peptides, proteins, or chemicals directly on the surface (B).

Figure 8

RBC mimicking membranes by part of the RBC components and exhibition of erythrocyte membrane-camouflaged polymeric nanoparticles.

Figure 9

Erythrocytes help phagocytose complements, erythrocytes, and complement-opsonized particles interact through C3b/C4b (CR1) and are phagocytosed by macrophages, and erythrocytes are decomposed by phagosomes to release iron, porphyrin, globin, and HO (heme oxygenase) for recycling.