Red blood cell membrane-camouflaged nanoparticles: a novel drug delivery system for antitumor application

Abstract

Erythrocytes (red blood cells, RBCs) are the most abundant circulating cells in the blood and have been widely used in drug delivery systems (DDS) because of their features of biocompatibility, biodegradability, and long circulating half-life. Accordingly, a "camouflage" comprised of erythrocyte membranes renders nanoparticles as a platform that combines the advantages of native erythrocyte membranes with those of nanomaterials. Following injection into the blood of animal models, the coated nanoparticles imitate RBCs and interact with the surroundings to achieve long-term circulation. In this review, the biomimetic platform of erythrocyte membrane-coated nano-cores is described with regard to various aspects, with particular focus placed on the coating mechanism, preparation methods, verification methods, and the latest anti-tumor applications. Finally, further functional modifications of the erythrocyte membranes and attempts to fuse the surface properties of multiple cell membranes are discussed, providing a foundation to stimulate extensive research into multifunctional nano-biomimetic systems.

Keywords: ABC, accelerated blood clearance; APCs, antigen presenting cells; Antitumor; AuNCs, gold nanocages; AuNPs, gold nanoparticles; Biomimetic nanoparticles; C8bp, C8 binding protein; CR1, complement receptor 1; DAF, decay accelerating factor; DDS, drug delivery systems; DLS, dynamic light scattering; Dox, doxorubicin; Drug delivery; ECM, extracellular matrix; EPR, enhanced permeability and retention; ETA, endothelin A; EpCam, epithelial cell adhesion molecule; FA, folic acid; GA, gambogic acid; H&E, hematoxylin and eosin; HRP, homologous restriction protein; MCP, membrane cofactor protein; MNCs, magnetic nanoclusters; MNs, magnetic nanoparticles; MPS, mononuclear phagocyte system; MRI, magnetic resonance imaging; MSNs, mesoporous silica nanoparticles; Membrane; NIR, near-infrared radiation; Nanoparticles; PAI, photoacoustic imaging; PBS, phosphate buffered saline; PCL, poly(caprolactone); PDT, photodynamic therapy; PEG, polyethylene glycol; PFCs, perfluorocarbons; PLA, poly(lactide acid); PLGA, poly(d,l-lactide-co-glycolide); PPy, polypyrrole; PS, photosensitizers; PTT, photothermal therapy; PTX, paclitaxel; RBCM-NPs, RBCM-coated nanoparticles; RBCMs, RBC membranes; RBCs, red blood cells; RES, reticuloendothelial system; ROS, reactive oxygen species; RVs, RBCM-derived vesicles; Red blood cells; SEM, scanning electron microscopy; SIRPα, signal-regulatory protein alpha; TEM, transmission electron microscopy; TEMPO, 2,2,6,6-tetramethylpiperidin-1-yl oxyl; TPP, triphenylphosphonium; UCNPs, upconversion nanoparticles; UV, ultraviolet; rHuPH20, recombinant hyaluronidase, PH20.

Graphical abstract

Figure 1

The historical process of RBCs as drug carriers.

Figure 2

Schematic preparation of red blood cell membrane-derived vesicles (RVs). Fresh whole blood was centrifuged and repeatedly washed to obtain clean RBCs, and then RVs were obtained through further hypotonic and extrusion treatment.

Figure 3

Schematic diagram of electrostatic interactions between negatively and asymmetrically charged RVs with negatively and positively charged polymeric cores, respectively. The negatively charged nanoparticles and the negatively charged RVs produce strong electrostatic repulsion, resulting in the fusion of the nanoparticles with the intracellular membrane side, while the positively charged nanoparticles and the negatively charged RVs produce a strong affinity to collapse the lipid bilayer. Adapted with permission from Ref. . Copyright © 2014 Royal Society of Chemistry.

Figure 4

Schematic of RBCM-NP preparation by three different methods. (A) Co-extrusion method; (B) microfluidic electroporation method; Adapted with permission from Ref. . Copyright © 2017 American Chemical Society. (C) cell membrane-templated polymerization. Adapted with permission from Ref. . Copyright © 2015 Wiley Online Library.

Figure 5

Red blood cell membrane-camouflaged nanoparticle achievement of antitumor effect. Different core nanoparticles are coated with RVs and then enter into the blood by intravenous (i.v.) injection, evading the immune system to realize long-term circulation, penetrate into the tumor tissues owing to the EPR effect, and finally enter into the tumor cells via endocytosis to achieve diagnosis and treatment of cancers.

Figure 6

Schematic design of ligand-modified drug or photosensitizer-loaded RBCM-NPs combined with phototherapy for targeting and sequential drug delivery. Ligand-modified RBCM-NPs are injected into to mice to achieve active targeting into tumor cells. Under laser irradiation, light-sensitive nanocarriers or PS can provide strong thermal energy, triggering the destruction of cores and resulting in the release of PTX.