Red Blood Cell Membrane as a Biomimetic Nanocoating for Prolonged Circulation Time and Reduced Accelerated Blood Clearance

Abstract

For decades, poly(ethylene glycol) (PEG) has been widely incorporated into nanoparticles for evading immune clearance and improving the systematic circulation time. However, recent studies have reported a phenomenon known as "accelerated blood clearance (ABC)" where a second dose of PEGylated nanomaterials is rapidly cleared when given several days after the first dose. Herein, we demonstrate that natural red blood cell (RBC) membrane is a superior alternative to PEG. Biomimetic RBC membrane-coated Fe(3)O(4) nanoparticles (Fe(3)O(4) @RBC NPs) rely on CD47, which is a "don't eat me" marker on the RBC surface, to escape immune clearance through interactions with the signal regulatory protein-alpha (SIRP-α) receptor. Fe(3)O(4) @RBC NPs exhibit extended circulation time and show little change between the first and second doses, with no ABC suffered. In addition, the administration of Fe(3)O(4) @RBC NPs does not elicit immune responses on neither the cellular level (myeloid-derived suppressor cells (MDSCs)) nor the humoral level (immunoglobulin M and G (IgM and IgG)). Finally, the in vivo toxicity of these cell membrane-camouflaged nanoparticles is systematically investigated by blood biochemistry, hematology testing, and histology analysis. These findings are significant advancements toward solving the long-existing clinical challenges of developing biomaterials that are able to resist both immune response and rapid clearance.

Nanoparticle‐Based Antivirulence Vaccine for the Management of Methicillin‐Resistant Staphylococcus aureus Skin Infection

“…In contrast, there was no visual evidence of GC formation in the PBS or nanotoxoid(−) immunization groups, confirming the non-immunogenicity of the naturally derived nanoparticle vector itself. [33] Flow cytometry results (Figure 3b) showed that 45.6% of B220 + IgD low B cells in the dLNs of the nanotoxoid(Hla) group exhibited a GL-7 + germinal center phenotype. In contrast, only 15.7% and 13.6% of cells in mice administered with PBS and nanotoxoid(−), respectively, exhibited the same phenotype.…”

Erythrocyte-derived nano-probes functionalized with antibodies for targeted near infrared fluorescence imaging of cancer cells

“…Bossa et al reported detectable levels of autologously-derived EGs containing dexamethasone in plasma of humans at 14 days postinfusion [45]. In a recent study, Rao et al demonstrated that erythrocyte-membrane coated Fe 3 O 4 nanoparticles were retaind in mice circulation at 48 hours post injection [46].…”

Gambogic acid-loaded biomimetic nanoparticles in colorectal cancer treatment

“…However, an anti-PEG immunological response is observed after the first dose of PEGylated NPs injected in vivo, leading to the accelerated blood clearance phenomenon upon repeated injection of the PEGylated NPs. 19 Therefore, more and more attention has been focused on natural lipids 20 and cell membranes. 21,22 Membrane coating has been tried in an attempt to disguise NPs as autologous cells by a novel nanocoating technology.…”

“…In consideration of enormous quantity in vivo as well as simple structure and properties, red blood-cell membrane (RBCm) was the earliest and most widely explored for building synthetic biomimetic nanocarriers. [23][24][25][26][27] RBCm coating containing membrane proteins (eg, CD47, 28 C8bp, 29 and HRP 30 ) can retain their original biological properties completely, 22 disguise NPs as RBCs, 31 evade the immune response from the mononuclear phagocyte system to prolong systemic circulation without the accelerated blood clearance phenomenon, 19 and concurrently reduce reticuloendothelial system uptake. 32 This provides more opportunity to accumulate at tumor sites.…”

“…32 This provides more opportunity to accumulate at tumor sites. Research has shown that the RBC-NP platform does not induce immune responses on the cellular level or the humoral level, 19 highlighting its superior biocompatibility. This conforms to some of the requirements of a desired drug-carrier system, ie, evading the host immune system while delivering its "cargo" safely to its "destination".…”