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 fi rst 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 fi rst 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-camoufl aged nanoparticles is systematically investigated by blood biochemistry, hematology testing, and histology analysis. These fi ndings are signifi cant advancements toward solving the long-existing clinical challenges of developing biomaterials that are able to resist both immune response and rapid clearance.