Organ-targeted intravenous (IV) delivery of polymeric nanoparticles (NPs) remains a translational drug delivery challenge, as an overwhelming fraction of the administered dose is typically cleared due to fouling at the nano-bio interface. As a solution, we have developed choline carboxylate ionic liquid (IL)-coated polymeric nanoparticles (IL-NPs) that are able to bypass this mechanism of clearance by exhibiting affinity to red blood cells (RBCs) in whole blood, resulting in significant in vivo targeted delivery to the first capillary bed encountered post-IV injection in both mice and rats. Here, we demonstrate that choline carboxylate ionic liquid-coated polymeric nanoparticles exhibit in situ ex vivo affinity to mouse and human red blood cell membranes in whole blood, and examine the mechanism of action engaged by IL-NPs at the RBC membrane interface. We report the physicochemical impact of varying the anionic alkyl chain structure in choline-based carboxylate ILs, which interfaces on the outermost layer of the NP coating, and reveal that membrane saturation, temperature dependence, and membrane anion transporters all play a role in in situ RBC hitchhiking by IL-NPs.