Insights into the physicochemical interactions of ionic liquid-coated polymeric nanoparticles with red blood cells

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 <i>in vivo</i> 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 <i>in situ ex vivo</i> 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 <i>in situ</i> RBC hitchhiking by IL-NPs.