The authors demonstrated that nanoparticles with Ter119 on the surface had markedly prolonged PK and reduced uptake by the RES vs. membrane. Finally, we discuss the key current challenges faced by these and other RBC-based DDSs including the issue of potential unintended and adverse effect and contingency steps to ameliorate this and other concerns. Visual Abstarct Section 1.?Introduction. RBC and liposomes: a historical overview. Mephistopheles, seeking Dr. Fausts signature around the devils contract, coined an aphorism Blood is usually a juice of a very special kind, which could characterize todays field of hematology. Indeed, the mystical ever-changing liquid Norverapamil hydrochloride is usually enormously important and complex. Take, for example, the ubiquitous corpuscles that paint blood red. Their narrative speaks of a dualism of many sorts including changing their very color from crimson in arteries to purple in veins. Two individuals discovered erythrocytes independently. In 1658, Jan Swammerdam, a Dutch biologist, described miniature corpuscles in frog blood. In 1674, erythrocytes were redescribed by his famous compatriot, inventor of advanced microscopes and amateur-scientist Antonie van Leeuwenhoek. Royalties paid Norverapamil hydrochloride visits to him in the city of Delft to honor his discoveries. During a European tour in 1698, Peter the Great met Leeuwenhoek, who presented to the young Russian Emperor an optical device to observe blood in the capillaries. Both the Latin and English terms, erythrocytes and red blood cells (RBCs) are misnomers, as RBCs are not complete cells. Cells, especially blood cells C leukocytes, lymphocytes, monocytes and even cell remnants platelets, are more complex structurally and functionally, diverse and Norverapamil hydrochloride heterogenous, delicate and capricious, reactive and dangerous than RBCs. Remnants of reticulocytes, RBCs lack nuclei and organelles, and are in essence membrane vesicles filled with hemoglobin. Yet, of course these refined biconcave discs are not that simple. Indeed, in the three centuries that ensued CD52 since their discovery, RBCs have become the subject of many revelations. Accolades for RBC studies include Nobel Prizes to Ronald Ross for studies of the pathogenesis of malaria (1902), Jules Bordet for the discovery of the complement system (1919), Karl Landsteiner for the discovery of blood groups that enabled blood transfusion (1930), George H. Whipple for studies of anemia (1934), Max Perutz for studies of hemoglobin (1959), Peter Agre and Roderick McKinnon for discovery of aquaporins in RBC membranes (2003), Tu Youyou for new therapy against malaria (2015), and William Kaelin, Peter Ratcliffe, and Gregg Semenza for studies of biomedical Norverapamil hydrochloride features of oxygen and erythropoietin (2019). RBCs are abundant, docile, and incredibly stable. As a blood transporting agent, these features lend themselves to carry drugs. Indeed, ideas to encapsulate pharmacological brokers into isolated RBC to prolong circulation evolved nearly half a century ago [1, 2]. Alas, soon after these promising initial studies, the pandemics of HIV, hepatitis, and other infections transmitted with blood products all but decimated RBC-based drug delivery research for several decades. Liposomes, artificial multimolecular assemblies made of phospholipids, cholesterol and other components, which form membranous structures with sizes ranging Norverapamil hydrochloride from <100 nm to ~500 nm, were discovered, or rather, invented in the early 1960s in Cambridge by Alec D. Bangham [3C5]. Curiously, he was a hematologist studying blood coagulation. Liposomes initially attracted the attention of basic researchers as models of biological membranes. This aspect remains an important area of liposome research. However, within a decade of their discovery, liposomes became a cornerstone in drug delivery research, giving rise to multiple formulations of synthetic nanocarriers. These advanced means for delivery of drugs in the body have yet to be the focus of a coveted Nobel Prize (which actually might happen in a few months this year, taking into account the global impact of BioNTech/Pfizer and Moderna COVID19 vaccine designed by the team led by Drew Weissman and Kati Kariko, based on altered mRNA packed into lipid nanoparticles). Today, the internet search terms erythrocyte and RBC yield several orders of magnitude more hits than liposome, reflecting the relative.