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The most abundant protein in blood is hemoglobin (Hb, 12-15 g/dL in blood).This fact indicates that oxygen transport is the most crucial for life activity.Hb is compartmentalized in red blood cells (RBCs), and the intracellular Hb concentration is 35 g/dL.In spite of its abundance in blood, Hb becomes toxic once it is released from RBCs.Hemoglobin-vesicles (HbV) are artificial oxygen carriers that mimic the cellular structure of RBCs to replace the blood transfusion.In contrast to other liposomal products containing antifungal or anticancer drugs, one injection of HbV in place of a blood transfusion is estimated as equivalent to a massive dose, such as several hundred milliliters or a few liters of normal blood contents.The fluid must therefore contain a sufficient amount of Hb, the binding site of oxygen, to carry oxygen like blood.Encapsulation of Hb can shield various toxic effects of molecular Hbs.On the other hand,the liposomal structure, surface property for biocompatibility, the balance between the stability (during storage and circulation in blood) and instability (for the prompt degradation in RES) must be considered to establish an optimal transfusion alternative.HbV is much smaller than RBC (250 vs.8000 nm), but it recreates the functions ofRBCs;(i) The oxygen-unloading of HbV is slower than that of a cell-free Hb solution;(ii) The colloid osmotic pressure is zero.For a massive dosage,HbV has to be co-injected with or suspended in a plasma substitute such as albumin;(iii) The viscosity of HbV is adjustable to that of blood;(iv) HbV is finally captured by RES, and then degraded and excreted promptly;(v) Coencapsulation of an allosteric effector regulates oxygen-affinity;(vi) Hemolysis is minimal during circulation and the lipid bilayer membrane prevents a direct contact of Hb and vasculature;(vii) Reaction of NO is retarded by an intracellular diffusion barrier, and HbV does not induce vasoconstriction.The obvious advantages of HbV are that it is pathogen free and blood type antigen free;moreover, it can withstand long-term storage for stockpiling.HbV has a variety of potential applications not only as a transfusion alternative but also as an oxygen or CO therapeutic fluid that cannot be attained by the present RBC transfusion.