Artificial red cells. A link between the membrane skeleton and RES detectability?

Factors governing nonspecific reticuloendothelial system (RES)-detectability are largely unknown. Will a liposome that mimics the lipid composition of the outer leaflet of the erythrocyte membrane be invisible to the RES? On both experimental and theoretical grounds we believe the answer is no, in part because 1) sorption of proteins is believed to be important in determining RES uptake, 2) a membrane skeleton is apparently necessary to inhibit protein sorption into erythrocyte membranes and 3) Neohemocytes (a liposome encapsulated hemoglobin product) currently lack a membrane skeleton. Neohemocytes with erythrocyte outer leaflet lipid composition do have extended circulation half-times, but these are at least two orders of magnitude shorter than the circulation half-times of erythrocytes. How might a membrane skeleton modulate RES-detectability? Can avoidance of opsonization result in part from the properties of the membrane skeleton? If so, then how? To explore and quantify such questions we have developed a theoretical, statistical-thermodynamic model of protein binding into membranes. It predicts that the membrane area available for rapid lateral diffusion is critically important in controlling the amount of sorbed protein per unit area, and that a membrane skeleton can reduce a protein's sorption by several orders of magnitude. Based on theoretical results, we offer a speculative model for the detection of non-self lipid bilayers by the RES.