Can we produce synthetic red blood cells lacking antigens?
Actually there are such particles. It is estimated that about 20% of the hemoglobin (HGB hereafter) is in HGB vesicles (HbV hereafter) formed by RBCs. So sure, it is possible to use small particles instead of RBCs, but these vesicles have major and minor antigens on their surface. According to some of the articles they cause other complications too by blood transfusions and they are destroyed by the immune system within 3 to 7 days. So they don't solve the problem.


In Vivo Volume and Hemoglobin Dynamics of Human Red Blood Cells
Artificial Oxygen Carriers (Hemoglobin-Vesicles) as a Transfusion Alternative and for Oxygen Therapeutics
Red blood cell vesiculation in hereditary hemolytic anemia
The red cell revisited--matters of life and death.
Red blood cell microparticles and blood group antigens: an analysis by flow cytometry
Hemoglobin-Vesicles as Oxygen Carriers
Physiological Capacity of the Reticuloendothelial System for the Degradation of Hemoglobin Vesicles (Artificial Oxygen Carriers) after Massive Intravenous Doses by Daily Repeated Infusions for 14 Days


HGB vesicles without major and minor antigens are not a perfect solution either (I think), because the immune system tends to attack such things. For example by viral infections the MHC1 levels are low (in cells with nucleus) to avoid T cell response and the NK cells does not like that, so they destroy such cells. I am almost sure something similar would happen with this kind of vesicles as well. At least afaik. the immune system checks not just the presence of these antigens, but their composition as well. So if a RBC is under stress, then it changes the antigen composition on its surface and the leukocytes destroy it if necessary. According to some of the experiments PEG can cover HbV antigens and increase immune compatibility, so having less surface antigens seems to be a better choice than having more.


Development of a Synthetic Blood Substitute Utilizing Hemoglobin Vesicles
Biocompatibility of Hemoglobin Vesicles, a Cellular-Type Artificial Oxygen Carrier, on Blood Cells and Plasma Proteins In Vitro and In Vivo
Artificial Oxygen Carriers, Hemoglobin Vesicles and Albumin−Hemes, Based on Bioconjugate Chemistry
Hemoglobin Vesicles, Polyethylene Glycol (PEG)ylated Liposomes Developed as a Red Blood Cell Substitute, Do Not Induce the Accelerated Blood Clearance Phenomenon in Mice


HGB vesicles have another problem. The HGB inactivates in them without reduction (metHb formation). Only Fe2+ HGB can carry oxygen. This can be solved with methylene blue according to this study.


Red Blood Cells Donate Electrons to Methylene Blue Mediated Chemical Reduction of Methemoglobin Compartmentalized in Liposomes in Blood
Inhibition of methemoglobin formation in aqueous solutions under aerobic conditions by the addition of amino acids


We cannot use free HGB either, because it would decrease the NO levels and lead to endothelial dysfunction. I think to small particles would have the same effect because of increased surface.


Mechanisms of Slower Nitric Oxide Uptake by Red Blood Cells and Other Hemoglobin-containing Vesicles
Microparticles in stored red blood cells as potential mediators of transfusion complications
Removal of Cellular-Type Hemoglobin-Based Oxygen Carrier (Hemoglobin-Vesicles) From Blood Using Centrifugation and Ultrafiltration


According to other studies RHSA-heme (serum albumin bound to synthetic heme) is another option. It seems to be safe if you replace only 20% of blood volume (of rats). I think a complete transfusion is not safe, because it would reduce the NO levels as we already discussed. I have not found an experiment which does complete transfusion.


Safety evaluation of an artificial O2 carrier as a red blood cell substitute by blood biochemical tests and histopathology observations.
Exchange transfusion with synthetic oxygen-carrying plasma protein “albumin-heme” into an acute anemia rat model after seventy-percent hemodilution


So there is ongoing research in the topic. There is progress, but none of the current solutions is perfect I think.