Hemoglobin-based oxygen carriers: evolution, translational applications and clinical considerations.

Tissue survival depends on adequate oxygen delivery, yet when red blood cell (RBC) transfusions are unavailable or contraindicated, restoring oxygen delivery remains an urgent clinical need. To meet this need, researchers have developed hemoglobin-based oxygen carriers (HBOCs) that transport oxygen via cell-free hemoglobin circulating in plasma. However, the intrinsic toxicity of cell-free hemoglobin (Hb) has slowed its clinical translation. More fundamentally, it has shifted the field's focus from universal blood substitutes toward indication-specific solutions. Despite persistent mitigation efforts, no HBOC has gained full Food and Drug Administration (FDA) approval for human use, suggesting that these toxicities are not tractable engineering problems but intrinsic liabilities of the cell-free Hb molecule. A meta-analysis of early clinical trials reported increased risks of death and myocardial infarction with several HBOCs, prompting a clinical hold on HBOC trials in the United States. In this review, we trace the evolution of engineering strategies and examine the functional mechanisms that underpin these approaches. We then evaluate HBOCs not as universal RBC substitutes but as context-dependent strategies for oxygen delivery across acute resuscitation, organ preservation, and hypoxia-driven pathologies, followed by a safety assessment. In each scenario, clinical value rests on providing temporary oxygen support when standard transfusion is unavailable or inadequate, rather than on replicating the full functionality of RBCs. Although a universal RBC substitute remains a distant goal, HBOCs are progressively evolving into oxygen therapeutics specific to indications. Their clinical adoption will require rigorous evidence of long-term safety, manufacturing reproducibility, and clinically meaningful efficacy in well-defined patient populations.