Nanozymes for Advanced Hemoglobin-Based Oxygen Carriers: Applications in Blood Substitution, Wound Healing, Antitumor Therapy, and Beyond.

Oxygen delivery and reactive oxygen species regulation are tightly linked in physiology, with red blood cells serving both as oxygen transporters and as a key antioxidant barrier. This dual function has motivated decades of research into hemoglobin (Hb)-based oxygen carriers (HBOCs), yet conventional designs remain susceptible to oxidative damage and lack the redox machinery of erythrocytes. In parallel, nanozymes-nanomaterials with enzyme-mimetic catalytic activities-have emerged as powerful tools in redox medicine. Their integration with HBOCs has created a new class of self-protecting, multifunctional, and stimuli-responsive oxygen therapeutics. This review summarizes the foundations and biomedical potential of nanozyme-integrated HBOCs and Hb-derived nanozymes. We outline how metal, carbon, and metal-organic framework nanozymes replicate key antioxidant functions, including superoxide dismutase-, catalase-, and peroxidase-like activity. Embedding such nanozymes into HBOCs imparts intrinsic oxidative protection and additional capabilities such as carbonic anhydrase-like catalysis, transforming passive oxygen carriers into intelligent blood substitutes. We then highlight applications beyond transfusion, including wound healing, where photothermal nanozyme-HBOC hybrids enable light-controlled oxygen release and antibacterial action, and cancer therapy, where catalytic HBOCs alleviate tumor hypoxia and enhance radiotherapy, photothermal therapy, and photodynamic therapy. Finally, we discuss Hb-derived and erythrocyte-templated nanozymes for biosensing, radioprotection, and infection control.