Metal-organic frameworks for the fabrication of hemoglobin-based oxygen carriers: A comprehensive review

Transfusions of red blood cells (RBCs) are a cornerstone of modern medicine but face major challenges, including limited supply, short shelf life, and risk of infection. Hemoglobin-based oxygen carriers (HBOCs) have long been investigated as blood substitutes, yet instability, oxidative toxicity, and rapid clearance of free hemoglobin (Hb) have hindered clinical translation. Metal-organic frameworks (MOFs) have recently emerged as a promising platform to overcome these limitations. Their crystalline, porous structures can encapsulate Hb, protect it from denaturation and oxidation, and modulate oxygen (O₂) binding and release. In this review, we provide a comprehensive overview of MOF-based HBOCs, covering both large-pore systems that allow post-synthetic Hb loading and zeolitic imidazolate frameworks enabling in situ biomimetic mineralization. We highlight how encapsulation conditions and additives influence Hb loading, stability, and O₂ transport, and we examine the role of surface modifications, including poly(ethylene glycol), polydopamine, metal-phenolic networks, and RBC membrane coatings, in enhancing antioxidant protection, circulation time, and immune evasion. In vitro data consistently demonstrate high biocompatibility, reduced protein fouling, and minimal hemolysis, while in vivo studies reveal extended circulation half-lives, favorable biodistribution, and therapeutic efficacy in hemorrhagic shock models. We also compare MOF-based HBOCs with alternative nanocarriers and polymer-stabilized systems, emphasizing their unique advantages and remaining challenges. Finally, we discuss key hurdles for translation, including long-term stability, safety, scalable manufacturing, and regulatory considerations. Together, recent advances position MOF-Hb composites as highly promising candidates for next-generation O₂ therapeutics bridging the gap between transfusion medicine and nanomedicine.