Biorthogonal PEGylation of Hierarchical Porous Metal–Organic Frameworks as Robust, Functional Nanocarriers for Hemoglobin-Based Oxygen Delivery

Adequate oxygenation is critical for therapy and recovery across diverse biomedical contexts. Oxygen (O 2 ) carriers not only serve as potential blood substitutes in hemorrhage but also alleviate tumor hypoxia to enhance radiotherapy, photodynamic therapy, and related treatments. They further promote wound healing, protect tissues from ischemia–reperfusion injury in myocardial infarction or stroke, and improve organ transplantation outcomes by sustaining graft oxygenation. Synthetic hemoglobin (Hb)-based O 2 carriers (HBOCs) represent a promising approach to mitigate hypoxia; however, maintaining Hb stability, O 2 -binding capacity, and circulation longevity remains challenging. Metal–organic framework nanoparticles (MOF NPs), known for their tunable porosity, hold potential for Hb encapsulation and O 2 delivery, but their predominant microporous structure and poor physiological stability hinder biological applications. Here, we present an ″inside-out″ engineering strategy to construct a robust HBOC by integrating hierarchically porous UiO-66 NPs (HP-UiO-66 NPs) with diphenylcyclooctyne–azide click chemistry to anchor a covalent PEG shell. The introduction of mesopores enables efficient Hb loading while preserving microporosity for O 2 diffusion. The mild, biorthogonal PEGylation preserves Hb’s O 2 -binding functionality and substantially enhances colloidal and physiological stability. PEGylated HP-UiO-66 NPs remain stable in biological media for over 7 days, outperforming unmodified analogues prone to phosphate-induced degradation. Comprehensive in vitro studies reveal promising biocompatibility, and pharmacokinetic and biodistribution studies confirm prolonged circulation and selective organ accumulation. This work establishes HP-UiO-66 NPs as a versatile platform for O 2 delivery, highlighting the synergistic potential of pore engineering and surface modification strategies to advance MOF-based biomacromolecule delivery for critical care applications.