Metal–Organic Framework Encapsulating Hemoglobin as a High-Stable and Long-Circulating Oxygen Carriers to Treat Hemorrhagic Shock

Abstract

As an oxygen-transporting protein, free hemoglobin (Hb) often suffers from the disadvantage of undesirable stability and short blood circulation, which severely impairs the potential clinical applications as the blood substitute. In this work, Hb was facilely encapsulated into a kind of metal−organic frameworks (MOFs) (ZIF-8) inspired by the natural biomineralization process. The obtained ZIF-8 encapsulating Hb (ZIF-8@Hb) showed the small hydrodynamic size of 180.8 nm and neutral zeta potential of −2.1 mV by adjusting the ratio of Hb in ZIF-8 frameworks. Intriguingly, Hb encapsulated by ZIF-8 exhibited significantly enhanced stability in alkaline, oxidation, high temperature, or enzymatic environment compared with free Hb because of the excellent protective MOF coatings. More importantly, the negative charge of Hb neutralized the original positive charge of ZIF-8, which led to the better biocompatibility, lower protein adsorption, and macrophage uptake of ZIF-8@Hb than bare ZIF-8 nanoparticles. Furthermore, ZIF-8@Hb displayed extended blood circulation with the elimination half-life of 13.9 h as well as reduced nonspecific distribution in normal organs compared with free Hb or ZIF-8 nanoparticles. With the above advantages, ZIF-8@Hb showed significantly extended survival time of mice in a disease model of hemorrhagic shock compared with free Hb or bare ZIF-8 nanoparticles. Overall, this work offers a high-stable and long-circulating oxygen carrier platform, which may find wide applications as a blood substitute to treat various oxygen-relevant diseases.

Oxygen‐Enriched Metal‐Phenolic X‐Ray Nanoprocessor for Cancer Radio‐Radiodynamic Therapy in Combination with Checkpoint Blockade Immunotherapy

“…When the 4T1 tumor volume reached around 100 mm 3 , Hb@Hf-Ce6 NPs solution was intravenously injected into the mice. IVIS LuminaXR was used to scan the whole mice body at time points (1,4,8,12, and 24 h). The data was calculated by region of interest.…”

“…One promising approach is to delivery oxygen directly. [ 4 ] Hemoglobin (Hb), as oxygen‐transport metalloprotein in the red blood cells, can be employed as a candidate for oxygen delivery owing to its safe and effective oxygen‐carriers capability. However, free Hb molecules fail to be employed directly as oxygen provider due to their nephrotoxicity and immunogenicity.…”

Methods of Encapsulation of Biomacromolecules and Living Cells. Prospects of Using Metal–Organic Frameworks

“…Bacterial cell membranes can be utilized as a scaffold for MOF to form microcapsules with selective release of their content [145]. In some cases, MOFs can have a separate protective function, e.g., that similar to antifreeze proteins which prevent ice crystal growth; this can be used for cryopreservation of erythrocytes [36]. [165,167] Low [169] 0.6 to 13.8 h [172] Nontoxic [171] High [171,173] High [26,31] Micelles 4-20% [174,175] 10-100 nm [176] -Rarely [10,177] Low Depends on the polymer nature [174] Low [14] Variable [174] Low [177] Organic gelpolymer matrices 90-800% [178,179] 20-200 nm [180] to hundreds of microns 0.1-100 nm Yes Moderate…”

“…The composite decomposes at pH 5.0 in cell lysosomes, which reduces the risk of accumulation of nanoparticles in vivo. Administration of the com­posite significantly extended the survival time of mice subjected to hemorrhagic shock [ 36 ].…”

“…Bacterial cell mem­branes can be utilized as a scaffold for MOF to form microcapsules with selective release of their content [ 145 ]. In some cases, MOFs can have a separate protective function, e.g., that similar to antifreeze proteins which prevent ice crystal growth; this can be used for cryopreservation of erythrocytes [ 36 ].…”