Metal-Phenolic Networks as Broad-Spectrum Antioxidant Coatings for Hemoglobin Nanoparticles Working as Oxygen Carriers

Abstract

Timely administration of donor red blood cells (RBCs) is a crucial and life-saving procedure to restore tissue oxygenation in patients suffering from acute blood loss. However, important drawbacks of using allogenic RBCs are their limited availability and portability, specific storage requirements, short shelf life, or the need for blood type matching. These limitations result in serious logistical challenges that make the transfusion of donor RBCs difficult in extreme life-threatening situations prior to hospital admission. Thus, the engineering of hemoglobin (Hb) nanoparticles (Hb-NPs), which are free from the aforementioned limitations, has emerged as a promising strategy to create RBC substitutes to be used when donor blood is not available. Despite the tremendous progress achieved in recent years, many challenges still need to be overcome. For example, it is still difficult to create Hb-NPs with a high Hb content while also preventing the autoxidation of Hb into nonfunctional methemoglobin (metHb). Herein, the fabrication of small, solid Hb-NPs with an antioxidant coating is reported. By desolvation precipitation, Hb-NPs with an average hydrodynamic diameter of ∼250 nm and a polydispersity index of ∼0.2 are fabricated. A metal-phenolic network (MPN) layer consisting of a phenolic ligand (i.e., tannic acid) cross-linked through iron­(III) ions is deposited onto the Hb-NPs surface to render antioxidant protection. The resulting MPN-coated Hb-NPs (MPN@Hb-NPs) maintain the ability of the encapsulated Hb to reversibly bind and release oxygen. The antioxidant properties are demonstrated, showing that MPN@Hb-NPs can effectively scavenge multiple reactive oxygen and nitrogen species, both in solution and in the presence of human RBCs and two relevant cell lines, namely, macrophages and endothelial cells. Importantly, these outstanding antioxidant properties resulting from the MPN translate into decreased metHb conversion. Finally, the newly reported MPN@Hb-NPs are also biocompatible, as shown by hemolysis rate and cell viability studies and can be used to protect the cells from oxidative damage. All in all, we have identified a novel strategy to minimize heme-mediated oxidative reactions that could potentially bring this new generation of Hb-based oxygen carriers a step closer to the clinic.

Perfluorocarbon Nanoparticles Incorporating Ginkgolide B: Artificial O2 Carriers with Antioxidant Activity and Antithrombotic Effect

“…In addition, GB and PFTBA‐L@GB significantly boosted the extent of ROS‐scavenging. Different from Hb with oxidative side reaction, [22] PFTBA‐L@GB had a good antioxidant effect and had no obvious toxic side effect on cell survival rate. This was most likely attributable to the antioxidant effects of GB against oxidative stress induced by H 2 O 2 [23] .…”

Research Progress in Oxygen Carrier Design and Application

“…MPNs composed of different metal ions and phenolic ligands exhibit excellent functional tunability, antioxidant, anti-inflammatory, and antibacterial properties . The Hosta-Rigau group reported a simple coating method based on the self-assembly of coordination complex MPNs: synthesis of MPNs using tannic acid (TA) and Fe 3+ cross-linkers . First, MPN maintains the ability of Hb to reversibly bind and release oxygen.…”

“…47 The Hosta-Rigau group reported a simple coating method based on the self-assembly of coordination complex MPNs: synthesis of MPNs using tannic acid (TA) and Fe 3+ cross-linkers. 48 First, MPN maintains the ability of Hb to reversibly bind and release oxygen. Second, as a substitute for antioxidative-coated PDA, MPN will not degrade under physiological conditions and can be retained in blood circulation for a long time.…”

Metal–organic framework-based oxygen carriers with antioxidant activity resulting from the incorporation of gold nanozymes

“…At present, Hb has been encapsulated within liposomes, polymersomes or polymeric particles to name a few. [3][4][5][6][7][8] In our group, we have recently reported the fabrication of nanoparticles (NPs) fully made of Hb by electrospray 9 or desolvation precipitation, 10,11 and also its encapsulation within poly(lactic-co-glycolic acid) (PLGA)-NPs 12,13 or metalorganic framework (MOF)-based nanocarriers (NCs). 14,15 We have demonstrated, amongst others, that the resulting HBOCs were able to reversibly bind and release oxygen over multiple rounds.…”