Nanomaterial-related hemoglobin-based oxygen carriers, with emphasis on liposome and nano-capsules, for biomedical applications: current status and future perspectives

Abstract

Oxygen is necessary for life and plays a key pivotal in maintaining normal physiological functions and treat of diseases. Hemoglobin-based oxygen carriers (HBOCs) have been studied and developed as a replacement for red blood cells (RBCs) in oxygen transport due to their similar oxygen-carrying capacities. However, applications of HBOCs are hindered by vasoactivity, oxidative toxicity, and a relatively short circulatory half-life. With advancements in nanotechnology, Hb encapsulation, absorption, bioconjugation, entrapment, and attachment to nanomaterials have been used to prepare nanomaterial-related HBOCs to address these challenges and pend their application in several biomedical and therapeutic contexts. This review focuses on the progress of this class of nanomaterial-related HBOCs in the fields of hemorrhagic shock, ischemic stroke, cancer, and wound healing, and speculates on future research directions. The advancements in nanomaterial-related HBOCs are expected to lead significant breakthroughs in blood substitutes, enabling their widespread use in the treatment of clinical diseases.

Keywords: Cancer; Hemoglobin-based oxygen carriers (HBOCs); Hemorrhagic shock; Nanomaterials; Oxygen transport.

Fig. 1

Schematic representation of the application of Nano-HBOCs in hemorrhagic shock, ischemic stroke, cancer, wound healing, and other disease treatment

Fig. 2

A Nanoparticle preparation, stability behavior, blood circulation, and oxygen supplying of ZIF-8@Hb are shown in figure. B Survival curves of mice with hemorrhagic shock following intravenous injection of PBS, Hb, ZIF-8, and ZIF-8@Hb. C Oxygen dissociation curves of Hb and ZIF-8@Hb. D Biodistribution of Hb, ZIF-8, and ZIF-8@Hb after intravenous injection for 12 h. E Biodistribution of Hb, ZIF-8, and ZIF-8@Hb after intravenous injection for 24 h. A–E Reproduced with permission [76]. Copyright 2019, American Chemical Society

Fig. 3

A Illustration of the CPTK@PMH nanoerythrocyte formation and metabolic microenvironment modulation in ischemic brain: nanoerythrocyte accumulation in ischemic core via microthrombus binding and uptake by neurovascular unit after blood brain barrier penetration; B hypoxia-responsive oxygen release to relieve necroptosis; C oxygen balance regulation to alleviate acute reperfusion injury via oxygen enrichment, ROS scavenging and microglia polarization; D repair promotion achieved by metabolic microenvironment modulation via energy and glucose metabolism activation and blood brain barrier protection. A–D Reproduced with permission [83]. Copyright 2019, Nano Today.

Fig. 4

The design and function of DOX/Hb loaded PLGA-cancer cell membrane nanoparticles (DHCNPs) for homologous targeting and O2 interference. A Synthesis of oxy-DHCNPs. DHCNPs were prepared by extrusion with preformed DOX/Hb-PLGA NPs, DSPE-PEG, and MCF-7 cancer cell membrane, and then were oxygenated to obtain oxy-DHCNPs. B Cellular functions of DHCNPs, including homologous targeting, downregulation of predictive markers (HIF-1α, MDR1, and P-gp), and inhibited DOX export. (C): MCF-7 tumor growth curves of different treated groups (scale bar 50 µm). (D): Survival rates of tumor-bearing mice in various groups. A–D Reproduced with permission [85]. Copyright 2017, Advanced Functional Materials.

Fig. 5

A Schematic illustration showed the Hb@Hf-Ce6 nanoparticles-mediated X-ray induced radiotherapy-radiodynamic therapy-immunotherapy for the eradication of both primary and distant tumors. Hb was encapsulated in the Hf-phenolic coordination nanoplatform for oxygen delivery through self-assembly. B The oxygen release behavior of hemoglobin (Hb) and Hb@Hf-Ce6 NPs (NP) with/without X-ray irradiation was evaluated by Ru(bpy)₃Cl₂ probe. Hb and NP were oxygenated previously. C Tumor volume growth curves for primary tumors. D Tumor volume growth curves for distant tumors. A–D Reproduced with permission [184]. Copyright 2021, Advanced Science.

Fig. 6

A Schematic depiction of oxygen-augmented immunogenic PDT with C@HPOC for eliciting the anti-metastatic and abscopal effect. Human serum albumin (HSA) was hybridized with oxygen carrying hemoglobin (Hb) via intermolecular disulfide bonds to form a hybrid protein oxygen nanocarrier with Ce6 loaded (C@HPOC). Under laser irradiation, oxygen self-supplied nanoparticles (C@HPOC) elevated the generation of cytotoxic ¹O₂ and moreover triggered immunogenic cell death (ICD). C@HPOC-mediated PDT not only destroyed the primary tumors but also inhibited the distant tumors and lung metastasis by systemic anti-tumor immune responses. B Confocal images of cellular uptake and ROS generation in 4T1 tumor cells. C Growth curves of primary tumor on mice after various treatments. D Growth curves of distant tumor on mice in different treated groups. E Immunofluorescence staining detection of CD8 T cells (red) in tumor tissues. A–E Reproduced with permission [197]. Copyright 2018, American Chemical Society Nanomaterials.

Fig. 7

A The schematic illustration of the light-responsive MoS2 QDs integrated inverse opal microcarriers for controllable oxygen delivery and tissue repair. The H&E staining of B–D repaired samples after implantation for 2 weeks. Vessels in the samples are indicated with grey arrowheads. B Control, C Experimental I, D Experimental II. The Masson staining of E–G repaired samples after implantation for 2 weeks. Granulation tissue thickness in the samples are indicated with black arrowheads. E Control, F Experimental I, G Experimental II. B–G The scale bar is 200 µm. A–G Reproduced with permission [233]. [88]. Copyright 2020, American Chemical Society Nanomaterials. Copyright 2019, small. H Schematic illustrations of wound healing using NIR responsive separable MNs which encapsulate BP QDs and oxygen-carrying Hb. I Corresponding double immunofluorescent staining of CD31 and α-SMA on day 9. The arrows indicate the vascular ducts. The scale bars are 100 μm. J Corresponding quantitative analysis of the blood vessel density on day 9. The scale bars are 50 μm. H–J Reproduced with permission