Ferritin: A Promising Nanoreactor and Nanocarrier for Bionanotechnology

Abstract

The essence of bionanotechnology lies in the application of nanotechnology/nanomaterials to solve the biological problems. Quantum dots and nanoparticles hold potential biomedical applications, but their inherent problems such as low solubility and associated toxicity due to their interactions at nonspecific target sites is a major concern. The self-assembled, thermostable, ferritin protein nanocages possessing natural iron scavenging ability have emerged as a potential solution to all the above-mentioned problems by acting as nanoreactor and nanocarrier. Ferritins, the cellular iron repositories, are hollow, spherical, symmetric multimeric protein nanocages, which sequester the excess of free Fe­(II) and synthesize iron biominerals (Fe2O3·H2O) inside their ∼5–8 nm central cavity. The electrostatics and dynamics of the pore residues not only drives the natural substrate Fe2+ inside ferritin nanocages but also uptakes a set of other metals ions/counterions during in vitro synthesis of nanomaterial. The current review aims to report the recent developments/understanding on ferritin structure (self-assembly, surface/pores electrostatics, metal ion binding sites) and chemistry occurring inside these supramolecular protein cages (protein mediated metal ion uptake and mineralization/nanoparticle formation) along with its surface modification to exploit them for various nanobiotechnological applications. Furthermore, a better understanding of ferritin self-assembly would be highly useful for optimizing the incorporation of nanomaterials via the disassembly/reassembly approach. Several studies have reported the successful engineering of these ferritin protein nanocages in order to utilize them as potential nanoreactor for synthesizing/incorporating nanoparticles and as nanocarrier for delivering imaging agents/drugs at cell specific target sites. Therefore, the combination of nanoscience (nanomaterials) and bioscience (ferritin protein) projects several benefits for various applications ranging from electronics to medicine.

Ferritin nanocages as efficient nanocarriers and promising platforms for COVID-19 and other vaccines development

“…For instance, smaller nanoparticles (< 20 nm) are more easily transported to the lymph nodes [ 148 ] and are most capable of perturbing membranes [ 149 , 150 ], whereas intermediate-sized nanoparticles (20–100nm) are most capable of circulating in the blood for long periods of time and avoiding clearance [ 148 ]. Superparamagnetic iron oxide, platinum, gold, silver, quantum dots (composed of group IIB-VIA or group IIIA-VA elements on the periodic table), and other inorganic nanoparticles have been demonstrated to be useful to a wide range of biomedical applications including targeted delivery of drugs, biosensing, imaging, antimicrobial therapy, and photothermal therapy [ 105 , [150] , [151] , [152] , [153] , [154] , [155] ]. Drawbacks to their clinical use, however, includes their toxicity, induced by harmful metal ions or uncontrolled protein corona formation, poor solubility, and propensity to aggregate into structures larger than their optimal nano-size [ 152 , 154 , 156 , 157 ].…”

“…These highly desirable characteristics have allowed for the application of ferritin as an “inorganic material” in medicine [ [152] , [153] , [154] ]. For instance, apoferritin has been successfully used as a biotemplate for synthesizing CdSe, CdS, ZnSe, ZnS, PbS, and other quantum dots within its protein shell, mimicking ferritin's natural iron biomineralization process, and allowing for enhanced biocompatibility of these materials [ 151 ].…”

“…In addition, ferritin has been shown to bind to a few other receptors including Tim-1, Tim-2, Scara5, and CXCR4 [ 160 ]. Ferritin's intrinsic tumor-selective properties, as well as the ability to engineer additional tumor-targeting moieties on its surface has been the subject of many studies on ferritin-coated chemotherapeutic drugs, ferritin in photothermal therapy (PTT) and ferritin in photodynamic therapy (PDT), and in bioimaging and other biomedical uses [ [86] , [87] , [88] , 105 , 151 , [158] , [159] , [160] , [161] , [162] ] ( Fig. 5 ).…”

“…Using encapsulation processes discussed earlier, many anti-cancer drugs have been loaded inside ferritin nanocages including doxorubicin, carboplatin, and cisplatin, exhibiting improved circulation time, decreased toxicity, and greater accumulation at the tumor sites [ 87 , 147 , 161 , 162 ]. Ferritin has also been used to encapsulate gadolinium and superparamagnetic iron oxide nanoparticles for application in magnetic resonance imaging (MRI), resulting in reduced toxicity, higher relaxivity of the MRI contrast agent, and significant signal increase with greater specificity for cancer cells [ 87 , 115 , 151 , 161 , 162 ]. The use of ferritin as a delivery platform for photothermal agents and photosensitizers, which generate heat and reactive oxygen species, respectively, has been shown to reduce the side effects of these therapies in normal tissues [ 115 , 148 ], improve cellular uptake [ 115 ], and inhibit tumor growth [ 87 , 115 ].…”

A Multivalent Vaccine Based on Ferritin Nanocage Elicits Potent Protective Immune Responses against SARS-CoV-2 Mutations

“…Owing to the capacities that ferritin offers, ferritin nanocages have been proposed in many studies as vaccine platforms against different diseases, including cancer [ 21 , 22 , 23 ], various viruses [ 24 , 25 , 26 ], and other pathogens [ 27 ]. It has been shown that ferritin nanocages have lymph-node target ability, which makes them able to elicit efficient antigen delivery to antigen-presenting cells (APCs) [ 22 , 28 ], high immunogenicity [ 27 , 29 ], and stability [ 30 , 31 ]. Moreover, the structure of ferritin has the advantage of displaying various antigens by fusing to their surface [ 27 , 32 ].…”