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Abstract

This review briefly describes the concerns of nanobiotechnology in the design and development of novel vaccines using the most known nanocarriers, including nature-made nanocarriers (such as bacterial spores, virus-like particles, exosomes, and bacteriophages), man-made nanocarriers (such as Proteosomes, liposomes, virosomes, SuperFluids, and nanobeads), and their applications in therapeutic and protective immunization, as well as their advantages and disadvantages. Here, we focus on the development of nano-based vaccines as “nanovaccines” for inducing immune systems, and the foreseeable promises and problems when compared with existing vaccines. Also, we review a potential nano-hazard for vaccines, so-called nanobacterial contamination.

Keywords

Nanocarrier ; Nanovaccine ; Bacterial spore ; Proteosome ; Exosome ; Liposome ; Virosome ; SuperFluid ; Nanobead ; Virus-like particle (VLP) ; Bacteriophage ; Nanobacteria

1. Introduction

Vaccination is the most effective strategy for reducing high morbidity and mortality rates, as well as diminishing the enormous social and economic impact associated with disorders. Vaccines are utilized to stimulate the immune system to initiate an immune response against specific targets, such as cancer cells and microbial agents  [1]  and [2] . Various types of vaccine may be used to treat cancers, such as whole tumor cell vaccines, dendritic cell vaccines, idiotype vaccines, antigen or adjuvant vaccines, viral vectors, and DNA vaccines  [3] , [4] , [5] , [6] , [7]  and [8] . Although the immunologic effect is not always sufficient to reverse the progression of cancer, vaccines are generally well tolerated and provide useful anticancer effects in some situations  [9] . Antigen cancer vaccines are typically composed of a cancer associated antigen, not normally present on healthy cells, along with other components (i.e. adjuvants) utilized to stimulate the immune responses against the antigens, resulting in the destruction of malignant cells, without harming normal cells, and preventing recurrence  [10] .

On the other hand, infection can protect against subsequent disease by induction of both humoral and cellular immunity, but, inert protein-based vaccines are not as effective  [11] . CD8 T cells play a vital role in protective immunity against many intracellular pathogens and cancer, but are notoriously difficult to activate by vaccination and immunotherapy  [12] . Vaccines that require a specific immunization sequence with repeated doses (such as prime-boost) are very efficient, but complicated to administer, where logistic considerations of vaccine distribution are critical  [13] .

As a novel approach, simple inert nanocarriers able to generate strong protection after a single dose could be useful for a variety of applications  [14] . These nanomaterials could be classified as nature-made and man-made nanocarriers/nanoparticles. In fact, nanobiotechnology is particularly used in developing a new generation of more effective vaccines (i.e., nanovaccines) capable of overcoming the many biological, biophysical, and biomedical barriers that the body builds against standard intervention  [15] . Nanoparticles show much promise in cancer therapy, by selectively gaining access to tumors, due to their small size and modifiability  [16] . Nano-sized particles have similarly been used for vaccine construction against microbial agents  [17] . Typically, nanoparticles are defined as particles between 0.1 and 100 nm  [18] . Nanoparticles are formulated out of a variety of substances and fabricated to carry an array of substances in a controlled and targeted mode  [19] . Nanocarriers are prepared to take advantage of fundamental cancer morphologies and modes of development, such as rapid cellular proliferation, antigen expression, and leaky tumor vasculature  [20] . Additionally, nanocarriers are promising as the delivery systems for DNA vaccines  [21] . Nanoemulsions or nanosized aerosol vaccines are also under development  [22]  and [23] . Although many reports have shown that safe, biocompatible materials could be engineered into nanoparticles that contain drugs or vaccines, researchers are trying to develop new materials for vectors that interact specifically and predictably with cells. Nanosystems will be designed to evade normal barriers and stimulate antigen-presenting cells of the immune system  [24] , [25]  and [26] . Scientists are also looking to these “smart” targetable nanoparticles as magic bullets that could seek out and destroy individual cancer cells while bypassing healthy ones  [27] . Hence, various types of nano-scaled material have been employed for the design and fabrication of nanovaccines (Table 1 ), based on nature or man-made nanocarriers. Bacterial spores, Proteosomes, exosomes, liposomes, virosomes, SuperFluids, nanoparticle-based nanobeads, virus-like particles and bacteriophages are some instances of nano-sized vehicles that are reviewed here as potential nanocarriers for vaccine delivery to immune systems  [28] . Nanobacteria are another important subject for review here, because of their role in the contamination of vaccines and some complicated disorders  [74] . Because nanobacteria have been found to be a contaminant in previously assumed-to-be-sterile medical products, we also aim to discuss it as a nano-hazard in this review  [75] .

Table 1. Characteristics of nanocarriers as nanovaccines.
Nanocarrier Source Size (nm) Immune response Ref. no.
Spore Bacterial Various Humoral-cellular [29] , [30] , [31] , [32] , [33]  and [34]
Proteosome Membrane protein-based 20–800 Humoral-cellular [35] , [36] , [37] , [38] , [39] , [40]  and [41]
Exosome Cellular 50–100 Cellular [42] , [43]  and [44]
Liposome Lipid-based Various Humoral-cellular [45] , [46] , [47] , [48] , [49]  and [50]
Virosome Liposome + viral env proteins Various Humoral-cellular [51] , [52] , [53]  and [54]
SuperFluid Biodegradable polymer 25–250 Humoral-cellular [55] , [56] , [57] , [58]  and [59]
Nanobead Inert nanomaterial 40 Humoral-cellular [60] , [61] , [62]  and [63]
VLP Viral Various Humoral [64] , [65] , [66] , [67]  and [68]
Phage Bacterial Various Humoral-cellular [69] , [70] , [71] , [72]  and [73]

2. Nature-made nanocarriers

2.1. Bacterial spores

Through evolution, nature has produced highly complex nanoarchitectures using macromolecules, especially polysaccharides, nucleic acids, and proteins  [76] . Understanding the principle of how these macromolecules interact to fabricate nano-scaled structures, it should be possible to exploit this science in the design and development of novel artificial structures and tools  [77] . The advantage of this “learning from nature” approach is that it well defines the bionanofabrication processes that already exist in bacteria  [78] . Microorganisms have novel and interesting structures, such as bacterial spore coats  [79] , which have protective characteristics  [80] . Bacterial spores are dormant life forms with formidable resistance properties. These nanostructures attribute multiple layers of protein, which encase the spores in a protective and flexible shell [81] , [82] , [83] , [84]  and [85] . The shield has features that are pertinent for merging with nanobiotechnological fields, such as self-assembling protomers, and a capacity for engineering and delivering foreign molecules  [86] . In fact, the spore coat could be employed not only as a delivery vehicle for various molecules, but also as a source of novel self assembling biomolecules  [87] . The coat can act as a device for heterologous antigen presentation and prophylactic immunization  [29] .

There are a number of attributes that make bacillus spores particularly suitable candidates for vaccine vehicles  [30]  and [31] . Two distinct approaches are accessible for vaccination. In the first approach, an antigen or epitope is engineered onto the spore coat by fusing a spore coat gene with the antigen sequence  [32] , [33]  and [34] . In the second, the antigen is expressed constitutively in the vegetative cell by fusion of the antigen gene to the transcriptional and translational sequences of a suitable bacillus gene  [88] , [89]  and [90] . Spores carrying this modified gene are used for oral delivery and then germinate in the gastrointestinal system  [91] , [92]  and [93] . Consequently, the spore offers unique capabilities for nanovaccine development that could ultimately lead to improved public health, both in developed and developing countries.

2.2. Virus-like particles

Virus-Like Particles (VLPs) structurally mimic the viral capsid, and have been extensively and successfully employed as nanovaccines  [94] . The capability of VLPs to include nucleic acids and small biomolecules has also made them novel vehicles for gene and vaccine deliveries  [95] . The repetitive surface of VLPs has regularly been used as a template for bionanofabrication  [96] . Recent progress has been shaped towards the development of virus capsids, along with the precise spacing of surface peptide domains, which enables the modification of the capsid shield through the fabrication of repetitive chemical adducts on a nanoscale platform  [97] . Recently, capsid engineering has been improved for bacteriophage and plant virus capsids, with an extension to purified VLPs  [98] . VLPs of various viruses have been confirmed as very immunogenic and are already in use as nanovaccines in humans or animals  [99] . For instance, the immunization of young healthy women with VLPs composed of the major structural protein, L1 , of HPV 16 , induced high titer neutralizing antibodies, and protected them from HPV infection and associated cervical dysplasia  [64] . The vaccination mode decreases the incidence of cervical cancer; however, a longer follow-up is essential to confirm this action. VLPs have additionally been employed to deliver immunogenic epitopes of other pathogens. They have several advantages as immunogens in the form of short peptides  [65] .

The linking of VLPs to adjuvant molecules was also shown to improve the immunogenicity of the nanobioparticles  [66] . For instance, the nontoxic subunit of cholera toxin (CTB) was chemically linked to VLPs via biotin-streptavidin  [67] . There was a higher level of Env-specific serum IgG1 , secretory IgA antibodies and cellular immune responses than in either the absence of CTB or when CTB was just co-injected  [68] . As there is increasing awareness of the VLP structure, it is expected that the development of VLPs as nanovaccines, as carriers for delivering small molecules, and as the basis for nanoarrays, will continue with even greater potency  [100] , [101]  and [102] .

2.3. Bacteriophages

While the study of the interaction of phage nanobioparticles and animals is still in its infancy, the capacity of a few of the well-studied phage strains to deliver antigenic gene products has been investigated  [103] , [104]  and [105] . Phage vaccines introduced in 1985 showed that it was possible to manufacture bacteriophages that display foreign proteins fused to their normal coat proteins  [106] . Following the description of phage display technology, its power was greatly improved using the affinity selection to isolate phages that displayed specific peptides from random peptide collections  [107] , [108]  and [109] . Employment of this technology for the development of vaccines and diagnostics has become an industry  [110] , [111]  and [112] . Additionally, it was also possible to use specific epitopes that have been chosen on the basis of biological experiments  [113] . For instance, a vaccine using a phage display system provided complete immunological protection to mice nasally challenged with live respiratory syncytial virus  [114] . A similar approach was applied to construct a phage carrying a gene product protection against Yersinia pestis infections  [69] . The phage IgG2 responses were indicated to be significantly higher following intramuscular phage vaccinations with the phage vaccine than with the plasmid DNA vaccine  [70] . Moreover, it was demonstrated that the phage nanovaccines might be made more efficient via decorating their coats with phage fusion proteins displaying immunogenic antigens for dendritic cells  [71] . This could be accomplished using a peptide that has an attaching epitope for the CD40 receptor, which has numerous functions in the activation of antigen-presenting cells  [72] . This requirement for the peptide display by phage vaccines can be enhanced by application of a developed dual expression system that permits the generation of phages with mosaic heads that can accommodate recalcitrant recombinant fusion proteins. This system employed bacteria carrying a prophage that is deficient in a major head protein, along with the plasmids carrying foreign head protein genes for both wild-type and recombinant phages  [73] .

2.4. Exosomes

Exosomes are small (50–100 nm), spherical vesicles manufactured and released by most cells, like B cells  [115] , T cells  [116] , mast cells  [117] , epithelial cells  [118] and Dendritic Cells (DCs)  [119] , to facilitate intercellular communication. These vesicles are of an endosomal origin, which are secreted in the extracellular milieu following the fusion of late endosomal multivesicular bodies with the plasma membrane  [120] . Exosomes have a defined protein composition, which confers specific biological activities contingent on the nature of the producing cell  [121] . In the multivesicular bodies of antigen presenting cells, exogenous antigens are loaded onto MHC molecules and when the multivesicular bodies fuse with the cell membrane, the MHC molecules are incorporated into the cell membrane  [122] . The internal vesicles are simultaneously released as extracellular exosomes  [123] .

Exosomes from antigen presenting cells bear not only MHC class I and II, but also costimulatory molecules, such as CD54 ,CD80 and CD86 , and they are enriched in tetraspanin proteins, like CD63 and CD81   [124]  and [125] . Tetraspanin proteins have been proposed to have a modulatory role in several different cell processes, including adhesion, migration and proliferation  [126] . Exosomes have been confirmed to be present in bronchoalveolar lavage  [127] , human plasma  [128] , malignant effusions [129]  and [130] and on the surface of follicular dendritic cells  [131] ; however, their physiological roles in vivo are still unclear. They have been suggested to participate both in T cell stimulation  [42]  and [43] and in tolerance induction  [44] . Studies in mice have demonstrated the potential of exosomes as immunotherapeutic agents in infections  [132] , transplantations  [133] , and cancer  [134] , [135]  and [136] .

The mechanisms for how exosomes stimulate T cells are unknown. Some reports indicate that the exosomes from antigen presenting cells can stimulate T cell clones, on their own  [122] and more efficiently, if the exosomes come from mature dendritic cells  [42]  and [136] . Other studies confirmed that exosomes require the presence of dendritic cells to efficiently stimulate T lymphocytes  [43] , [137]  and [138] . Some reports have employed T cells  [43]  and [139] , hybridomas  [43]  and [136] or clones  [122] , [42] , [137]  and [138] when looking at the capability of exosomes to stimulate T cells in an antigen-specific manner. These studies demonstrate that exosomes can directly stimulate viral-specific peripheral CD8+ T cells  [140] .

Although exosomes express tumor antigens, leading to their proposed utility as nanovaccines, they also can suppress T-cell-signaling molecules and induce apoptosis  [141] . The first phase I clinical trial using autologous exosomes has indicated the feasibility of large-scale exosome production and the safety of exosome administration  [142] . Exosomes manufactured by dendritic cells are named “dexosomes” and contain essential components to activate both adaptive and innate immune responses  [143] . For instance, dexosome nanovaccines have been developed that employ patient-specific dexosomes loaded with tumor antigen-derived peptides to treat cancer  [144] . The Exosome Display Technology manufactured by Anosys provides the capability to manipulate exosome composition, and tailor exosomes, with new desirable characteristics, opening up opportunities in the field of recombinant vaccine and monoclonal antibody preparation  [145] . This is gained via generating gene coding for the chimeric proteins, attaching an exosome addressing sequence to antigens or biologically active proteins  [146] . The resulting proteins are targeted to the exosomal compartment and released in the extracellular milieu enclosed to exosomes  [147] . Exosome research continues to reveal unique potential that broadens its field of application.

3. Man-made nanocarriers

3.1. Proteosomes

Proteosomes are vaccine delivery vehicles by virtue of their nanoparticulate nature, forming vesicles and vesicle clusters comparable to the size of small viruses  [148]  and [149] . Proteosome has been used to describe preparations of the outer membrane proteins from microorganisms  [150] , [151] , [152] , [153]  and [154] . Proteosomes are described as comparable in size to certain virus particles that are hydrophobic and safe for human application  [155] . Proteosomes are said to be useful in formulating vaccines with a variety of proteins and peptides  [156]  and [157] . Proteosome vaccine vesicles and vesicle clusters may range in size from 20 to 800 nm, based on the type and amount of antigen encapsulated with the proteosomes  [158] . The hydrophobic nature of the proteosome porin proteins also contributes to vaccine delivery capabilities by facilitating interaction of the vaccine nanoparticles with, and uptake of, the nanovaccines by cells that initiate immune responses  [159] . The fact that proteosomes are effective nasal vaccines is considered to be particularly related to this enhanced recognition and uptake afforded by the particulate and hydrophobic nature of proteosomes  [160] . This nanocarrier is being applied to develop nanovaccines for influenza  [35]  and [36] allergies  [37] , plague  [38] , Shigellosis  [39] , respiratory syncytial virus  [40] , and AIDS  [41] .

3.2. SuperFluids

SuperFluids are being developed for nanoencapsulating potent viral antigens in biodegradable polymer nanospheres for controlled release. These nanocarriers are supercritical, critical, or near-critical fluids, with or without polar cosolvents  [161] . Application of SuperFluids reduces the exposure of viral antigens, such as HIV and influenza, to potentially denaturing organic solvents, such as methylenechloride and ethyl acetate, and improves the stability of protein antigens in the body at an ambient temperature for a long time. Therefore, the nanocarriers enhance the capability of nanoencapsulated vaccine antigens to induce the production of protective and neutralizing antibodies  [55]  and [56] .

This controlled release nanovaccine delivery system has the capability to deliver different types and combinations of HIV or influenza vaccine candidates (such as whole inactivated virus particles, DNA plasmids, and subunit protein antigens)  [57] , [58]  and [59] . The polymer nanoencapsulation technology will decrease cost by eliminating unnecessary processing steps, while improving the manufacturing environment  [162] . The nanocarrier technology is portable, inexpensive, and amenable to large-scale processing  [163] .

Several enabling nanotechnologies have been developed, according to SuperFluids, for the enhanced delivery of nanovaccines and nanodrugs, ranging from potent anticancer therapeutics to large recombinant proteins. One of these technologies is protein nanocarriers  [164] . Protein nanocarriers can be generated without reduction in protein integrity and efficacy in a solvent-free process, based on a SuperFluids rapid expansion mechanism for the enhanced drug delivery of protein macromolecules. This technology can be applied to the pulmonary delivery of proteins and polypeptides. It also is used for oral or depot delivery of vaccine antigens. Another form of these technologies is polymer nanospheres  [165]  and [166] . Biodegradable polymeric nanospheres can be manufactured utilizing SuperFluids technologies for the controlled delivery and release of proteins through reverse engineering of the rapid expansion mechanism  [167] . This technology can be employed for oral or depot delivery of proteins and controlled-release adjuvants of vaccine antigens for infectious diseases  [168] . The other generation of these technologies is phospholipid nanosomes  [169] . Phospholipid nanosomes or small uniform liposomes for the enhanced delivery of hydrophilic and hydrophobic drugs can be produced without the use of toxic organic solvents, using a similar mechanism  [170] . This technology can be employed for intravenous and topical administration of small hydrophilic nanodrugs, proteins and genes  [171] .

3.3. Nanobeads

Nanoparticle-based nanobeads serve as nanovaccine fabrication and more effective immunization  [172] . Although a number of adjuvants are currently confirmed for use in animal species, only alum has been widely employed in humans  [173] . While it induces strong antibody responses, cell-mediated responses are often low, and inflammatory reactions at the site of injection are usual  [174] . Immunological characteristics of a novel nanobead adjuvant have been investigated in a large-animal sheep model  [175] . Contrarily to alum, the antigen covalently bound to nanobeads induced substantial cell-mediated responses, along with moderate humoral responses  [60] . No adverse results were recognized at the site of immunization in the sheep  [61] . Thus, nanobead adjuvants in veterinary species may be useful for the induction of immunity to viral pathogens, where a cell-mediated response is favorable  [62] . These findings also highlight the useful ability of nanobead vaccines for intracellular pathogens in humans  [63] .

Nanobeads measure 40 nm  [176] . Most adjuvants only stimulate antibodies against a particular disease. Nanobead technology gives the immune system a further boost, also producing T cells which are required to eliminate viruses or cancer  [177] . The size of 40 nm is critical, as it is similar in size to many viruses, where the nanobeads are taken up abundantly by the immune system and tricked into manufacturing high levels of many types of T-cell  [178] . Covalently attached peptide to inert carrier nano-beads can induce both cellular and humoral immunity in large outbreed animals, such as sheep  [179] . This fact indicates that combining several peptides in the peptide-nano-bead based vaccine approach can improve immunogenicity and may be beneficial when dealing with a highly variable pathogen like foot-and-mouth disease virus  [180] .

3.4. Virosomes

Virosomes were developed from liposomes by combining liposomes with fusogenic viral envelope proteins  [181] . Unlike viruses, virosomes are not capable of replication but are pure fusion-active vesicles  [182] . Due to the presence of specialized viral proteins on the surface of virosomes, they can be applied to the active targeting and delivery of their content at the target site  [183] . Viruses have developed the ability to fuse with cells during the course of evolution, allowing for release of their contents directly into the cell  [184] . This is because of the presence of fusogenic proteins on the viral surface that facilitate this fusion. If these fusogenic viral proteins are reconstituted on the surface of a liposome, then, the liposome also acquires the ability to fuse with cells  [185] . This is an extremely useful tool in active transport, because it allows the direct release of the liposomal contents into the cell. As there is no diffusion of bioactive material involved, it results in a more effective delivery. In another words, virosomes are reconstituted viral envelopes that retain the receptor binding and membrane fusion activities of the virus from which they are derived  [186] .

Upon endocytosis, the low pH in the endosomes induces fusion of the virosomal membrane with the endosomal membrane, causing the release of the contents of the virosome into the cytoplasm of the cell  [187] . The fusion process is mediated by hemagglutinin, the major envelope glycoprotein of the influenza virus  [188] . Virosomes can be manufactured by detergent solubilization of the membrane of an enveloped virus, sedimentation of the viral nucleocapsid, and subsequent selective removal of the detergent from the supernatant, to produce reconstituted membrane vesicles consisting of viral envelope lipids and glycoproteins  [189] . The most common viruses used in the fabrication of virosomes are: Sendai, Semliki Forest, influenza, herpes simplex, and vesicular stomatitis [190] , [191] , [192] , [193]  and [194] . The size and surface characteristics of virosomes can be measured through microscopic visualization. Almeida and colleagues published the first report on the generation of lipid vesicles containing viral spike proteins derived from the influenza virus  [195] . They succeeded in producing membrane vesicles with spike proteins protruding from the vesicle surface using preformed liposomes and hemagglutinin and neuraminidase, purified from the influenza virus  [196] . Visualization of these vesicles by electron microscopy revealed that they very much resembled the native influenza virus. Consequently, they were called virosomes  [197] .

Reconstituted virosomes or artificial viral envelopes appear to be ideally suited as nanovaccine formulations for the delivery of protein antigens to the cytosol of antigen presenting cells, and thus, for the introduction of antigenic peptides into the MHC class I presentation pathway  [198] . Cytotoxic T-cell activity can be induced by immunization of mice with an antigenic peptide or an entire protein encapsulated in virosomes  [51] . The action of influenza virosomes is likely to involve both delivery of the enclosed antigen to the cytosol of antigen presenting cells and the powerful helper activity of the virosomal hemagglutinin. Although the immune responses elicited by DNA-virosomes are moderate, they are promising and warrant further research to ultimately develop effective DNA-based virosomal nanovaccines  [199] . The presence of virus proteins not only allows the liposome to target a particular cell, but also allows it to fuse with the cell, ensuring direct delivery of the incorporated material  [200] .

The key feature of the immunopotentiating reconstituted influenza virosomes is cytoplasmic delivery of the molecules encapsulated in or associated with the nanoparticle, as opposed to plain liposomes being a prerequisite for efficient immune activation  [201] . Two human nanovaccines based on this technology (i.e., hepatitis A virus and influenza) have been successfully transferred to the market. Several additional candidates are also under development  [202] , [203]  and [204] . The excellent immunogenicity, as well as superior tolerability, of virosomal nanovaccines has been clinically approved. In the trivalent influenza nanovaccine, the virosome components (hemagglutinin and neuraminidase), which are isolated from virus strains yearly recommended by the World Health Organization, correspond to the nanovaccine protective antigens  [202] .

Furthermore, virosomes have been shown to induce cytotoxic T cell responses specific to encapsulated peptides. Therefore, they may also be employed to incorporate other unrelated antigens in the virosomal membrane; for example, a virosomal hepatitis A virus nanovaccine is currently on the market [203]  and [204] .

Further development of virosomal nanovaccines will include the formulation of peptide epitopes (e.g. malaria, and hepatitis C)  [205]  and [206] and approaches based on the use of recombinant protein  [52] or nucleic acid  [53] . Because virosomal nanovaccines can induce both cellular and humoral responses, these efforts are not limited to prophylactic purposes, but aim also for therapeutic applications in the field of chronic infectious diseases and cancer  [54] .

3.5. Liposomes

Liposomes are vesicles of varying size consisting of a spherical lipid bilayer and an aqueous inner compartment that is produced in vitro   [207] . First, liposomes were employed as a model to study the effect of narcotics on lipid bilayer membranes  [208] . Later, the liposomal structures were used as an immunological adjuvant  [209] . Since these early experiments, liposomes have become an established carrier and delivery vehicle in the field of pharmaco- and immuno-therapy.

Various aspects of immune responses mediated by liposomes in vivo show their promise in the development of optimized and subunit-defined nanovaccines  [210] . The extensive literature demonstrates that liposomes are endocytosed and they undergo processing through a very well characterized endocytic pathway, delivering their contents, including peptide antigens  [211] to lysosomes  [212] . Liposomes are a unique among delivery systems in that they are capable of modulating the generation of both CD4+   [45] and CD8+   [46] mediated immune responses, and generation of Th1 ,Th2 or Th1 / Th2   [47] phenotypes, and may possess the capacity to modulate a Th1 / Th2 switch  [48] . The induction of cell-mediated immune responses clearly proposes the occurrence of intracellular delivery of antigen to antigen presenting cells via the classical MHC I and MHC II pathways. Additionally, liposomes might act as adjuvants through the nonclassical pathway mediated by CD1 molecules  [49] . Liposomes have also been reported to promote the development of T-cell independent immune responses  [213] , and are recognized for their potential to promote long-term immunity through the development of T-cell memory  [214] .

The findings outlined above show the versatility and capability of liposomes for cell-mediated immunization. However, the specific mechanisms by which they modulate antigen presentation remains unclear  [215] , and their delivery mechanisms have not been optimized for immunization purposes. It has been suggested that immunization by the use of liposomes with entrapped DNA could circumvent the request for muscle involvement and facilitate  [216] , instead, the uptake of DNA by antigen presenting cells infiltrating the site of injection or in the lymphatics, at the same time protecting DNA from extracellular degradation  [217] . Moreover, transfection of antigen presenting cells with the liposomal DNA and subsequent immune responses to the expressed antigen could be promoted by the judicious choice of vesicle surface charge, size, and lipid composition or by the coentrapment of DNA with the plasmids expressing appropriate cytokines or immuno-stimulatory sequences  [218] .

Procedures have been now developed, by which plasmid DNA can be quantitatively entrapped into large  [219] or small  [220] neutral, anionic, or cationic liposomes that are capable of transfecting cells in vitro with varying efficiency  [221] . Using liposomes, immunization of inbred or outbred mice by a variety of routes, including the oral route  [222] , with cationic liposomal DNA, led to much greater humoral and cell-mediated immune responses, including cytotoxic T cell  [50] immune responses to the encoded antigen, than those gained with naked DNA or DNA complexed to preformed similar liposomes. This approach to genetic immunization mimics the way by which immunity is acquired in viral infections, where both the viral DNA and the envelope proteins it encodes contribute to the immune responses against the virus  [223] . This technology has been further advanced by the finding that coating liposomes containing the DNA and protein nanovaccines with mannose residues, via incorporation into the bilayers of a mannosylated lipid, further potentiates immune responses to the nanovaccine, presumably by the targeting of such liposomes to the mannose receptors on the surface of antigen presenting cells  [224] .

4. Nanobacteria

Nanobacteria are novel self-replicating- and mineralizing agents. The nanobioparticles have been purported to be living organisms that are 80–500 nm in size  [225] . Nanobacteria have been identified by National Aeronautics and Space Administration (NASA) scientists as a potential culprit in kidney stone formation among astronauts. With the potential for future exploratory space missions to the Moon and Mars, longer missions, and exposure to the elements of outer space, health is a major concern for astronauts  [226] . The concept that nanobacteria are living organisms is still controversial, because research into their putative nucleic acid has not been completed yet. However, researchers have provided additional clues to understanding nanobacteria and its link to pathologic calcification-related diseases  [227] .

Nanobacteria are, in fact, an abiotic phenomenon  [228] . First reports stated that the investigators could obtain nanobacteria-like particles from healthy human serum by following a previously published protocol, but they observed that these nano-sized organisms were identical to the nanoparticles that are obtained when CaCO3 precipitates  [229] . Further investigations indicated that varying the levels of CO2 and NaHCO3 in the growth medium that was used to incubate the human serum could change the appearance of the nanobacteria-like particles and, so, it could be concluded that the nanobacteria are CaCO3 precipitates  [230] . In another study, the nanobacteria strain Nanobacterium sp. strain Seralab 901045 was analyzed  [231] . This strain was submitted to a comprehensive battery of tests, and the researchers concluded that there was no evidence to support the theory that nanobacteria are living organisms, and instead proposed that they are self-propagating nanoparticles that comprise a fetuin-containing mineral–protein complex  [232] .

On the other hand, nanobacteria are cytopathic in cells and invade mammalian cells in a distinctive pathway. Nanobacteria trigger mammalian cells that are not commonly phagocytic to engulf them, subsequently  [233] . The nano-organisms are one of the agents for cell vacuolization, poor thriving and unexpected cell lysis, problems generally encountered in mammalian cell cultures. Electron microscopy and FITC staining with specific monoclonal antibodies revealed that nanobacteria were bound on the surface of the fibroblasts  [234] . This means that nanobacteria were internalized, either by receptor-mediated endocytosis or in a closely related manner. Fibroblasts indicated apoptotic abnormalities and death after internalization, if subjected to a high dose of nanobacteria per cell  [233]  and [234] .

In summary, nanobacteria are non-detectable organisms with present sterility testing procedures; however, they are detectable with advanced culture and immunoassays. They are commonly present in serum and blood products and subsequently in cell cultures and antigens (such as nanovaccines derived therefrom). Also, they may be present in antibody and gammaglobulin products. Nanobacteria are a potential risk because of their cytotoxic properties and capability of infecting fetuses. Thus, their pathogenicity should be scrutinized  [235] .

5. Conclusions

Nanobiotechnology in nanomedicine is in its infancy, having the potential to change medical research dramatically in the twenty-first century. Nanocarriers can be employed for analytical, nanoimaging  [236] , nanodiagnostic  [237] , [238]  and [239] , nanotherapeutic  [240] , and nanovaccination (Table 1 )  [241] goals. Objectives, such as targeting cancer  [242] , drug delivery  [243] , improving cell-material interaction  [244] , scaffolds for tissue engineering  [245] , gene delivery systems  [246] , and providing innovative opportunities in the fight against incurable diseases  [247] , will improve the use of nanobiotechnologies. Having more knowledge about nanobiotechnological tools and techniques  [248]  and [249] , there has been great progress on recognizing the function of biological nanostructures and their interaction and integration with several non-living systems. However, there are still open issues to be considered, mainly related to the biocompatibility of the nanomaterials which are entered into the body  [250] . Many novel nano-sized materials and nanocarriers are expected to be used, with an enormous positive impact on human health. In fact, the side-effects can be significantly reduced by delivering the vaccine agents using nanocarriers. For example, the vision is to improve health by enhancing the efficacy and safety of vaccination using nanobiotechnological approaches  [251] .

On the other hand, the safety of nanovaccines is equally important. This concept has been found to be useful in employing nanovaccines. However, with nanovaccines, the particles are cleared slowly over a prolonged time period and this may induce toxicity  [251] ; thus, nanobacterial contamination would be possible. In recent years, some scientists have evaluated different nanomaterials with different assays to show their heterogeneous responses and their activities in life systems  [252] . They also predicted the nanotoxicity of nanomaterials and their safety in human studies. Their efforts will help to speed up nanotoxicological tracking of nanomaterials by applying high-throughput assays and evaluation acceleration using nanomaterials for clinical trials, to manage disorders in the near future  [251]  and [253] .

In conclusion, “Nanobiotechnology” will play a key role in the medicine of tomorrow (i.e., Nanomedicine) providing revolutionary opportunities for therapeutic and protective ways to improve health and enhance human physical abilities, and enable precise and effective modern nanovaccines tailored to the patient  [254] .

Acknowledgments

The present study was partly supported by Golestan University of Medical Sciences (GOUMS) and the Iranian Nanotechnology Initiative Council (INIC) .

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