Application of Nanomaterials and Biomaterials in Nanovaccinology

    


    


    Figure 3: Nanoparticle platform vaccine technologies [1].

    

Self–assembled peptide nanoparticles (SAPNs): Self–assembled peptide nanoparticles were expressed and produced in Escherichia Coli as 180 repeated peptide constituents forming a scaffold with the immune stimulatory property. These platforms are suitable for a wide range of antigens but has be more specifically studied in the development of seasonal Flu and COVID-19 vaccines [68,89,90].

Carbon-based nanostructure systems: Carbon-based nanostructure systems, including Carbon Nanotubes (CNTs), carbon magnetic nanoparticles, and carbon nanoparticles, are other Nano biomaterials that are interestingly under investigation. Their dual functions of drug/ antigen carrier and adjuvant immune stimulatory potentials are being evaluated by different research teams [67,68,91-106]. The research showed that functionalized MWCNTs using a silicon reaction together with INH drug increase the level of performance and reduces the effective dose of the drug in the treatment of tuberculosis [107]. Another characteristic of functionalized CNTs is penetration into the bacterial membrane. Sheikhpour et al. found that CNTs functionalized with carboxylic acid had antimicrobial effects on Staphylococcus aureus by destroying membrane integrity and increasing drug efficiency [108]. Conventional vaccines and nano vaccines are different in activation of the immune response, dose number, cellular uptake, lymph node accumulation, antigen presentation, and migration-activation and cytokines secretion. Lower required dose, increased robust reuptake by DCs, greater accumulation in lymph nodes, increased cellular immunity, and more stimulatory cytokine secretion are shown as the most important advantages of nanotechnological vaccines [102].

CNTs are promising multidisciplinary nanostructures in biomedicine. However, toxicity of CNT and its biocompatibility are important milestones in biomedical administration [92,106]. Long-term exposure to CNTs can cause persistent inflammation, lung cancer, fibrosis, and gene damage in the lung. The presence of MWCNTs inside the body led to the production of cytokines such as TNF-α and IL-1β from immune cells, which play a role in toxicity. SWCNTs also cause acute effects such as inflammation, granuloma synthesis, collagen deposition, fibrosis, and genotoxicity. However, by using new methods such as functionalization, it is possible to produce nanotubes with greater length, greater width, and greater curvature to some extent with less toxicity [109]. Polymeric functionalization with phospholipid PEG derivatives and surfactants would remarkably improve CNTs’ biocompatibility; Moreover, functionalization would also facilitate secondary conjugation with drug molecules [94-99]. In the study, it was found that the simultaneous administration of functionalized carbon nanotubes and meropenem in nanofluid conditions caused a significant decrease in the growth of Pseudomonas aeruginosa and antibiotic resistance by increasing the stability of the drug [110]. Functionalized CNTs are not intrinsically immunogenic but are capable of activating immune system cells, including monocytes, macrophages, and DCs, after cellular reuptake. The application of SWCNTs is proposed as immune stimulator candidates and antigen carriers in vaccine studies [67,97,102]. For example, Meng et al. showed that SWCNT-conjugated tumor cell lysates resulted in better immune responses than free tumor cell lysate [97,111]. Zeinali et al. also reported that immunization with BCG vaccine as PPD-SWCNT induced a higher level of Th1 cell response in comparison to free PPD [97,112]. Hadidi et al. also confirmed the immune modulatory properties of PL-PEG-SWCNTs. Their results showed that PL-PEGSWCNTs concentration and PL-PEG-SWCNT–alum-HB vaccine concentration ratio directly affects the expression of activation and maturation markers in MDDC. These data support the idea of the co-adjuvant potential of PL-PEGSWCNT- alum compounds [97]. Different CNTs with different lengths and surface modifications were found to directly affect anti-azoxystrobin IgG antibodies in animal studies [113].

Carbon magnetic nanoparticles are traceable materials, potentially effective in active targeting to DCs. Graphene oxides and fullerene (C60) would potentiate antigen presentation to DC s and MHC- I APCs and T cells, respectively [67].

CNTs internalization is through direct translocation due to its needle-like structure or by endocytic-phagocytic mechanisms. Mechanism of cells reuptake is CNTs type, synthesis method, impurities, size, and surface functional groups [102]. CNTs reuptake by macrophages is mostly mediated by MACROs receptors and would generally end in activation of inflammatory pathways, cytokine secretion, and cell apoptosis /necrosis. PL-PEG-SWNTs smaller than 400 nm internalize non-phagocytic cells, including COS7 and MCF7, through passive diffusion, while larger ones would prefer the endocytosis pathway. The interaction and reuptake of CNTs by phagocytic cells are highly dependent on both natures of phagocytic cells and CNTs functionalization type. So, different cellular signaling pathways might be activated by amine or carboxyl functional groups on the CNTs surface [114-116]. Monocyte-Activating Nanotubes (MA-CNTs) are Oxidate-MWCNT-NH3+ induce maturation of dendritic cells, cytokines production of IL-6, TNF-Alfa, NFKB signaling activation, and cytokine secretion by T helpers. So, Oxidate-MWCNT-NH3+ would be prospecting immune therapeutics in cancer management [117,118]. Carboxylate Pl-PEG-CNTs activate DC maturation and activation as well as IL6, IL10, and TNF and NFKB production. On the other hand, pure CNTs would activate oxidative stress and caspase-1 pathways, IL-1 production, and cause cytotoxicity [102]. It has been stated that ammonium-functionalized CNTs and ox-CNTs would modulate the immune system without induction of cell apoptosis [119,120]. Allen et al. first describe CNTs’ enzymatic biodegradation and elimination by Horseradish Peroxidase (HRP) [102,121]. PEGylated CNTs would experience auto degradation by Myeloperoxidase (MOP), Eosinophil Peroxidase (EPO), and hypochlorous acid in side neutrophils [122]. Macrophage NADPH oxidase-dependent ROS, lignin peroxidase, xanthine oxidases, and manganese peroxidases are responsible for CNTs biodegradation [123,124]. Biodegraded CNTs would finally eliminate by exocytosis through the trans-Golgi complex [102].

CNTs immune modulation capacities include immune stimulation and immune suppression. Immuno stimulation would happen through cellular (macrophage-monocyte) response, DCs, lymphocyte and complement system activation, plus IL-6, IL-12, and Il-2 production. Immunosuppression would occur through the Cyclooxygenase (Cox) pathway, prostaglandin, and Il-10 secretion [102].

It could be concluded that functionalized CNTs might be a potential candidate in vaccine developments. CNTs’ physiochemical and structural properties are of great concern in biocompatibility, biodegradability, immunomodulatory, and design of antigen cargos. Further studies on how CNTs physicochemical modification would alter its interaction with immune cells have become necessary in finding the best options for cancer and infectious diseases, including HIV and Covid-19 [102].

Physicochemical properties of nanomaterial: It should be noted that physicochemical properties play important roles in the design and development of nano formulations with improved antigen delivery and presentation that target vaccine molecules to specific sites and induce desired immune responses [125-127]. From this point of view, shape, size, surface charge, surface volume ratio, porosity, hydrophobicity, hydrophilicity, and crystallinity are key factors that affect nanoparticles’ pharmacokinetic and pharmacodynamics parameters as well as antigen release and degradation kinetics [127].

The sizes of nanomaterial determine the mechanism of cellular uptake and specificity [127]. It has been reported that large PLGA nanoparticles (1, 7, and 17μm) showed a reduced internalization rate in comparison to smaller ones (300 nm). Smaller nanomaterial (20–200 nm) were readily endocytosed by the resident DCs, whereas larger sizes (500– 2,000 nm) were effectively taken up by the migratory DCs, and particles less than 200 nm size were drained into the lymph nodes. On the other hand, particles up to the 20 nm range were suitably transported to the APCs [127].

Particle shape also affects the cellular interaction, intracellular trafficking, and rate of antigen release inside the host cells, phagocytosis rate and the activation of signaling pathways, and improvement of antigen processing and presentation to T-cells. For example, Spherical gold nanoparticles were actively internalized by bone marrow-derived dendritic cells and were able to induce a stronger immune response in comparison to cube,rod, or worm-shaped particles. Particle shape would also affect localization. It is said that nanorods were practically delivered to the cell nucleus; however, nanosheets have remained in the cytoplasm after endocytosis [127,128].

Surface charge is also effective in antigen internalization. This electrostatic interaction was exemplified by the observation of significantly improved internalization of cationic polystyrene nanoparticles by the APCs in comparison to neutrally charged particles. Surface functionalization and modification with TLR-7, TLR-8, TLR9 agonists, CD47 molecules, TLR2, and TLR4 agonists, and galactose were also reported to activate the complement pathway, increased cytokine production and the expression of immune regulatory genes [127,129].

Hydrophobicity and hydrophobicity also matter in nano vaccines. Hydrophobic polymeric nanostructures are strong inducers of pro-inflammatory cytokines and co-stimulatory molecules than hydrophilic structures. Hydrophobic polymeric nanostructures also facilitate opsonization by increasing the immunoglobulin adsorption on the cell surfaces [127,128].

Nano Vaccines

Nano vaccines are suitable tools for targeting organs or tissue where disease or infection originated from, while conventional vaccines would affect the whole body. Nanoparticles are applicable to improve the solubility of hydrophobic compounds for parenteral administration. They maintain the integrity of antigens against degradation, stabilize peptides, proteins, or nucleic acids and reduce required doses. In addition, mucosal immunity, antigens protection against enzymatic‐acidic degradation, and a depot reservoir system with controlled release patterns are listed as other advantages of nano vaccines [130].

Membrane based cancer nano vaccines: Traditional membrane-based cancer nano vaccines are classified as a single-cell type (e.g. erythrocytes, lymphocytes, etc.); however emerging membrane-based cancer nano vaccines are categorized as exoxomes, hybrid cells and microcapsules with outstanding antitumor capacities (Figure 4). The membrane fraction of hybrid cells group might be separated from cancerous cells, dendritic cells and erythrocytes. Hybrid membranes were reported to demonstrate enhanced antigen delivery efficiency and precise targeting via lymph node guiding. There are currently 12 ongoing clinical trials conducting hybrid membrane strategy in vaccine development. Nie et al. developed an adjuvant and antigen co-delivery nano vaccine based on Escherichia coli and tumour cell membranes with a potent antitumor activity in vivo [131,132].

Figure 4: Emerging membrane-based nano vaccines: a) exosome membrane, b) hybride membrane, c) microcapsule [132].

    


    


    Figure 4: Emerging membrane-based nano vaccines: a) exosome membrane, b) hybride membrane, c) microcapsule [132].

    

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Exosomes are one of the most unique nannocarriers from membrane-enclosed Extracellular Vehicle group (EV). Exsomes’ size normally varies between 30 to 150 nm. Desirable size, biocompatibility, in vivo stability, and target-specifi c delivery makes them potential candidate as adjuvant and antigen carriers. Exosomes are also considered as agents for local and systemic cell-to-cell communication through transfering functional substances to recipient cells. The studies’ results reveal that exosomes can be exploited as biomarkers and immunotherapeutic agents for nano vaccines development [131,132]. DC-derived Exosomes (DEXs) form a new class of vaccines for cancer immunotherapy which elicit strong immune responses and tumor suppression in animal cancer models. DEXs efficacy have been investigated in patients with advanced melanoma and Hepatocellular Carcinoma (HCC) [133]. Promising outcomes reveal that DEXs can serve as novel cancer nano vaccines due to their in herited antitumor properties. Schirrmacher and Barz reported that Tumor-Derived Exosomes (TDEs) displayed antigens similar to their corresponding tumor cells in Cytotoxic Lymphocytes (CTLs [134].

Wei et al. designed a chimeric-membrane nano vaccine based on exosomes from macrophage-tumor hybrid cells. Their customized nano vaccines targeted lymph nodes and T-cells in a unique ‘direct exosome interaction’ manner with long-lasting induction of tumor regression in various cancer models, especially when combined with anti-PD1 therapy [132,134]. Exosomes’ capability as adjuvant was also investigated in combination with genetically improved murine melanoma B16 cells. They successfully induced immunostimulatory signals in mice 7 days after the last immunization. These results reveals the potential benefits of exosomes as adjuvant and carriers for future cancer vaccine development [135]. Exosome-based vaccine candidates for cancer, hepatitis B, AIDS, and other infectious diseases are under investigation by researchers all over the world [131].

As for microcapsule-based nano vaccines, Wang et al. prepared a self-healing microcapsule system that can generate a desirable tumor microenvironment in situ, wherein antigen release, APC cells recruitment and acid microenvironment are deigned to work in a synergetic manner to promote anti-tumor activity [132]. Currently, Wei et al. have also designed two microcapsule-based nano vaccines with potent antitumor activity in various hematological cancer and solid tumor models in vivo [132].

New era in vaccinology and Biomaterials’ Role: Weak immunogenicity and short-term stability are most common limitations associated with subunit antigens. Biomaterials offer many advantages including biocompatibility, adjustable immunogenicity, low immunological reaction and desirable stability in comparison to conventional vaccine delivery systems. In the recent decade, biomaterial-based platforms such as synthetic and natural polymers, lipids, crystalline scaffolds, microneedles, and other particles have rapidly come out in order to improve vaccine essentials including efficacy, safety and stability simultaneously but only a few of suggested systems provide sustained or controlled release properties. For example, synthetic biodegradable polyesters are suitable for antigen encapsulation (e.g., single / double emulsion solvent evaporation and spray drying). Polyesters are compatible with various administration routes (e.g., dermal, intranasal and subcutaneous) and offer a flexible formulations and platforms for enriched immune response. However, stability and production of a local acidic environment following hydrolysis is their main bottle neck in proteins formulation.

Melt extrusion or co-extrusion with other materials has been investigated to design implantable vaccines for HPV (human papillomavirus) and seems promising. Figure 5 illustrates some of the commonly used synthetic polymers in vaccine formulations [136-139]. Biomaterials application have been suggested as one of the standard protective solutions to overcome these problems and augment immunization. Biomaterials are good in stabilizing host antigens and achieving sustained release pattern. However, there is still a significant challenge in vaccine formulation to achieve optimal therapeutic efficacy. Figure 6 illustrates some commonly used polysaccharides in vaccine formulations that might overcome some of formulation challenges in vaccine developments. Dextran, alginate, chitosan, hyaluronic acid and starch been described as applicable polysaccharides in controlled vaccine delivery.

Figure 5: Commonly used synthetic polymers in vaccine formulations [136].

    


    


    Figure 5: Commonly used synthetic polymers in vaccine formulations [136].

    

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Figure 6: Common polysaccharides in vaccine formulations [136].

    


    


    Figure 6: Common polysaccharides in vaccine formulations [136].

    

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Distinguished properties of natural polysaccharides that have attracted attention are their desirable water solubility, ease of preparation, simple chemical modification and flexibility of administration in oral and intranasal routs [136].

Chitosan has been highly recommended in vaccine formulation of hydrogels and Metal–Organic Frameworks (MOFs) against infectious diseases owing to its high safety and ease of clearance. This phenomenon might be explained by chitosan’s strong electrostatic interaction owing to its positively charged nitrogen that synergistically enhances APC uptake and immune activation.

Figure 7 briefly illustrates several antigen/biomaterial interaction approaches. The interaction might be classified into five categories; surface adsorption, mixing, encapsulation, conjugation. Surface adsorption is completely based on electrostatic or hydrophilic/hydrophobic interactions that lead to the weak antigen attachment and burst release in vivo. However, encapsulation and conjugation through chemical bonding and cross linkage of antigen with selected biomaterials would lead to improved immunogenicity. This assumed to be happened because of gradual degradation of biomaterials intra/extracellular environment. Currently, simultaneous adsorption and encapsulation interactions are the most commonly applied interactions for improving vaccines sustained release pattern. Pulsatile release seems to be a better alternative in comparison to a single injection followed by several booster shots. This methodology is suggested to avoid immune cell exhaustion and reduced antibody-antigen affinity that normally occur in booster single shots. It might be concluded that biomaterials application in antigen delivery and vaccine development seems effective in improving vaccine stability and performance but there are still questions that need to be addressed by researches [136].

Figure 7: Schematic antigen/biomaterial interaction approaches [136].

    


    


    Figure 7: Schematic antigen/biomaterial interaction approaches [136].

    

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Conclusions

Low rate of patient response and off-target adverse events of nanomaterial’s application in vaccine development indicate that many challenges exist and should be addressed to achieve more successful platforms [128]. The key principle is how to trigger appropriate antigen-specific immune responses by stimulating immune cells and inducing innate/adaptive immune responses. The flexible design of nanostructures endows nano vaccines with improved specific immune responses. These vaccine types mainly benefit from their unique drug/antigen delivery, adjuvant properties and customized immunomodulation properties in nano scale [127]. Currently, most vaccines are administered by a parenteral route, which is invasive and has poor patient compliance. However, nanomaterial application in vaccine development provided various options for vaccine administration, including topical, intranasal, inhalation, and oral administration for both therapeutic cancer vaccines and preventive vaccines for infectious diseases [128].

In general, toxicity, scale‐up process in sterile conditions, and difficulties in presenting naive antigens are critical limitations in vaccine platforms. However, with the advent of new techniques such as scaled‐up methodology for spray drying, some obstacles of scale‐up are eliminated, but there is still a long path to omit this millstone [128,129]. Nanotechnology platforms tend to intensify immunogenicity by effective targeted antigen delivery through their immune-modulatory properties; improved formulation stability, controlled release pattern, less immune toxicity and immunosuppression, surface modification, co-delivery of antigens and adjuvants, customized differentiate cellular and humoral immune responses and scalability. Additionally, nanoparticles could be tailored for single dose, non-invasive administration of antigens through immune engineering methods and co-encapsulation with stimulatory molecules.

Although nanotechnology-based vaccines are currently in different stages of clinical trials, these considerations would potentiate ongoing strategies in nanomaterial application, nano vaccines, and anti-infective treatments. More effective vaccines are to be developed by compromising nano vaccines and immune cell interactions. It has been well established that physicochemical properties of nanomaterial, including type, size, shape, surface charge, and hydrophobicity level, are the main factors affecting interactions, antigenicity level, adjuvant properties, and host immune response. Thus it might me concluded that, emerging nano vaccines and nanobiomaterials are beneficial tools for next generation vaccines with optimum efficacy for different route of administrations and targeted immune cells as well as improved safety and more flexible dosing regimen.

Author Statements

Acknowledgements

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Conflict of Interest

We should acknowledge our team in Pasteur Institute of Iran that shows high attribution in writing this manuscript.

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Citation: Hadidi N, Sheikhpour M, Mohebbi M, Sadat SM. Application of Nanomaterials and Biomaterials in Nanovaccinology. Austin J Biosens & Bioelectron. 2023; 8(2): 1047.

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