Bio- and Nano-Material-Based Strategies for Allergy Therapy: Comparison
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An allergic reaction is the useless response of the immune system toward a harmless substance (allergen) and is the consequence of a failure in the development of tolerance. Allergen-specific immunotherapy (AIT) is the only allergy treatment that can provide long-term effects since it tries to address the underlying pathological mechanism, changing the immune response to the allergen from a Th2 response towards a Th1 or a regulatory (Treg) response.

  • allergy
  • nano-materials
  • immunotherapy

1. Bio- and Nano-Material-Based Strategies for Allergy Therapy

In some cases, especially in severe allergy reactions, the administration of the allergen during AIT (even if it is performed at extremely low doses) can trigger an undesired immune response that can be potentially life-threatening. For this reason, alternative allergen administration strategies have been developed to maintain the therapeutic potential of AIT while decreasing the associated risks. One of the most common strategies is the use of hypoallergenic immunotherapy agents, which have been modified to keep the immunotherapeutic potential from the original allergen, while drastically reducing the likelihood of producing an undesired allergic response [1]. An alternative strategy is to use different delivery vehicles that can concentrate the allergen in target cells, organs, or tissues, decreasing the dose of allergen needed for the therapy and, therefore, diminishing the risk of undesired reactions [2][3][4][5]. These delivery vehicles are usually bio- and nano-materials whose properties can be tuned for each specific application, depending on the cargo to be loaded inside, the route of administration, and the target cells or organs. Additionally, these materials can also inherently act on the allergic response (either positively or negatively) without the need for a therapeutic cargo, depending on their composition, size, and other physicochemical characteristics, so some could be used directly as a therapeutic option in allergy [6]. Therefore, there are three main strategies in which bio- and nano-materials can be used as a therapeutic tool in allergic diseases:
  • Using bio- and nano-materials with a direct effect on cells involved in the allergic response.
  • Use of bio- and nano-materials as allergen delivery vehicles for immunotherapy.
  • Use of bio- and nano-materials as co-delivery systems containing the allergen and immunomodulatory molecules.

2. Using Bio- and Nano-Materials with a Direct Effect on Cells Involved in the Allergic Response

In this therapeutic strategy, the effect is caused directly by the interaction of the material with a certain cell type involved in the allergic response, without any cargo being delivered from the material. Therefore, the administration route and the therapeutic potential of each particular strategy will depend on the participating cell type. For example, materials that interact with cells involved in the sensitizing stage of allergic diseases will possess a principally prophylactic potential since their effect will probably be very limited once sensitization has already occurred. One of the processes that can be affected by this type of approach is allergen processing. Allergens display a particular processing kinetic, even if they share structural characteristics with non-allergenic proteins. The Allergenicity of an antigen is reflected by increased resistance for endolysosomal processing. High allergenic potential of Bet v 1 (major birch pollen allergen) has been attributed to its limited susceptibility for proteolytic degradation in DCs [7]. Nevertheless, decreasing antigen processing by means of the use of nanoparticles may switch DCs toward a tolerogenic state. DCs treated with polyvinyl alcohol-coated super-paramagnetic iron oxide nanoparticles (PVA-SPIONs) showed a decrease in antigen processing, expression of MHCII, and stimulation of CD4+ T cells in vitro, suggesting an intrinsic capacity of PVA-SPIONs for immune-modulation affecting DCs function [8]. However, it is worth noting that in the case that a similar prophylactic approach was successfully translated to the clinic, its use would be limited to high-risk individuals exposed to specific allergenic substances.
On the other hand, materials can interact directly with effector cells involved in triggering the allergic response, such as MC or basophils. As an example of this, we can find the work of Ryan et al. [9], where fullerenes were shown to exhibit a direct effect on MC behavior in vitro, decreasing the IgE-induced release of mediators. Furthermore, when this material was evaluated in a murine model of anaphylaxis, fullerene administration also partially prevented the decrease in body temperature and the release of histamine. Approaches similar to this have greater applicability in the clinic, as they could potentially be used for a wide range of allergies in which different allergenic proteins are involved. However, this material could be difficult to translate into the clinic due to some safety concerns of carbon-based materials that must be administered systemically (as is the case here) [10]. In any case, the limitations of this type of treatment are the same as for available treatments where only the effects of an individual reaction are addressed (such as with antihistaminic drugs), since there is no long-term effect of the treatment, and re-exposure to the allergen will re-induce a reaction. For this reason, most of the studies being carried out in bio- and nano-materials for allergy therapy are being focused on developing different AIT strategies involving these materials as delivery systems.

3. Use of Bio- and Nano-Materials as Allergen Delivery Vehicles for Immunotherapy

The use of a delivery vehicle can improve AIT efficacy and reduce the side effects by several mechanisms [11][12][13]. Firstly, by targeting nanocarriers towards specific cell types, the needed dose of allergen is decreased. Secondly, previously unsuitable administration routes or types of cargo can be employed for AIT with the help of these delivery vehicles. For example, a labile protein could be administered orally if included within a protective material, or a nucleic acid could be used for AIT if a carrier is specifically designed to enable its intracellular release in target cells. Thirdly, selective delivery to target organs or tissues can also be achieved, such as targeting tolerogenic organs. Through these works, it becomes clear that the route of administration of the immunotherapy agent is critical for its efficacy. Examples of each of these types of strategies are shown below to illustrate the broad range of possibilities available when combining AIT with bio- and nano-materials, as well as to reveal unexplored options for further research.
The first aspect to consider when formulating nanoparticles for AIT is the type of interaction between the allergen and the nanocarrier. Two main options are available: either the allergen is chemically conjugated to the nanocarrier (mainly on the particle surface), or the allergen is physically entrapped (encapsulated) within the nanocarrier. An important early work that investigated these options [14] reported the effect of three different ovalbumin (OVA)-carrying nanoparticles: non-biodegradable polystyrene nanoparticles with conjugated OVA, biodegradable PLGA nanoparticles with conjugated OVA, and PLGA nanoparticles with encapsulated OVA. The results obtained in vivo showed that OVA-conjugated polystyrene nanoparticles were effective as a tolerogenic prophylactic agent, but they induced anaphylaxis when administered to pre-sensitized animals. On the other hand, OVA-conjugated PLGA nanoparticles were also effective as a prophylactic treatment, and furthermore, they did not induce anaphylaxis in pre-sensitized mice and could partially inhibit Th2 responses (but not airway inflammation) when used as a therapeutic agent. This result highlights that the composition of the nanoparticles used for AIT and, more importantly, their biodegradability constitutes a major parameter driving their effect in vivo. Remarkably, OVA-encapsulated PLGA nanoparticles inhibited Th2 response and airway inflammation in mice, both prophylactically and after sensitization. These results indicate that the best option to develop nanoparticles for AIT is the use of biodegradable nanoparticles encapsulating the allergen.
Based on the results mentioned above, the simplest strategy to achieve material-driven AIT is to encapsulate allergenic proteins within nanoparticle formulations. Formulating the allergen within a particulate form can by itself ease its interaction with certain immune cells and increase the therapeutic immune response. Nanoparticles with many different compositions might be used for this application (lipidic [15], inorganic [16], polymeric [17]), although the most common material found in the literature for this application is polymeric nanoparticles. As an example of this line of work, Pohlit et al. developed acid-labile polymer-lipid nanoparticles loaded with allergens, including grass pollen allergen and house dust mite allergen [18]. When these nanoparticles were incubated with DCs in vitro, they did not induce maturation of the DCs, but they were capable of inducing the immune response of co-cultured T cells. Rebouças et al. prepared poly(anhydride) nanoparticles loaded with peanut proteins for in vivo allergy immunotherapy [19]. After intradermal particle administration, a mixed Th1/Th2 response was observed, with a more pronounced Th1 response when spray-dried nanoparticles were used compared to lyophilized ones. This response would be more suitable for allergen immunotherapy and was characterized by lower IgE and IL-5 levels and higher IFN-γ production. These results highlight that other formulation parameters may have a critical impact on therapeutic efficacy, in addition to the selection of cargo and particle composition.
Besides directly using the allergenic protein as the therapeutic cargo, a nucleic acid cargo can also be used, such as mRNA of plasmid DNA encoding the target allergenic protein. By using nucleic acid cargo, several advantages can be achieved. On the one hand, after delivery to the target cells, the nucleic acid can induce the expression of the therapeutic protein for some time, so the dose of the protein produced can easily surpass what could have been directly delivered to the same target cell by an analogous carrier particle. On the other hand, if there is an off-target release of the cargo outside of cells, the nucleic acid will not give rise to the production of the protein in those locations (out of the target region of the body). Since the specific IgE of the patient will only recognize the already-formed protein and not the nucleic acid that encodes it, this would greatly reduce the chances of triggering an undesired allergic reaction as a consequence of the treatment. As an example of this type of strategy, dendrosomes carrying plasmid DNA (containing the Betv 1a gene) were administered in the footpad of Balb/c mice in a prophylactic scheme (that is, prior to sensitization with the allergen rBetv1) [20]. The nanocarrier is critical in this type of strategy since it allows the intracellular delivery of the nucleic acid. The in vivo administration of these dendrosomes produced an increase in the IgG2a/IgG1 ratio and also an increase in IFNγ production in splenocytes, together with an inhibition of IgE and lower basophil degranulation. All these parameters indicate the induction of a stronger Th1 response.
The administration route is a critical parameter for successful AIT, both in terms of efficacy and safety. An advantage of the use of nanocarriers compared to administering the free therapeutic molecule is that it is possible to select the carrier composition and structure, as well as to tune its physicochemical properties to optimize the formulation for a specific route of administration. One common administration route used for allergy immunotherapy is the sublingual route. Among the main reasons to perform sublingual immunotherapy (SLIT) are the easy and non-invasive administration procedure, as well as the large number of immune cells in the oral mucosa, which can lead to a successful therapeutic effect. The use of DC-targeted nanoformulations allows for decreasing the amount of allergen necessary to obtain the desired effect while reducing undesired side-effects. In this context, aptamer-targeted PLGA nanoparticles loaded with OVA were developed to be captured by DCs in the sublingual mucosa during SLIT [21]. The aptamer-targeted OVA-loaded PLGA nanoparticle formulation used for SLIT was found to be the optimal treatment scheme when compared not only with free OVA administered sublingually but even with free OVA administered subcutaneously. The results showed a marked decrease in IgE, IL-4, and IL-17 levels, as well as a reduction in T cell proliferation and an increase in IFN-γ and TGF-β. This work highlights the great potential of DC-targeted nanoparticles to enable effective SLIT with greatly reduced allergen doses. As another example highlighting the potential of nanostructure-mediated SLIT for allergy, Rodriguez et al. reported the evaluation of mannose-modified dendrimers linked to a Pru p 3 peptide [22]. The mannose modification provided targeting towards DCs, and in a peach anaphylaxis mouse model, the authors found an optimal SLIT dose that could generate a strong long-term tolerance to the allergen [22]. Similar dendrimer-based structures for SLIT in a mouse model of Pru p 3-induced anaphylaxis were also previously reported by the same group using CpG-decorated dendrimers instead of mannose-modified ones [23].
Another interesting administration route is intranasal administration. In this context, Corthésy et al. designed a system for intranasal administration based on allergen-loaded gas-filled microbubbles [24]. When administered in a mouse model of allergic asthma, these microbubbles induced a tolerogenic response, with an increase in Foxp3+ CD4+ T cells (Tregs), IL-10, TGF-β, and the Th1 cytokine IFN-γ. Interestingly, this treatment did not just provide an effect when administered prophylactically, but also after the animals had already been sensitized to the allergen. In this context, the treatment could reduce the number of eosinophils and, decreasing the overproduction of mucus, improve lung functionality. Yet another interesting administration route for allergy immunotherapy is epicutaneous, since there is a large number of immune cells (such as Langerhans cells and other DCs) in the upper layers of the skin. In this regard, a particularly relevant biomaterial-based strategy is the use of microneedle (MN) patches. MN patches consist of arrays of needle-like structures of hundreds of µm in length that can be made of different materials (such as metals, polymers, or ceramics). Due to their short length, MN arrays do not produce any bleeding or pain when inserted into the skin since they do not reach the depth at which blood vessels and nociceptors are located. This eases the translation of MN-based therapeutics since they would be easy to adopt in populations where fear of needles can hinder successful adoption (such as in children). As an example of this strategy, Kim et al. prepared MN patches containing a Dermatophagoides farinae extract [25]. When this system was administered in vivo, the treatment produced a decrease in Th2 response and an increase in the Treg population (Foxp3+ CD4+ T cells) without significant side effects. The specific effects produced by the treatment included a decrease in IgE, epidermal thickness, and eosinophil count, together with an increase in IgG4, among other changes. When compared with subcutaneous immunotherapy (SCIT), the therapeutic effect observed with 10 µg of extract within MN patches was similar to that obtained with 100 µg of extract in SCIT, and clearly superior to that obtained with 10 µg of extract in SCIT.
Finally, besides adapting the materials for a particular route of administration, an area of nanomedicine development with great potential for AIT is the design of nanocarriers with a particular biodistribution profile that enables selective organ delivery. In the case of AIT, there are some organs that are considered “tolerogenic”, since the microenvironment surrounding particular types of immune cells in these organs facilitates the generation of regulatory T cells (Tregs) or other types of specific tolerance-generating mechanisms. Examples of these organs are the liver [26] and the spleen [27], and, as recently proposed, potentially also the lungs [28][29]. In the context of liver-targeted delivery for AIT, Liu et al. prepared targeted PLGA nanoparticles loaded with the allergen OVA. Once systemically administered, these nanoparticles accumulated in the liver, where they released their cargo within liver sinusoidal endothelial cells (LSEC)  [26]. LSEC act as antigen-presenting cells that can lead to the generation of Treg cells. In vivo, this nanoparticle-based strategy led to an increase in the production of TGF-β, IL-4, and IL-10, and it also reduced the allergic response towards OVA when used as a prophylactic strategy.

4. Use of Bio- and Nano-Materials as Co-Delivery Systems Containing the Allergen and Immunomodulatory Molecules

The third (and more technically complex) option for immunotherapy is the use of the materials as co-delivery systems to transport the allergen to certain cells in combination with other molecules, such as immunosuppressive drugs as rapamycin that generate a tolerogenic microenvironment [30]. The idea behind this co-delivery strategy is to bias the cellular response towards the generation of tolerogenic dendritic cells and Treg cells, potentially enhancing AIT efficacy. This co-delivery approach can be combined with all of the strategies mentioned in the previous section regarding different types of cargos or administration routes.
One example of this co-delivery strategy was developed by Shahgordi et al., who prepared PLGA nanoparticles loaded with curcumin, OVA, or both [31] for SLIT in a mouse model of allergic rhinitis. OVA was, therefore, the allergen used for the immunotherapy, while curcumin would act as an immunomodulatory drug. The formulation produced a decrease in total IgE levels and eosinophil cell count, and an increased IFN-γ to IL-4 ratio when compared to the standard SCIT with OVA. The optimal treatment was found to be the combination of free curcumin with encapsulated OVA or free OVA with encapsulated curcumin, instead of the nanoformulation where both agents were co-loaded. In another example, Hong et al. prepared methoxy poly(ethylene glycol)-poly(D,L-lactide) (mPEG-PDLLA) nanoparticles to co-deliver the peptide IK (an OVA epitope fragment) and the adjuvant R848, which is a Toll-like receptor (TLR)-7 ligand [32]. As in the previous case, the co-loaded molecule R848 was included in the formulation to modulate the immune response. Since oral administration was selected, the target cells that interacted with the nanoformulation to yield a therapeutic effect were intestinal DCs. The results obtained show the successful generation of tolerogenic intestinal DCs and the promotion of Tregs by the formulation, both in vitro and in vivo. This led to the inhibition of the allergic response in vivo, preventing the body temperature decrease and the appearance of diarrhea. This improvement in clinical symptoms was accompanied by a decrease in the levels of OVA-specific IgE, OVA-specific IgG1, IL-4, and IL-13, as well as an increase in the levels of OVA-specific IgG2a and IFN-γ [32].
A clear sample of the combination of co-delivery approaches can be found in a recent work by Yu et al. regarding MN arrays for peanut allergy immunotherapy [33]. In this work, the authors prepared an MN formulation that dissolves once inserted in the skin, releasing a combination of three cargos within the superficial layers of the skin. The combined cargo consisted of peanut allergen, 1,25-dihydroxyvitamin D3 (VD3), and CpG oligonucleotide. The peanut allergen acts as the main agent responsible for the immunotherapy, while the other two components (VD3 and CpG) act as modulators of the immune response. On one side, VD3 is an immunosuppressant that has been shown to bias the immune responses towards a tolerogenic profile. On the other hand, CpG is an agonist of TLR-9 driving Th1 responses, and CpG oligodeoxynucleotide nanomedicines have been thoroughly studied for allergy treatments, among other therapeutic applications [34]. The combination of these two agents was selected to drive the immune response away from the Th2 profile. In a mouse model of peanut allergy, this co-delivery system led to a decrease in allergy scores, specific IgE, and intestinal and mucosal MC, and eosinophils. Furthermore, this was accompanied by an increase in the levels of IL-10, TGF-β, and Treg-like cells.
Regarding the comparison of tolerogenic co-delivery with other strategies, Liu et al. recently reported the efficacy of LSEC-targeted (liver-accumulating) OVA-loaded PLGA nanoparticles compared with non-targeted OVA-loaded PLGA nanoparticles that also include one immunomodulatory agent, either curcumin or rapamycin [35]. Similar efficacy of LSEC-targeted formulations and non-targeted RAPA/OVA co-loaded nanoparticles was found regarding OVA-specific antibodies (IgE, IgG1, and IgG2a) as well as IL-4, IL-5, IL-10, TGF-β, and IFN-γ levels. Furthermore, these nanoparticles showed significant therapeutic efficacy in two different mouse models sensitized with OVA: allergic airway disease and anaphylaxis.
To end this section of the article, Table 1 includes the main characteristics of the different therapeutic strategies described here for different allergic disease models using bio- or nano-materials.
Table 1.
Main characteristics of the bio- or nano-material-based strategies for allergy therapy described in the article, in the order in which they appear in the text.
Bio- or

Nano-Material		 Experimental

Model		 Therapeutic

Mechanism		 Administration Route Specific Cell Targeting Cargo Ref.
PVA-SPIONs Incubation with CD4+ T cells in vitro Direct decrease in antigen

processing		 N/A (in vitro incubation) No None [8]
Fullerenes Passive anaphylaxis mouse model (DNP as hapten allergen) Direct effect on MC, decreasing IgE-induced release of mediators Intraperitoneal injection No None [9]
Polystyrene and PLGA nanoparticles Allergic airway inflammation mouse model (OVA as allergen) Immunotherapy through allergen delivery Intravenous injection No OVA (conjugated or encapsulated) [14]
PEG acetal dimethacrylate nanoparticles Incubation with DCs

co-cultured with T cells in vitro		 Immunotherapy through allergen delivery (pH-cleavable carrier) N/A (in vitro incubation) No OVA, grass pollen extract, dust mite allergen. [18]
Poly(anhydride) nanoparticles Particle administration to non-sensitized mice Immunotherapy through allergen delivery Intradermal injection No Peanut extract [19]
Dendrosomes Prophylactic use in mice, prior to sensitization with rBetv1 Indirect immunotherapy through delivery of plasmid encoding allergen Footpad injection No Plasmid DNA encoding Betv 1a [20]
PLGA nanoparticles OVA-induced allergic rhinitis mouse model Immunotherapy through allergen delivery Sublingual DC-targeted with aptamer OVA [21]
Dendrimer Pru p 3-induced anaphylaxis mouse model Immunotherapy through allergen delivery Sublingual DC-targeted with mannose Pru p 3 peptide [22]
Gas-filled microbubbles OVA-induced allergic asthma mouse model Immunotherapy through allergen delivery Intranasal No OVA [24]
Hyaluronate-based

microneedle patches		 Atopic dermatitis mouse model Immunotherapy through allergen delivery Epicutaneous No Der f1 dust-mite allergen [25]
PLGA nanoparticles OVA-induced allergic airway disease mouse model Immunotherapy through allergen delivery Intravenous injection LSEC-targeted with mannan or peptide OVA [26]
PLGA nanoparticles OVA-induced allergic rhinitis mouse model Immunotherapy through

co-delivery of allergen and modulatory molecules		 Sublingual No Curcumin and OVA [31]
mPEG-PDLLA nanoparticles OVA-induced food allergy model Immunotherapy through

co-delivery of allergen and modulatory molecules		 Oral No Peptide IK (OVA fragment) and R848 (TLR-7 ligand) [32]
Dissolving microneedle patches Peanut allergy mouse model Immunotherapy through

co-delivery of allergen and modulatory molecules		 Epicutaneous No Peanut allergen, VD3, and CpG oligonucleotide [33]
PLGA nanoparticles OVA-induced allergic airway disease and OVA-induced anaphylaxis mouse models Immunotherapy through

co-delivery of allergen and modulatory molecules		 Intravenous injection No (comparison with LSEC-targeted without co-delivery) OVA plus rapamycin or curcumin [35]

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