Polymeric Nanoparticles for Inhaled Vaccines

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1		Nusaiba Al-Nemrawi	--	4094	2022-11-01 08:49:46	\|
2	format correct	Vivi Li	+ 22 word(s)	4116	2022-11-02 02:16:36	\|

This entry is adapted from the peer-reviewed paper 10.3390/polym14204450

Many studies focus on the pulmonary delivery of vaccines as it is needle-free, safe, and effective. Inhaled vaccines enhance systemic and mucosal immunization but still faces many limitations that can be resolved using polymeric nanoparticles (PNPs). Biocompatible and biodegradable PNP use has increased for pharmaceutical delivery including vaccines. PNPs can incorporate different antigens and deliver them to antigen-presenting cells.

inhaled vaccine vaccine immunization nanoparticles polymeric

1. Introduction

Pulmonary drug delivery is an attractive route for drug administration and targeting, especially in comparison with intravenous injection. Pulmonary drug delivery is a non-invasive technique that uses accessible large mucosal surface areas for rapid absorption and activation ^[1]. Pulmonary delivery in the form of dry powder inhalations (DPI) maintains vaccine constancy and integrity. High density of antigen-presenting cells (APC) such as alveolar macrophages (AMs) and dendritic cells (DCs) in the lung serves as an ideal target for the antigen to stimulate a strong immune response that results in mucosal and systemic immunity ^[2]. Therefore, pulmonary drug delivery has gained substantial interest over the past few decades.

Most pathogens enter the body via mucosal surfaces. As such, mucosal vaccination can be used to considerably improve the mucosal immune response. Vaccine administration through mucosal surfaces such as oral, rectal, vaginal, nasal, intranasal or pulmonary tissue can effectively trigger mucosal immune response ^[3]. As such, mucosal vaccines are feasible for large-scale vaccination and eliminate the risk of blood-borne infections posed by injected vaccines ^[4]. The benefits of mucosal vaccines also include convenient distribution and administration as well as improved patient compliance ^[5]^[6].

Unfortunately, mucosal vaccines still face challenges that include low delivery of preventive viral epitopes and inadequate humoral and cell-mediated response. Mucosal vaccines are also inefficient adjuvants when used in certain protocols ^[7]. The typical delivery carrier for vaccines should have high efficiency, low cytotoxicity without harmful effects to normal cells, good reproducibility and easy preparation ^[4]^[8]. Polymeric nanoparticles (PNPs) have been identified as an ideal carrier system for vaccine delivery that can fulfill these important requirements ^[9].

Recently, biocompatible and biodegradable PNP use has increased for pharmaceutical delivery including vaccines ^[10]. PNPs can incorporate different antigens and deliver them to APCs. Antigens are protected from degradation by different enzymes and provide controlled antigen release, which may reduce the number of required doses ^[8]^[10]. In addition, PNPs have demonstrated adjuvant properties such as inducing cellular and humeral antigen immunogenicity ^[11]^[12]. Other advantages include the fact that PNPs are non-viral vectors, non-immunogenic, biocompatible and have a large specific surface area ^[8]. PNP absorption by APCs have also been shown to not only induce but also increase an effective immune response ^[8]^[11]. Finally, many polymers such as chitosan and poly (D, L-lactide-co-glycolide) (PLGA) are compatible with vaccine loading ^[13]^[14].

2. Nanoparticles for Inhaled Vaccines

2.1. Polymeric Nanoparticles and Drug Delivery

Recently, PNPs have become the focus of medical application development because of their simplicity of preparation and design, biocompatibility, and variety of structures. Further, PNPs show enhanced efficacy and bioavailability compared with conventional drugs. Their ability to transport active ingredients to the targeted tissue or organ without affecting the drug stability and in higher concentrations made them favorable over other formulations. Moreover, PNPs can be used to control, delay, or sustain drug release.

PNPs are particles with a size range of 10–100 nm. Although 100 nm-size nanoparticles (NPs) offer the advantage of high-efficient intracellular uptake, NPs larger than 100 nm are preferred for their higher drug loading ability ^[15]. NPs have a high surface area-to-volume ratio, making them appropriate for drug delivery applications ^[1]^[16]^[17].

PNPs can be classified into two main types: nanocapsules and nanospheres. Nanocapsules act as a reservoir for drug retention in an aqueous or oily liquid in the vesicle core enclosed by a solid polymeric shell. Meanwhile, nanospheres are defined as a solid matrix polymer in which molecules are either trapped in the sphere center or adsorbed at the nanoparticle surface ^[18]^[19]^[20].

Polymers are the main component used in PNP formulation. Both natural and synthetic polymers have been used in PNP formulation that allow for degradation or metabolization over time in biological systems. The polymer properties affect the overall physicochemical properties and behavior of the PNP carriers ^[21]^[22]. The choice in polymer is critical to ensure the safety, efficacy, biodegradability, toxicity, encapsulation efficiency, stability, cost and availability of the drug delivery system ^[23]. For example, natural polymers (e.g., cyclodextrin) used in preparing PNPs release the imbibed drug faster than synthetic polymers (e.g., PLGA) that provide sustained release over several weeks ^[24]^[25]^[26]. The most commonly used natural polymers for PNP formulation are sodium alginate, gelatin, albumin and chitosan. On the other hand, polylactides (PLAs), polyglycolides (PGAs), PLGAs, polycaprolactone (PCLs), polyanhydrides, polycyanoacrylates, poly (malic acid) (PMLA), polyorthoesters (POEs), polyglutamic acid (PGA), poly (vinyl alcohol) (PVA), poly (N-vinyl pyrrolidone) (PVP), polyacrylamide (PAM), poly (methyl methacrylate) (PMMA), polyacrylic acid (PAA or Carbomer), polyethylene glycol (PEG) and poly (methacrylic acid) (PMAA) are the major synthetic polymers used for PNP formulation ^[26]^[27].

PNPs can be prepared using a variety of methods, including solvent evaporation, supercritical fluid, nanoprecipitation technology, salting-out, dialysis techniques and multiple emulsions ^[28]. The method of preparation and controlling the experimental conditions also influence the formed PNP properties along with their body performance. PNPs are currently used to treat, prevent and diagnose diseases ^[29]^[30]. These PNPs have been used to load different pharmaceuticals and target other tissues in the body. Specifically, PNPs have been used for cancer therapy, vaccine delivery and targeted antibiotic delivery ^[31]^[32]. The details of these medical NP applications have been discussed in detail in many reviews ^[33]^[34].

Unluckily, PNPs are facing many challenges in various aspects, such as the use of high amounts of emulsifier. Emulsifier-free or surfactant-free emulsion is now a hot topic in the PNP industry where green procedures that do not rely on chemical emulsifiers are used ^[35]. These procedures often use reagents consisting of monomers (mostly acryl or vinyl monomers) and a water-soluble initiator (ionizable initiator) to stabilize the formed PNPs. Other researchers have applied the principles of nucleation and particle growth mechanisms without using emulsifiers ^[27]^[36]. Additionally, the use of natural emulsifiers derived from plants, bacteria and fungi have also been used to eliminate synthetic harmful emulsifiers ^[37].

Unfortunately, many factors essential to these procedures are still uncontrolled and require attention. Moreover, the scale-up process for industrial production of these green products is another problem. Both clinical and pharmaceutical outcomes of lab formulations are subject to alteration during the scale-up process ^[38]. Reproducibility is another challenge that faces green synthesis of manufacturing PNPs. Some technologies, including supercritical fluid technology, microfluidizer and membrane extrusion technology, have promising scale-up competencies, but only a small number of products produced by these technologies have reached the market ^[39].

The regulatory requirements for the potential PNPs, including those prepared by green synthesis, are also considered a challenge. The FDA, EMA and other regulatory agencies around the world inspect new PNPs on product-by-product basis. For Investigational New Drug (IND) applications, the preclinical and clinical validation review are mandated by FDA. The appropriate identification includes structure, quality, purity, synthesis methodology, etc. To ensure the efficacy and safety of nanoparticles, additional data such as nanoparticle morphology, size, size distribution, shape, surface additives, specific physic-chemical information and coating effect should be also detailed. PNPs that have successfully reached the market use PNPs, PLGA NPs (e.g., Neulasta^® and Copaxone^®, Macugen^® (Bausch & Lomb, Laval, QC, Canada), Eligard^® (Tolmar, CO, USA), PegIntron^® (Merck, NJ, USA) and Pegasys^® (Genentech, CA, USA).

2.2. Nanoparticles Drug Delivery to the Lungs

The delivery of particles to the different regions of the lungs depends on the particle size of the formulation. Based on the particle size, there are three different mechanisms of drug deposition through the pulmonary route, impaction, sedimentation, and diffusion ^[40].

In impaction, the aerosol particles go through the oropharynx and upper respiratory passages at a very high velocity. The particles then interact with the respiratory wall and are deposited in the oropharynx regions ^[41]. This mechanism can be observed with particle sizes greater than 5 µm mainly in dry powder inhalation (DPI) and metered dose inhalators (MDI) ^[42]. In the DPI, the deposition is mainly affected by the inspiratory effort of the patient. If the force of inhalation is insufficient, the dry powder will be deposited in the upper airways due to the mass of the particles ^[42]. In the MDI, high particle sizes also tend to lead to the deposition of the particles in the upper respiratory tract region despite the high speed of the generated aerosol ^[42]^[43].

Gravitational forces are mainly responsible for the second mechanism, which is particle sedimentation. Particles with certain mass and sizes between 1 to 5 µm are deposited in the smaller airways and bronchioles ^[44]. Sedimentation is also influenced by the breathing mechanism; slow breathing patterns provide a sufficient period for efficient sedimentation ^[45].

The diffusion process plays a major role in the deeper alveolar areas of the lungs. The Brownian motion of the surrounding molecules in the aqueous lung surfactant causes a random movement of the particles that leads to the dissolution of the drug in alveolar fluid when in contact with the lung surfactant which is essential for diffusion ^[46]. In addition, the diffusion process is also affected by concentration gradient ^[47]. Particles smaller than one to 0.5 µm are mainly deposited in the alveolar region, while most of the particles, because of their smaller sizes, are exhaled ^[47].

Moreover, depending on the location of deposition which is mainly affected by the particle size ^[43], the nanoparticles can interact with different cell types within the respiratory tract, such as epithelial cells and antigen-presenting cells.

The epithelial cells are tightly connected by intercellular junctions called tight junctions. Nanoparticles can pass the respiratory epithelia by two different pathways: through tight junctions between the cells or transcellularly by endocytosis ^[48].

The firmly sealed tight junctions in the epithelial cells make a barrier for particle permeation ^[49]. Moreover, the mucus layer, which covers the upper and central respiratory tract, as well as the clearance process in these regions create more barriers that reduce the uptake of nanoparticles in the respiratory lumen ^[49]. Therefore, agents, called penetration enhancers, which reversibly open the tight junctions are added to the formulations to enhance the transport of particles to the systemic and/or lymphatic circulation ^[50]. On the contrary, in the distal airway’s epithelium, just before the alveoli, the tight junctions between the epithelial cells are loose and particles up to 22 kDa can passively diffuse via paracellular pathways ^[50].

In addition to the paracellular route by which relatively small proteins are absorbed, larger proteins can be taken up from the respiratory tract by the transcellular pathway, which includes both nonspecific and specific (receptor-mediated) endocytosis ^[51]. The transport of antibodies and plasma proteins such as albumin across the epithelial cells occurs by receptor-mediated endocytosis ^[52]. On the other hand, it has been shown that macromolecular therapeutics pass the epithelial cells by nonspecific endocytosis ^[51].

There are a variety of immune cell populations in the lungs such as phagocytic cells (macrophages) and antigen-presenting cells (dendritic cells DCs) ^[53]. The main role of immature DCs, primarily within the mucosal tissue, is to recognize antigens by their protrusions into the airway or alveolar lumen ^[54]. In this mechanism, depending on the nature of the antigen, DCs get activated by their recognition receptors and enter the maturation process; once maturated, DCs rapidly migrate to the lymph nodes ^[55]. In the case of maturation, antigens are processed by the DCs and presented to naive T cells by the major histocompatibility complex (MHC II) in combination with upregulated co-stimulatory molecules on the DCs surface (CD40, CD80, CD86) and the release of cytokines ^[55]^[56]. The type and combination of the cytokines released will determine the nature of effector T cells induced (Th1, Th2, Treg, and Th17) ^[55]^[57].

NPs-based vaccination protocols that mainly target DCs are efficient and promising strategies for the induction and enhancement of immune responses for cancer treatment ^[58]^[59] in addition to viral and microbial infections ^[60]^[61]. NPs can extend the antigen exposure to immune cells, facilitate antigen capture by DCs and initiate antigen presentation pathways within these cells, thus enhancing T cell-mediated immune responses ^[62]. In addition, NPs delivery system could be used to enhance DCs activation by triggering cell-surface molecules. This mechanism enhances the internalization of NPs by DC and thus induces immune activation with separate and specific DCs-activating signaling pathways ^[63].

3. Polymeric Nanoparticles Used for Inhaled Vaccination

3.1. Nanoparticles for Inhaled Vaccines

The extensive mucosal surface area presented in the lung makes the pulmonary system an effective system for vaccine delivery. This offers the advantage of lower dosage requirement and compatibility with a wide variety of antigens, including DNA- and RNA-based vaccines, in comparison with injection ^[64]^[65]. Most respiratory pathogens enter our body via mucosal membranes to cause an immune response, inducing excellent primary protection from pathogens ^[66]^[67]. The presence of related lymphatic tissues in the pulmonary system, including larynx, nasopharynx, and bronchi epithelium, induces a mucosal immune response and expands local defense mechanisms to the systemic defense mechanisms ^[68]^[69]^[70]. The physiology through the lung has favorable properties for vaccination that eliminates many issues faced by other mucosal systems including poor absorption, rapid clearance, degradation by antigens and enzyme tolerance ^[71].

As previously mentioned, DPIs are simple, cheap, compressed and disposable in a single unit, making them ideal for vaccine administration. Most antigens, including those used as vaccines, are macromolecules susceptible to chemical and/or physical degradation, especially in liquid formulations ^[72]. The delivery of such molecules as dry powder aerosols is a promising option expected to improve stability ^[73]. For example, dry powder measles vaccine and insulin formulations showed room temperature stability, eliminating the need for refrigeration ^[74]^[75]^[76]. In another example, live attenuated tuberculosis vaccine bacille Calmette–Gue’rin (BCG) was prepared by spray-drying. The BCG vaccine aerosol showed high efficiency in guinea pigs compared with animals immunized with parenteral BCG ^[77]. Another successful market formulation with a relatively low cost is the dry powder influenza vaccine, Inflexal V^® (Crucell) prepared using liposomal NPs ^[78]. PNPs have been used to load different antigens for vaccine applications via different mechanisms including covalent binding, adsorption and encapsulation ^[79].

In general, PNPs are used as an antigen carrier or as an adjuvant to stimulate immunity in both prophylactic and therapeutic applications ^[80]^[81]^[82]. Figure 1 shows different types of nanoparticles that are used for mucosal vaccine delivery. As a carrier, PNPs are loaded with the antigen, then target the immune cell. In this case, the antigen and/or carrier are engulfed by the immune cell or the PNPs release the antigen which is later engulfed by the immune cells ^[83]. For PNPs to behave as a carrier, assembly of the antigen and PNP is important. PNPs may induce certain immune phases, which then boost antigen identification and immunity stimulation ^[84]. Interactions between the antigen and PNPs are achieved by physical adsorption, chemical conjugation or encapsulation ^[83]^[85]^[86]. Antigen adsorption on the PNP surface is a simple but weak process dependent on charge or hydrophobic interaction. These interactions allow for rapid antigen separation from the NPs in vivo. In contrast, encapsulation and/or chemical conjugation form stronger bonds between the PNPs and antigen where the antigen is only released from the PNPs once the nanoparticles are destroyed ^[87]. In chemical conjugation, crosslinking the antigen and PNP surface is chemically achieved so that PNP is taken up by the cell. The antigen is then released inside the cell following chemical destruction of the covalent bond ^[88].

Figure 1. Different types of nanoparticles that are used for mucosal vaccine delivery.

PNPs have been shown to work by themselves as immune stimulators or adjuvants. In this case, crosslinking between the PNP and antigen does not take place, and modification of the antigenic structure is possible when attached to the PNP interface ^[89]. Formulation of adjuvant PNPs with a specific antigen is possible by simply mixing the PNPs and the antigen directly before administration, which does not require strong association between the NPs and the antigen ^[90]. In general, when PNPs are the same size as the pathogen, they can be efficiently taken up by the antigen-presenting cells (APCs) to induce immune response ^[91]. It has been well established that dendritic cells generally uptake viruses with sizes ranging from 20 to 200 nm while macrophages uptake larger particles with sizes from 0.5 to 5 µm. In a study on polystyrene NPs, dendritic cells uptake particles with sizes of less than 500 nm ^[92]. In another study, PLGA NPs with a size of 300 nm were taken and activated by dendritic cells more favorably compared with particles larger than 1 μm ^[93].

Particle size is not the only factor that impacts PNP performance as an adjuvant in immunization. Other factors such as the preparation material are important. For example, amphiphilic poly (amino acid) (PAA) NPs 200 nm in size were taken up more effectively by dendritic cells than smaller ~30 nm NPs ^[94]. Surface charge also plays a major role in immune system stimulation ^[95]^[96]. PNPs with positive charge have been reported to cause higher uptake by APCs due to their stronger electrostatic interactions with the negatively charged cell membranes ^[97]. Positively charged polystyrene particles have been shown to be taken up by dendritic cells and macrophages more efficiently than neutral or negatively charged particles ^[92]. Furthermore, particle shape shows a dominant role in interactions between PNPs and APCs. It has been shown that the particle shape interface between particles and APCs affects macrophage phagocytosis ^[98]. For instance, Niikura et al. reported that spherical NPs are more effective in stimulating antibody response than cube and rod-shaped NPs, although the rod-shaped NPs were taken up more efficiently by APCs ^[99].

3.2. Chitosan and Chitosan Derivatives Nanoparticles

Chitosan is a polysaccharide composed of N-acetylglucosamine and glucosamine obtained via chitin n-deacetylation. Chitin is a biopolymer found in crustacean shells or fungi mycelium ^[100]. Chitosan is a non-toxic, biodegradable, and biocompatible cationic polymer. Because of these favorable biological characteristics, chitosan is used to deliver many pharmaceutical agents ^[101]^[102]. Chitosan also has interesting mucoadhesive properties that can stimulate immune system cells that has led to interest in its usage as an antigen vaccine carrier via the intranasal route ^[103]. The mucoadhesive properties of chitosan are primarily attributed to its amino groups that are easily protonated in weak acidic environments. This amine group interacts with the sialic acid moieties in mucin, the main protein component of mucus, which is negatively charged at physiological pHs by electrostatic forces ^[13].

Furthermore, chitosan nanoparticles (CS NPs) can protect vaccines from degradation via incorporation in the NP core. Chitosan has also been reported as an adjuvant for mucosal vaccination, especially when delivered intranasally. The mucoadhesiveness of chitosan allows the antigen to reside for longer durations at the mucosal surface, which is expected to enhance the APC antigen uptake. This effect has been shown to enhance immune cell stimulation ^[50].

It is important for the particles to penetrate mucus at a rate higher than the rate of mucosal renewal and clearance. Therefore, modifications of CS NPs were suggested to enhance its mucus-penetrating properties. One of these modifications is derivatization with poly (ethylene glycol) (PEG). PEG is a neutral hydrophilic polymer used to decorate CS NPs for many reasons including enhancing its mucus-penetrating capabilities in a process called PEGylation. PEGylation can minimize mucoadhesive interactions between CS and mucins, and thus allow rapid penetration through mucus ^[104]. The efficacy of PEG was related to its molecular weight as mentioned by Maisel et al.

Other researchers tried to enhance its mucus-penetrating properties by increasing the solubility of CS. For instance, Ways et al. synthesized four derivatives of CS (PEG, PHEA, POZ and PVP). The modified CS NPs showed enhanced and deeper muco-penetration into sheep nasal mucosa ^[105].

Additionally, both chitosan and CS NPs have been reported to produce a modulatory effect on the epithelial intercellular tight junction and increase paracellular drug transport ^[106]. Chitosan easily forms PNPs, making NP preparation a simple procedure where the NP size and charge can easily be tuned by controlling the experimental conditions and raw material properties ^[107]. CS NP formulation generally avoids excessive use of harmful organic solvent, which is often needed to enhance the entrapment or adsorption of therapeutic antigens and proteins ^[108]. Often, CS NPs are formed using cross-linking materials such as tripolyphosphate (TPP) to improve the encapsulation efficiency using the ionotropic gelation method ^[109].

The cationic nature of chitosan offers the advantage of carrying non-viral materials such as DNA for vaccination applications. Since nucleic acids have a strong negative charge, they can undergo electrostatic interaction with chitosan to form particulate entities known as polyplexes ^[110]. This interaction protects nucleic acids until they are delivered to the target site ^[106]. Bivas-Benita et al. showed that CS NPs are an ideal DNA vaccine delivery system due to their ability to protect the DNA from nucleases degradation and the enhanced immunity they provide by inducing dendritic cells maturation and increasing IFN-secretion from T cells after pulmonary immunization against tuberculosis ^[111].

CS NPs have also been used for mucosal vaccination of loaded antigen ^[13]^[112]. Live Newcastle virus loaded in CS NPs and delivered to chickens by intranasal and oral routes was shown to induce a higher IgA antibody response compared with chickens immunized with the plasmid control ^[113]. In other studies on recombinant pertussis toxin and Bordetella pertussis filamentous haemagglutinin loaded in CS NPs, very strong mucosal and systemic immune reactions were observed for nasal administration ^[114]. Further, systemic and local immune responses were induced after nasal administration of a diphtheria toxin mutant and CS in mice ^[115]. Other studies showed that influenza subunit virus vaccine delivered intranasally in CS NPs enhances both mucosal and systemic antibody and cell-mediated immune response in mice ^[116]. Furthermore, intranasal delivery of inactivated swine influenza A virus encapsulated in CS NPs enhanced mucosal antibody and cell-mediated immune responses in pigs. In this entry, the intranasal vaccination improved the mucosal secretory IgA in the respiratory tract and regional lymph nodes. It also enhanced the systemic IgG and T-cell responses against different subtypes of swine influenza A virus ^[117]. Borges et al. reported that intranasal delivery of hepatitis B vaccine loaded in CS NPs enhances the mucosal IgA antibody response ^[118]. Other studies demonstrate that intranasal immunization using CS NPs as a vaccine carrier induces both mucosal and systemic antibody responses against Pneumococcus, Bordetella and Diphtheria species ^[114]^[119]^[120].

Both humoral and cell-mediated immune responses against Streptococcus zooepidemicus were achieved when CS NPs were delivered intranasally in mice ^[97]. Likewise, tetanus toxoid encapsulated in CS NPs delivered intranasally to rats was effectively transported across the nasal epithelium and produced mucosal and systemic antibody responses that last longer compared to solubilized antigen ^[121]. It has also been reported that mice immunized intranasally using CS NPs encapsulated with influenza split virus vaccine were able to induce a higher response than soluble antigens. In this entry, both mucosal and systemic antibodies were enhanced as well as the cellular immune response indicated by increased IFNγ-secreting cell frequency in the spleen ^[116].

3.3. Polyesters: PLGA and PLA

PLGA is a copolymer of PGA and PLA. Both PLGA and PLA are FDA-approved polymers that are biodegradable, biocompatible and have been widely studied to design delivery systems for small drugs, peptides, proteins and other macromolecules such as RNA and DNA ^[122]^[123].

NPs prepared of PLGA, PLA and their derivatives are considered promising vaccine carriers. PLGA and PLA are believed to be able to improve antigen delivery to the immune system and to enhance mucosal surface interaction. PLGA and PLA increase epithelium penetration while maintaining full protection of the entrapped antigen and enhance antigen recognition by the mucosal immune system. PLGA and PLA can be used to achieve controlled release antigens in a predetermined manner ^[124]^[125]. All of these advantages make PLGA, PLA and their derivatives strong drug delivery candidates, especially for vaccine applications.

Hiremath et al. demonstrated that H1N1 influenza peptides encapsulated in PLGA NPs as a vaccine delivery system enhanced the virus-specific T cell response in pig lungs and reduced the virus load in their airways ^[126]. Furthermore, Mansoor et al. showed that bovine parainfluenza 3 virus antigen, encapsulated in PLGA NPs and administered intranasally to calves, had notably greater mucosal IgA responses compared with calves that received the commercially available respiratory vaccine ^[127]. The sustained immunological responses were attributed to the sustained antigen release from PLGA NPs in the nasal mucosa ^[127].

A combination of factors including hydrophobicity, particle size and polymer type play a vital role in generating mucosal immune response. Therefore, optimization of these variables is required. Many studies have been dedicated to the influence of particle size on immune response generated by the antigens encapsulated in polyester-based NPs following nasal administration. For example, the immune response to ovalbumin encapsulated by PLA NPs administered intranasally was found to be significantly greater than the response to PLA microparticles ^[128]. Moreover, it was reported that PLGA NPs with a ~200 nm size are optimal for dendritic cell interaction and induction of an effective cellular immune response ^[129]. Further, the ratio of PLA to PGA in PLGA was shown to affect the immune response and behavior of NPs when administered intranasally. In a study conducted by Thomas et al., intranasally delivered hepatitis B vaccine loaded in PLGA NPs with different ratios of PLA to PGA (PLGA 85:15 and PLGA 50:50). The results showed that the particle size and drug release increased with increasing glycolide monomer ratio, which led to decreased immune response ^[130].

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