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ACS Nano
ACS Nano
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ancac3
ACS Nano
1936-0851
1936-086X
American Chemical Society

39185745
10.1021/acsnano.3c10797
Review
Nanoplatform Based Intranasal Vaccines: Current Progress and Clinical Challenges
Bai Ziyi †
Wan Dandan †
Lan Tianxia †
Hong Weiqi
Dong Haohao
https://orcid.org/0009-0008-5672-1276
Wei Yuquan *
https://orcid.org/0000-0002-6513-6422
Wei Xiawei *
Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan 610041, P. R. China
* Y.W.: email, yqwei@scu.edu.cn.
* X.W.: email, xiaweiwei@scu.edu.cn.
26 08 2024
10 09 2024
18 36 2465024681
01 11 2023
08 04 2024
01 04 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by-nc-nd/4.0/ Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Multiple vaccine platforms have been employed to develop the nasal SARS-CoV-2 vaccines in preclinical studies, and the dominating pipelines are viral vectored as protein-based vaccines. Among them, several viral vectored-based vaccines have entered clinical development. Nevertheless, some unsatisfactory results were reported in these clinical studies. In the face of such urgent situations, it is imperative to rapidly develop the next-generation intranasal COVID-19 vaccine utilizing other technologies. Nanobased intranasal vaccines have emerged as an approach against respiratory infectious diseases. Harnessing the power of nanotechnology, these vaccines offer a noninvasive yet potent defense against pathogens, including the threat of COVID-19. The improvements made in vaccine mucosal delivery technologies based on nanoparticles, such as lipid nanoparticles, polymeric nanoparticles, inorganic nanoparticles etc., not only provide stability and controlled release but also enhance mucosal adhesion, effectively overcoming the limitations of conventional vaccines. Hence, in this review, we overview the evaluation of intranasal vaccine and highlight the current barriers. Next, the modern delivery systems based on nanoplatforms are summarized. The challenges in clinical application of nanoplatform based intranasal vaccine are finally discussed.

intranasal vaccine
nanoparticle
respiratory disease
mucosal delivery
mucosal immune response
lipid-based
polymeric
inorganic
biomimetic
National Natural Science Foundation of China 10.13039/501100001809 U19A2003 Excellent Young Scientists Fund 10.13039/501100010909 32122052 document-id-old-9nn3c10797
document-id-new-14nn3c10797
ccc-price
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pmc1 Introduction

The respiratory system, a complex network of airways and tissues, plays a crucial role in our physiological well-being by facilitating the exchange of oxygen and carbon dioxide.1 However, it is also a primary target for a wide array of infectious diseases, with respiratory infections representing a significant global health burden.2 The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, demonstrated the destructive consequences of respiratory infections.3 Despite substantial progress in vaccine development, the pandemic underscored the need for more effective and accessible vaccination strategies.4 Therefore, in this review, we explored the promise of nasal mucosal vaccination for combating respiratory infectious diseases.

Traditional vaccination routes typically involve intramuscular or subcutaneous injections, which generate systemic immune responses.5,6 However, these routes may not provide optimal protection against respiratory pathogens, as they fail to stimulate the mucosal immunity that is crucial for defending against respiratory infections. Notably, nasal mucosa, the thin membrane that lines the nasal passages, represents a strategic point of entry for many respiratory pathogens.7 Therefore, nasal mucosal vaccination holds great potential for conferring protection against respiratory infections (Figure 1),8,9 which is mainly resulting from the fact that intranasal delivery of antigens can elicit local mucosal-tissue-resident immunity (mucosal secretory IgA and resident memory T cells) at or near the site of SARS-CoV-2 entry.10−13 A good intranasal vaccine with full criteria to achieve a balanced immune response, involving both mucosal and systemic components, can be demanding. Based on the potential to prevent virus infection and transmission, great efforts have been made to develop the next-generation intranasal COVID-19 vaccines. According to the World Health Organization COVID-19 Vaccine Tracker system, over a dozen mucosal vaccine are being investigated in clinical trials, and most of these vaccines were dominated by viral vectors, including adenovirus, live-attenuated influenza virus, parainfluenza virus, live-attenuated respiratory syncytial virus, and Newcastle disease virus vectors. However, some unsatisfactory results were reported in recent clinical trials with weak systemic and local mucosal antibody responses that were induced by two viral vectored intranasal vaccines,14,15 suggesting the viral vector alone may not meet the requirements for large-scale production of nasal mucosal vaccines. Notably, the limitations of viral vectors may compromise their potential and efficiency as intranasal vaccine platforms. It has been reported that the vaccine efficiency can be severely hampered by the pre-existence of vector-specific immune responses in humans from natural exposure or previous vaccination. In addition, the use of live, attenuated virus and live viral vectors in intranasal vaccination may increase the risk that virus entry to the central nervous system is through the cribriform plate. Therefore, there is a pressing need to rapidly develop technologies for intranasal vaccine development.

Figure 1 Schematic illustration of different nonviral nanoparticles for intranasal vaccine. Immunogenic components (DNA, mRNA, peptides, proteins, etc.) are conjugated with or encapsulated in nanoparticles, including liposomes, immunostimulating complexes (ISCOMs), lipid nanoparticles (LNPs), polymeric nanoparticles (PNPs), lipid−polymer complexs (lipopolyplexs)., inorganic nanoparticles, virosomes, virus-like particles (VLPs), or outer membrane vesicles (OMVs), to improve safety and delivery efficiency. The nanobased vaccines are intranasally administered to generate mucosal immune response. The scheme was generated using Biorender.

Researchers are leveraging nanotechnology to improve the efficacy of nasal mucosal vaccines and address these challenges.16−18 Nanoparticles offer multiple advantages in drug delivery, including improved stability, controlled release, and the ability to enhance mucosal immune responses.19−21

In this review, we provide a comprehensive exploration of the potential of nanobased intranasal vaccines as a noninvasive and efficient solution to combat respiratory infectious diseases. At the outset, we will overview nasal mucosal vaccination and discuss the current barriers, elucidating the challenges that need to be overcome. Next, we will focus on the characteristics, drawbacks, and prospects of modern nonviral nanoparticles as intranasal vaccine delivery systems. These approaches are instrumental in enhancing the efficacy and safety of nasal mucosal vaccines. Finally, we will discuss the challenges in the clinical application of nanoparticle-based intranasal vaccines, emphasizing the need for extensive research and clinical trials to translate these strategies into real-world solutions.

2 Evaluation of Intranasal Vaccines and Clinical Barriers

2.1 Mechanism of Mucosal Immune Response Induced by Intranasal Vaccines

Many studies have demonstrated the efficiency of intranasal vaccines, and several have also been studied clinically (Table 1).22−25 In general, one imperative goal of these intranasal vaccines is inducing robust mucosal immune response to avoid the entry and replication of mucosal pathogens. Therefore, extensive adaptive immune response at local mucosal site is closely related to the protective efficiency of intranasal vaccines. The nasal cavity is rich in lymphoid tissue, commonly known as nasal-associated lymphoid tissue (NALT),26−28 which can induce multidimensional protective immune responses, including mucosal immunity, humoral immunity, cellular immunity, and trained immunity, thus exerting a broad spectrum of protective effects.29,30 The mucosal immune system is the primary immune barrier of the host resistance to pathogen invasion. Therefore, nasal administration induced mucosal immunity is the key to research (Figure 2). Functionally, the nasal mucosal immune system can be divided into induction site and effector site. NALT is a major site of immune induction, at which the induction of the immune response begins.27,28,31,32 NALT covers the basolateral sides of the nasal cavity in rodents. In humans, Waldeyer ring is prominent NALT structures.27,33 NALT is encompassed by epithelial cells and microfold (M) cells, which are specialized for antigen uptake. The basal site of M cell is a specialized lymphoid tissue rich in B cells, T cells, dendritic cells (DCs), and macrophages. As a transmembrane transporter, M cells are capable of endocytosing internalize antigens displayed on their external membranes. Subsequently, these antigens are conveyed to antigen-presenting cells (APCs), such as DCs and macrophages, where they undergo processing and presentation.26,34−36 Finally, the APCs migrate to the interfollicular T cell zone and follicular B cell zone, where these cells present the antigens to the surrounding naive T cells for initiating adaptive cellular immunity.37 Antigen-stimulated T cells produce interleukin-5 (IL-5) and transforming growth factor-β (TGF-β) to activate B cells, and then these activated B cells differentiate into antigen-specific IgA+ B cells. The antigen-specific T cells and IgA+ B cells further migrate to effector sites via the blood circulation and thoracic duct.38,39 The effector sites in the nasal mucosal immune system are the sites where B and T cells mount immune responses, including the lamina propria and the intraepithelial layer of the respiratory mucosa.26 Finally, in the presence of IgA-inducing cytokines (IL-6, IL-10, and IL-21) at the effector site, these IgA+ B cells terminally differentiate into IgA producing plasma cells.38 The IgA produced by plasma cells at the effector site binds to polymeric Ig receptor (pIgR) on epithelial cells and can transport into the lumen of the nasal cavity as sIgA. sIgA plays an important role in mucosal immunity by capturing upper respiratory tract pathogens and preventing them from adhering to the mucosal surface.40,41

Figure 2 Immune response in nasal cavity. The nasal cavity is rich in lymphoid tissue, commonly known as nasal-associated lymphoid tissue (NALT). NALT is encompassed by epithelial cells and microfold (M) cells, which are specialized for antigen uptake. As a transmembrane transporter, M cells are capable of endocytosing antigens presented on their outer membranes. These antigens are then transported to the antigen-presenting cells (APCs), including DCs, macrophages and B cells, for processing and presentation. Next, the APCs migrate to the interfollicular T cell zone and follicular B cell zone, where these cells present the antigens to the surrounding naive T cells for initiating adaptive cellular immunity. Antigen-stimulated T cells produce interleukin-5 (IL-5) and transforming growth factor-β (TGF-β) to activate B cells, and then these activated B cells differentiate into antigen-specific IgA+ B cells. Finally, in the presence of IgA-inducing cytokines (IL-6, IL-10, and IL-21) at the effector site, these IgA+ B cells terminally differentiate into IgA producing plasma cells. The IgA produced by plasma cells at the effector site binds to polymeric Ig receptor (pIgR) on epithelial cells and can transport into the lumen of the nasal cavity as sIgA, which plays an important role in mucosal immunity by capturing upper respiratory tract pathogens and preventing them from adhering to the mucosal surface. The scheme was generated using Biorender.

Table 1 Clinical Progress in the Development of Intranasal Vaccines for the Common Respiratory Infectious Diseases

disease	name of vaccine	type of vaccine	clinical trial number	phase	sponsor	refs	
Influenza	Vaccination	Subunit	NCT00197301	1/2	Hadassah Medical Organization	(83)	
SIIL LAIV	Live-attenuated	NCT01625689	1/2	PATH	(84)	
cH8/1N1 LAIV	NCT03300050	
LAIV H7N3	NCT01511419	
OVX836	Subunit	NCT03594890	1	Osivax	(85)	
BW-1014	Subunit	NCT05397119	1	BlueWillow Biologics	 	
Hemagglutinin (HA)	Inactivated	NCT03293732	1	Advagene Biopharma Co., Ltd.	(86)	
GHB16L2	Live-attenuated	NCT01369862	1/2	AVIR Green Hills Biotechnology AG	(87)	
CAIV-T UniFluVec	Live-attenuated	NCT00224783	1/2/3	MedImmune LLC	(88)	
NCT00192309	
NCT00192413	
NCT04650971	
Lactobacillus rhamnosus	Live-attenuated	NCT00620412	1	Tufts Medical Center	(89)	
H2N3MO 2003/AA	Live-attenuated	NCT01175122	1/3	NIAID	(90−95)	
ca Vaccine	NCT01995695	
Live-attenuated H7N9	NCT02251288	
A/Anhui/13 ca	NCT02151344	
influenza virus vaccine	NCT00516035	
Live Influenza A	NCT01854632	
Vaccine H7N3 (6-2)	NCT00853255	
AA ca	NCT00380237	
H9N2 (6-2) AA ca	NCT00722774	
H2N2 1960 AA ca	NCT00734175	
H6N1 Teal HK 97/AA	NCT00922259	
Influenza A H7N7	NCT00110279	
H5N1 (6-2) AA ca	NCT01534468	
NCT00488046	
A/17/CA/2009/38 (H1N1)	Live-attenuated	NCT01666262	1/2	Mahidol University	(96)	
Trivalent inactivated influenza virus	Inactivated	NCT00436046	1/2	NIAID	 	
vaccine	NCT03845231	
Flucelvax(R)	NCT05027932	
BPL-1357	
H5N1 Influenza	Adenoviral-vectored	NCT01806909	1	NIAID	(97)	
Vietnam 1194	
Hemagglutinin (HA)	
COVID-19	COVI-VAC	Live-attenuated	ISRCTN15779782	3	Codagenix; Serum Institute of India	(98)	
MV-014-212	Live-attenuated	NCT04798001 [	1	Meissa Vaccines, Inc.	(99)	
DelNS1-2019-nCoV-RBD-OPT1	Viral vector	ChiCTR2100051391	1	University of Hong Kong;	(100)	
Xiamen University; Beijing	
Wantai Biological Pharmac	
AVX/COVID-12-HEXAPRO	Inactivated	NCT05205746	2/3	Laboratorio Avi-Mex	(101)	
Covishield/ChAdOx1	Viral vector	NCT04816019	1	University of Oxford/AstraZeneca	(102)	
NDV-HXP-S	Viral vector	NCT05354024	2/3	Sean Liu, Icahn School of Medicine at Mount Sinai	(103)	
MV-014-212	Live-attenuated	NCT04798001	1	Meissa Vaccines, Inc.	(99)	
BBV154/iNCOVACC	Viral vector	CTRI/2022/02/040065	3	Bharat Biotech International Limited	(13)	
CVXGA1	Viral vector	NCT04954287	1	CyanVac LLC	(104)	
Razi Cov Pars	Subunit	IRCT20201214049709N3	3	Razi Vaccine and Serum Research Institute	(105)	
ACM-001	Subunit	NCT05385991	1	ACM Biolabs	(106)	
CIGB-669	Subunit	RPCEC00000345	1/2	Center for Genetic Engineering and Biotechnology	(107)	
RSV	SeVRSV	Viral vector	NCT03473002	1	NIAID	(108)	
RSV001	PanAd3-RSV	NCT01805921	1	ReiThera Srl	(109)	
MV-012-968	Live-attenuated	NCT04227210	1	Meissa Vaccines, Inc.	(110)	
RSV vaccine formulation 1	Live-attenuated	NCT04491877	2	Sanofi Pasteur, a Sanofi Company	 	
Ad26.RSV.preF	Ad26-vectored	NCT03334695	2	Janssen Vaccines and Prevention B.V.	(111)	
RSV	Live-attenuated	NCT03227029	1/2	NIAID	(112−116)	
DNS2/D1313/I1314L	NCT03102034	
RSV	NCT02794870	
D46/NS2/N/DM2-2-	NCT02952339	
HindIII	NCT03916185	
RSV LID DM2-2 1030s	NCT03422237	
RSV 6120/DNS1	NCT03099291	
RSV 6120/F1/G2	NCT04520659	
RSV	NCT03596801	
6120/DNS2/1030s	NCT03387137	
RSV cps2 Vaccine	NCT01968083	
RSV MEDI DM2-2	NCT01852266	
NCT02237209	
NCT01893554	
NCT01459198	
Tuberculosis	Ag85B-ESAT6 fusion protein H1	Subunit	NCT00440544	1	St George’s, University of London	 	
Pertussis	BPZE1	Live-attenuated	NCT03541499	2	NIAID	(117)	
BPZE1	Live-attenuated	NCT01188512	1	Inserm	(118, 119)	
NCT02453048	
BPZE1	Live-attenuated	NCT03942406	2	ILiAD Biotechnologies	(120)	
NCT05116241	
Vaccine GamLPV	Live-attenuated	NCT04036526	1/2	Gamaleya Research Institute of Epidemiology and Microbiology	 	

The ability to induce immunological memory is the most important feature of acquired immunity which is essential for long-term defense against pathogen infection. Following mucosal vaccination, cell-mediated immune responses are initiated.42 Upon T cell priming, effector T cells migrate to the respiratory tract by recognizing cognate antigens and responding to cytokine signals, engaging in antiviral effector activities, and eventually developing into tissue-resident memory (TRM) T cells.43−45 TRM cells are found in the upper respiratory tract and lower respiratory tract, reside within the tissue, and express cell surface markers, including integrin CD103 and C-type lectin CD69.46−50 Upon re-encountering antigenic pathogens, these TRM cells rapidly activate and promptly carry out effector functions, providing a front-line defense against pathogen infection.50,51 In the upper respiratory tract, TRM B cells are found in the adenoids and tonsils of humans,52 NALT of mice,53 and the submucosa of the nasal cavity and trachea of most mammals.54 In the lower respiratory tract, TRM B cells are present in nonlymphoid areas under the airway epithelium, in inducible bronchus-associated lymphoid tissue,55 and also in the respiratory tract themselves.54 In addition, TRM T cells are found in airway tracts, spanning nasal tissues and lungs.56 Specifically, TRM CD4+ T cells assist TRM B cells and CD8+ T cells in mediating influenza infection in mice.57,58 Previous studies have shown that natural infection can increase CD4+ and CD8+ TRM T cells in the nasal cavity.59,60 However, whether system mRNA vaccination can induce TRM alterations in the upper respiratory tract remains unclear. One study found increases in both CD4+ and CD8+ TRM cells following mRNA vaccination, while other studies did not find sufficient evidence for TRM generation.61−63 Administration of nonlive vaccines through the intranasal route has been demonstrated to address this issue. Combining intranasal administration of spike protein with systemic mRNA vaccination resulted in a higher presence of CD8+ TRM cells in nasal turbinate’s compared to either strategy used alone.30 These distinct TRM populations are likely to offer prolonged protection against infections at sites of pathogen entry. Therefore, the capacity to produce antigen-specific resident memory cells is a critical factor in the advancement of mucosal vaccines.

The ability to induce trained immunity is another key feature of effective vaccines. The trained immunity is induced by metabolic, functional, and epigenetic reprogramming of innate immune cells, including DCs, NK cells, and macrophage, which can enhance immunological response to subsequent stimulation.64 Various immune training agents, such as Bacillus Calmette–Guérin (BCG) vaccine,65 influenza vaccine,66 β-glucan,67Candida albicans,68 and lipopolysaccharide (LPS),69,70 have been shown to induce trained immunity. The BCG vaccine, a booster of trained immunity, modulates intracellular signaling pathways through its binding with Toll-like receptors 4 (TLR4) and TLR2, inducing a trained immune response.71 It trains monocytes through the activation of the mammalian target of rapamycin pathway, leading to increased glycolysis, oxidative phosphorylation, and glutamine metabolism.72 Additionally, BCG induces the trained immunity effect through epigenetic modifications of macrophages, leading to the generation of TNF-α, IFN-γ, and IL-1β, which potentially aids in preventing SARS-CoV-2 infection.65,73,74 Research has revealed that BCG vaccination triggers the release of proinflammatory cytokines, thereby providing protection against acute upper respiratory tract infections in the elderly.75 Consequently, harnessing trained immunity to strengthen preserved innate immune cells may be an approach for enhancing the immune responses to COVID-19 in the elderly. In another study, the quadrivalent inactivated influenza vaccine induced trained immunity can boost innate immune responses to against SARS-CoV-2 infection, thus reducing the risk of COVID-19.66 These results suggest that the ability to induce trained immunity of mucosal vaccines is essential to prevent pathogen reinfection.

Although mucosal vaccines are an effective means of inducing host defense against infection, there are also some challenges in practical application. In the development of intranasal vaccine, many factors restrict the antigen absorption and bioavailability. The size and lipophilicity of vaccine particles play a critical role in nasal permeation. Lipophilic molecules typically exhibit high membrane permeability utilizing transcellular pathways, whereas hydrophilic particles, especially those with a high molecular weight, typically show limited membrane permeability.76 Like other foreign substances, nasally administered vaccine antigens are easily captured by mucus and cleaned by nasal mucosal cilia.77,78 In addition, the local pH and enzymatic environment of the nasal mucosa would affect the stability of the intranasal vaccine.79 Furthermore, nasal volume is another challenge; the feasible volume for nasal administration is limited to 25–250 μL in human.80 All these barriers prevent the sufficient antigen delivery and then reduce the uptake and presentation of APCs which reside in the nasal cavity, thus hindering the initiation of protective immune responses.81,82 To overcome these physiologic, anatomic, and physical obstacles, researchers have created various vaccine delivery systems and adjuvants to promote the development of intranasal vaccines.

2.2 Clinical Barriers of Intranasal Vaccines

Multiple vaccine platforms were utilized to develop intranasal vaccine, including nonreplicating (adenovirus,11,13,102 parainfluenza virus104 or replicating viral, live-attenuated influenza virus,100 live-attenuated respiratory syncytial virus,121 recombinant Newcastle disease virus122) vectors, adjuvanted subunit protein-based vaccines.29,123−127 Among them, viral vector-based vaccine platform is one of the most dominant technologies for intranasal vaccine development. However, so far, only three virus-based intranasal vaccines have been granted approval for human use. These include FluMist,128 a weakened avian influenza virus vaccine approved by the U.S. Food and Drug Administration (FDA); iNCOVACC,129 a SARS-CoV-2 vaccine utilizing chimpanzee adenovirus vector, which received restricted emergency use authorization in India; and CA4-dNS1-nCoV-RBD,15 a nasal spray influenza virus vector vaccine approved for emergency use in China. Nevertheless, recent clinical studies of CA4-dNS1-nCoV-RBD15 and ChAdOx1 nCoV-19 (conducted by Oxford/AstraZeneca)14 vaccines reported only weak systemic and mucosal antibody responses were elicited after intranet, sally immunization. These results suggest current viral vector-based intranasal vaccine may not enough to completely inhibit virus transmission. In addition, it is worth noting that while these vaccines have potential benefits, the vaccine efficiency may be compromised by the preexisting viral vector-specific immunity from natural exposure or previous vaccination. For instance, preexisting anti-Ad5 immunity in humans severely hampers the seroconversion of neutralizing antibodies against SARS-CoV-2. In addition, the development of live attenuated and inactivated vaccines necessitates the large-scale cultivation of pathogens, posing a biosafety risk.

Other platforms, such as split, subunit, peptide, and nucleic acid vaccines, typically have good safety profiles and eliminate the need for culturing or growing live pathogens. However, typically, they require adjuvants to address their poor immunogenicity and delivery efficiency during nasal administration. Modern vaccines tend to rely on specific nanotechnology platforms, aiming for easy large-scale manufacturing and the induction of durable immune responses. Boosted by the rapid development of nanotechnology and the advanced studies on biomaterials and adjuvants, nonviral nanodelivery systems emerge as a carrier for intranasal vaccines (Figure 3). Hence, in the following sections, we delve into the key applications of crucial nonviral nanoparticles in intranasal vaccines including lipid-based nanoparticles, polymeric nanoparticles, inorganic nanoparticles, and biomimicry nanoparticles and provide insights into the future research.

Figure 3 Mechanisms of action of nanoparticles-based intranasal vaccines. The scheme was generated using Biorender.

3 Nanoplatform Based Intranasal Vaccines

3.1 Lipid-Based Nanoparticle System

A variety of lipid-based nanoadjuvant system have been developed for nasal vaccination, including, lipid nanoparticles, virosomes, and immunostimulant complexes (ISCOMs). These systems have recently been widely used as intranasal vaccine adjuvants, offering the advantages of preventing antigen degradation, improving cellular drug delivery, and reducing drug toxicity. Particularly, lipid nanoparticles, currently the most successful nonviral nanocarriers, are suitable for clinical translation. Given the recent surge of interest in lipid-based nanoadjuvants, this section describes/delineates their material properties and the impact on mucosal immunity while also evaluating their efficacy in intranasal vaccines.

3.1.1 Lipid Nanoparticles (LNPs)

Lipid nanoparticles (LNPs) are nanosized (<1 μm) lipid systems composed of two or more (typically four) lipids in varying proportions capable of forming various structures such as a nanostructured core, and multilamellar vesicles depend on the saturation and charge of the lipids.130 Typically, LNPs consist of cholesterol (contributing to stability), neutral helper lipids (supporting lipid bilayer structure), polyethylene glycol (PEG) lipid (reducing aggregation and nonspecific uptake), and cationic/ionizable lipid (forming complexes with negatively charged antigen) (Figure 4).131 LNPs, with advantages such as high encapsulation efficiency, low toxicity, enhanced cellular uptake, and high stability, have become relatively mature carriers. Dimethyldioctadecylammonium bromide (DDAB) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) constitute the commercially available LNPs formulation TransfectAce. DDAB, a quaternary ammonium lipid, can not only form complexes with mRNA effectively but also stimulate innate immune responses.132 Aibani et al. performed a comprehensive study with a pertussis intranasal vaccination, with LNPs composed of DDAB/DOPE and a triple-adjuvant system. The formulation of LNPs resulted in a more compact and uniform particle system, stimulating a more balanced Th1/Th2-type immune response both systemically and mucosally compared to a commercial acellular pertussis vaccine.133 Zhuang et al. modified LNPs with mannose and demonstrated that intranasal administration of mannose-conjugated LNPs yielded superior responses. The vaccine stimulates the production of antibodies (IgG, IgG1, and IgG2a) as well as cytokines (IL-4 and IFN-γ), primarily inducing a CD4 T lymphocyte response, and provides complete protection to mice against infection with a 10-fold LD50 lethal dose of H1N1 influenza virus.134 Notably, in the IgG2a/IgG1 isotype ratio, the addition of LNPs significantly induces an increase in the IgG2a proportion, indicating a tendency toward a Th1 phenotype.

Figure 4 Chemical structures of commonly used lipids and polymers as nanocarriers for intranasal vaccine.

Liposomes are typically closed spherical vesicles composed with the structure of phospholipid bilayer of amphiphilic phospholipids and helper lipids (e.g., cholesterol), demonstrating exceptional biodegradability.135 In general, liposome can be broadly divided into three parts, including polar headgroup, linker bond, and hydrophobic tail. Depending on the phospholipid substances used, liposomes can be neutral, cationic, or anionic.136−138 Multiple studies have shown that intranasal immunization with liposome-based vaccines can combat various pathogens, including influenza virus, Yersinia pestis, and Mycobacterium tuberculosis.139−141 Ai Ninomiya et al. discovered that mucosal CTLs and DCs were activated through intranasal immunization with multilamellar phospholipid-based liposomes, which carried influenza viral nucleoprotein.142 An earlier investigation demonstrated the interaction between cationic liposomes and the sialic acid with negatively charged in nasal mucin glycoprotein, leading to an enhanced affinity for NALT.143 Tada et al. developed cationic liposomes based on 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 3β-[N-(N′,N′-dimethylaminoethane)-carbamoyl] (DC-chol) combined with ovalbumin for intranasal vaccination and reported that the liposomes effectively stimulated Th2-mediated nasal immunity and mucosal cellular immune responses in mice. They further identified that the DOTAP/DC-Chol liposomes enhanced the uptake of ovalbumin by CD11C+ DCs in nasal-associated lymphoid tissue.144 In a recent study, it was shown that intranasal immunization with pneumococcal surface protein A (PspA) and DOTAP/DC-chol liposomes induced better protective PspA-specific antibodies in both mucosal and systemic compartments compared with PspA alone. The liposomes administered intranasally additionally prompted the generation of IL-17+ T cells (Th17 cells) specific to PspA and enhanced the absorption of PspA by DCs.145 These studies highlight the important role of cationic liposomes in cellular uptake. Certainly, the study conducted by Joseph and colleagues reveals that cationic liposomes, formulated with DOTAP, DMTAP, or polycationic sphingolipid ceramide carbamoyl-spermine (CSS) and cholesterol, elicit more robust nasal and mucosal cellular immune responses in mice when compared to other liposome formulations containing positively charged lipids (DC-Chol, DDAB, DSTAP) as well as neutral or negatively charged lipids. The study suggests that lipid formulations with positively charged components, including DMTAP, DOTAP, and CCS, may potentially upregulate the levels of molecules such as MHCII and CD40, irrespective of the presence of influenza antigens, and can also induce macrophages to produce IL-12 and IFN-γ.148 Additionally, Yusuf et al. developed DDA-based PEG-modified cationic liposomes for intranasal vaccination. These modifications enhance the liposomes’ ability to penetrate and permeate nasal tissues, exhibiting low cytotoxicity.146 Fan et al. conjugated thiolated hyaluronic acid with cationic liposomes, enabling easy surface decoration of particles with thiol-PEG. The nanostructure, with a DOTAP/HA-core and PEG shell, displayed enhanced stability, prolonged release of antigens, and reduced cytotoxicity, resulting in a robust induction of a balanced IgG1/IgG2c humoral immune response.147 These findings emphasize the significant potential of liposomes as adjuvants in the development of intranasal vaccines.

3.1.2 Immunostimulating Complexes (ISCOMs)

Immunostimulating complexes (ISCOMs) are self-assembling spherical cage-like structures composed of saponins, cholesterol, phospholipids, and antigens.149 Proposed in the 1980s, its primary feature is the integration of the natural adjuvant Quil A into cholesterol.150 Quil A comprises saponins derived from the bark of the South American tree Quillaja saponaria Molina, known for its potent adjuvant activity.151 ISCOMATRIX (IMX) possesses a structure and composition similar to ISCOMs but does not contain antigens. ISCOMs and IMX are typically 40 nm sized particles with a negative charge, both exhibiting highly immunostimulatory effects and lacking hemolytic activity.149 The formation of ISCOMs depends on hydrophobic interactions, enabling them to accommodate hydrophobic antigens, whereas effective loading of hydrophilic antigens necessitates specific modifications.152,153

ISCOMs and IMX vaccines have been developed for multiple diseases and have demonstrated good safety and tolerability in animal and human studies. Pandey et al. suggested that the hydrophobic properties of ISCOMs and IMX might facilitate their deposition in the nasal passage. In their study, ISCOMs or IMX was found to remain in the nasal cavity for 4 h, while the control group’s sodium hypochlorite solution was rapidly eliminated.154 Furthermore, intranasal administration of ISCOMs or IMX-based vaccines with various antigens can induce immune responses in the body, such as for influenza virus, Mycobacterium tuberculosis, and RSV.155−166 Several research studies have demonstrated that nasal administration of ISCOMs or IMX vaccines is effective against a range of pathogens, such as Helicobacter pylori, Costa Rican kissing bug, and chicken roundworm.167−170 These findings highlight the significant promise of ISCOMs or IMX as adjuvants in the development of intranasal vaccines. However, due to its toxicity, the clinical application of Quil A is restricted.171 Multiple ISCOMs vaccines have been authorized for veterinary use, while to date, no ISCOMs or IMX-based vaccines have received approval for human.172

Saponins, as a crucial component of ISCOMs, have been utilized as adjuvants for intranasal vaccines in several experiments, demonstrating protective effects against pathogens such as influenza virus and Toxoplasma gondii cyst.173−178 Due to demonstrating significant development potential in eliciting more powerful mucosal and systemic immune responses, current efforts are focused on the modifying synthesizing saponins to produce formulations that are both less toxic and more efficient. Shirahata et al. prepared simplified oleanolic acid saponins with a glycosyl ester moiety at C28. After intranasal administration, it showed a slight but significant enhancement of influenza virus sIgA as an adjuvant for the influenza split vaccine. Costa et al. conducted an activity analysis on another low-toxicity analog, QB-90, a saponin fraction extracted from Quillaja brasiliensis. Compared to Quil A, QB-90 exhibited stronger local mucosal immunogenicity, inducing higher levels of antigen-specific mucosal and systemic antibodies. Additionally, a study constructed ISCOMs containing QB-90 (IQB-90) for encapsulating OVA antigen and investigated their efficacy in inducing immune responses following intranasal administration. Compared to mice inoculated with antigens only and ISCOMs containing Quil A, mice with IQB-90 exhibited significantly higher and Th2-skewed (IgG1 and IgA) antigen-specific serum and mucosal immune responses in distal mucosal sites such as the nasal, vaginal, and intestinal regions.162 QS-21, a water-soluble fraction purified from Quil A via reverse-phase high-performance liquid chromatography, exhibits superior adjuvant activity and lower toxicity.179 It has been demonstrated that intranasal administration of DNA vaccines carrying the envelope-encoded proteins of HIV-1 with QS-21 as an adjuvant can effectively stimulate the Th1 subset. In comparison to the intramuscular route, intranasal administration exhibits more effective mucosal immune responses.180 QS-21 has become a popular adjuvant in vaccine research, and several adjuvant systems with different properties have been developed based on QS-21, serving as improved adjuvants and less toxic products.181−184 For instance, GlaxoSmithKline has developed the lipid-based adjuvant system AS01, which combines QS-21 with 3-O-desacyl-monophosphoryl lipid A, and has successfully obtained commercial vaccine approval (Shingrix).185 In the future, QS-21-based adjuvant systems could offer an option for the development of intranasal vaccines, necessitating further research.

Matrix-M, as the third generation of ISCOMs technology, is composed of two distinct particles, Matrix-A and Matrix-C (derived from purified Quillaja saponin), along with cholesterol and phospholipids.186,187 Matrix-M has been demonstrated to efficiently stimulate and mobilize immune cells like toward draining lymph nodes, eliciting robust immune responses.188,189 It has been employed in clinical trials for vaccines targeting influenza, malaria, and SARS-CoV-2.187,190−193 Notably, Matrix-M can also enhance mucosal immune responses. In a mice model, both intranasal and intramuscular administration of an H5N1 influenza vaccine (augmented with Matrix-M) led to a robust and cross-reactive serum antibody response and a balanced Th1/Th2 response (IgG1 and IgG2a antibodies, as well as cytokines such as IFN-γ, IL-4, IL-5).194 In this study, lymphocytes isolated from intranasally vaccinated mice produced the Th17 cell cytokine IL-17. However, there was no significant difference in IL-17 concentration between the groups with Matrix-M adjuvant and virosomal alone, suggesting that the role of Th17 cells in immune protection remains to be elucidated. Additionally, the authors suggested that mice vaccinated intranasally, regardless of the use of adjuvants, had a lower multifunctional CD4+ T-cell response (IFN-γ, IL-2, TNF-α) but still provided protection against lethal viral challenge. In another study, Kodama et al. constructed a DNA plasmid that encodes the P6 outer membrane protein of nontypeable Haemophilus influenzae. Following intranasal immunization of mice with DNA plasmid and Matrix-M, it induced the production of P6-specific nasal IgA and serum IgG, along with enhanced expression of Th1 and Th2 cytokines.156 These results highlight the potential future application of Matrix-M adjuvant in intranasal vaccine formulations.

3.2 Polymeric Nanoparticle (PNP) System

PNPs are nanocarriers composed of natural or synthetic polymer materials, with a wide range of applications, such as drug delivery, imaging, therapeutic, and theragnostic applications.195 PNPs can load different antigens through various mechanisms, such as covalent conjugation, adsorption and encapsulation,196,197 and offer the advantage of being easily generated and highly flexible for structural modifications. Adjusting the molecular weight or chemical structure of polymer materials enables precise control of their physicochemical properties, achieving the desired characteristics.198 There is an abundance of polymers for PNPs preparation, not all can be effectively translated to the clinic due to biocompatibility concerns. This section will discuss the most popular polymer nanoparticles for intranasal vaccine delivery, focusing on the modification of the polymer particle surface, particularly to induce mucosal immunity or enhance the capability for nasal administration.199

3.2.1 Chitosan

Chitosan, a natural polysaccharide, is derived from the deacetylation of the outer shell of crustaceans, composed of repeating d-glucosamine and N-acetyl-d-glucosamine units.200 With its biodegradability, strong biocompatibility, and mucosal adhesive properties, chitosan has garnered interest as an delivery system for intranasal vaccine (Figure 4).201 Utilizing chitosan-based delivery systems for vaccine administration can prevent antigen degradation, improve cellular uptake, and elicit immune responses.202 Mice experiments showed that the intranasal administration of chitosan nanoparticles loaded with recombinant MxiH antigen increased IgG and IgA compared to control groups. Due to the action of chitosan, there is an increased antigen uptake in the nasal epithelium and M cells, stimulating humoral and mucosal immune responses.203 Other studies have indicated that employing chitosan nanoparticles as vaccine delivery system for murine intranasal immunization can induce mucosal and systemic antibody responses to pneumococcus, pertussis, and diphtheria toxin strains.203−206 Research in other animals has indicated that chitosan nanoparticles encapsulated in intranasal vaccines generate more sustained systemic and mucosal antibody response levels and specific immune memory. Dhakal et al. revealed enhanced mucosal antibody and cellular immune responses in pigs using killed swine influenza virus encapsulated in chitosan nanoparticles. In this study, intranasal vaccine increased IgA secretion in the respiratory mucosa and enhanced systemic IgG and T-cell responses against various subtypes of swine influenza virus.207 Furthermore, it has been demonstrated that the intranasal delivery of live-attenuated vaccines encapsulated in chitosan nanoparticles to chickens can effectively induce IgA antibody responses.208 In particular, the recombinant hepatitis B surface antigen (HBsAg) is considered a relatively weak antigen. Research by Borges et al. indicates that loading HBsAg alone onto chitosan nanoparticles does not induce a systemic humoral immune response. However, when the immune modulator CpG ODN is coadministered, the production of antigen-specific systemic antibodies with a Th1 bias is observed.209 Similarly, studies based on improved chitosan-based formulations (with TLR7 agonist) to achieve synergistic effects reveal that the intranasal vaccine, over time, generates high levels of IgG and specific immune memory.210

Several chitosan derivatives have been prepared to enhance solubility and mucosal penetration ability and maintain a positive charge.211N-Trimethyl chitosan (TMC) is one of the most extensively studied quaternary chitosan derivatives, which exhibits favorable water solubility at physiological pH. TMC maintains the mucosal adhesion features of chitosan while showcasing outstanding abilities in enhancing absorption.212−214 Numerous studies have demonstrated the successful use of TMC as a nasal vaccine delivery system. Pardeshi et al. proved that TMC has superior nasal membrane permeability.215 In another study, a nasal nanocomplex based on TMC and dextran sulfate were constructed.216 Amidi et al. prepared nanoparticles by ionic cross-linking of TMC solution with tripolyphosphate. The study demonstrated that TMC nanoparticles increased the retention time of encapsulated antigens in the nasal cavity, enhanced antigen uptake by M cells, and stimulated DCs maturation.217 Notably, chitosan and its derivatives have been widely applied in DNA and siRNA delivery, with an increasing role in mRNA.218−220

3.2.2 Poly(lactic-co-glycolic acid) (PLGA)

Poly(lactic-co-glycolic acid) (PLGA), a polyester, is a copolymer of polylactides (PLA) and polyglycolides (PGA). Unlike chitosan, PLGA is a synthetic polymer (Figure 4). Most literature indicates that PLGA undergoes hydrolysis of its ester bonds to form lactic acid and glycolic acid, eventually being eliminated as carbon dioxide and water. PLGA has been approved by the FDA for its outstanding safety in vaccine and drug delivery as well as tissue engineering. GA nanoparticles have been studied in multiple clinical trials, but currently, there are no commercial vaccine available.221,222 It has excellent biocompatibility, and its biodegradability can be regulated by altering its composition, molecular weight, and chemical structure.223,224

Mucosal immune responses are influenced by various factors including molecular weight, hydrophobicity, particle size, and the type of polymer.225,226 It has reported that the immune response generated by antigens encapsulated after nasal administration is associated with the size of polyester nanoparticles. For instance, the immune response to ovalbumin encapsulated PLA nanoparticles administered through the nasal cavity is significantly greater than the response to PLGA particles.227 For PLGA, it has been reported that a diameter of approximately 200 nm is the optimal choice for interacting with DCs, inducing effective cellular immune responses. Additionally, the PLA/PGA ratio of the PLGA composition is a key factor influencing particle degradation and antigen release rate.228 The most used PLGA with a 50:50 PLA/PGA ratio composition exhibits the fastest biodegradation rate, completing within approximately 50–60 days. Due to the lack of methyl side groups, poly(acrylic acid) is more hydrophilic.229,230 Park et al.’s study suggests that an increased percentage of lactic acid leads to greater water absorption, accelerating the degradation of PLGA particles.231 Thomas et al. found that the ratio of PLA to PGA in PLGA influences the immune response of nanoparticles after nasal administration. The findings indicated an increase in both particle size and drug release with the rise in the glycoside monomer ratio, consequently resulting in a reduction in the immune response.232

In most cases, the residence time of PLGA nanoparticles in the nasal cavity is insufficient to meet the effective antigen absorption needs of APCs.233,234 Currently, the primary solutions involve modifying the surface of PLGA nanoparticles or binding other polymer particles with adhesive properties to extend their residence time in the nasal cavity. Multiple studies have shown that PEG coating increases the hydrophilicity of PLGA nanoparticles and enhances their biostability.235,236 Cu et al. demonstrated that PEG coating of the PLGA nanoparticles improves dispersion, neutralize charge, and enhance particle diffusion in cervical mucus (3- to 10-fold). Interestingly, Rajapaksa et al. conducted a study on the potential optimization of PLGA polymer particle uptake by M cells. Recombinant proteins containing Claudin 4 (a protein associated with M cell endocytosis) were incorporated to prepare PLGA nanoparticles. After nasal administration, it was found that they were significantly better absorbed by NALT M cells.235 Moreover, highly adhesive polymers such as chitosan or its derivatives are often used to modify the properties of PLGA nanoparticles. Coating the surface of PLGA particles with chitosan-based polymers results in the formation of positively charged nanoparticles, with a slight increase in size. Coating the surface of PLGA particles with chitosan-based polymers results in the formation of positively charged nanoparticles, with a slight increase in size. Pawar et al. conducted a study on nasal immunization with hepatitis B antigen-loaded in TMC-coated PLGA nanoparticles. Compared to mice immunized nasally with uncoated PLGA nanoparticles, there was a significant increase in antigen-specific antibodies.237 Additionally, the study suggests that, in comparison to chitosan coating, TMC can effectively reduce the clearance rate of PLGA particles from the nasal cavity, prolong their residence time, and enhance their entry into epithelial cells. Another study showed that compared to PLGA, TMC, and TMC-coated PLGA nanoparticles with ovalbumin, only TMC-NPs increased the residence time of the antigen in the nasal cavity and stimulated DCs maturation.238

3.2.3 Polyethyleneimine (PEI)

Polyethyleneimine (PEI) is a versatile candidate with regard to intranasal vaccine delivery. PEI is a cationic polymer composed of repeating units of ethyleneimine, resulting in a highly branched structure (Figure 4).239 This molecular architecture endows PEI with its properties, rendering it an attractive choice for enhancing vaccine effectiveness.240 A key advantage of PEI lies in its ability to form stable complexes with negatively charged molecules, including nucleic acids and antigens.241 These complexes shield bioactive substances from degradation, ensuring their integrity during the delivery process.242 Additionally, PEI exhibits mucoadhesive properties, allowing it to adhere to the mucus layer in the nasal passages.243,244 This adherence prolongs the residence time of vaccine formulations, facilitating enhanced absorption of antigens and adjuvants through the nasal mucosa.245 The cationic nature of PEI further facilitates cellular uptake, enabling efficient antigen presentation to the immune system.246 These inherent characteristics, position it as a compelling and adaptable solution for intranasal vaccine delivery.

It has been shown that PEI could efficiently deliver neoantigen peptides and CpG adjuvants, leading to enhanced activation and antigen cross-presentation in APCs. This personalized vaccine platform demonstrated robust priming of neoantigen-specific CD8+ T cells.247,248 A fluoroalkane-grafted polyethyleneimines-coated vaccine was also shown to facilitate DC maturation as well as antigen transportation and enable effective antigen cross-presentation.249 Notably, substantial efforts have been made to evaluate the efficacy of intranasally administered PEI-based vaccine. Additionally, mRNA vaccines complexed with modified PEI overcame epithelial barriers by opening tight junctions, enhancing paracellular mRNA delivery, and minimizing toxin absorption in the nasal cavity.250

Our group has demonstrated that PEI-complexed receptor binding domain (RBD) vaccines of SARS-CoV-2 outperformed various delivery systems including DOTAP, chitosan, anionic liposome, and neutral liposome, fostering higher antibody responses. In addition, the PEI-complexed RBD vaccine not only enhanced RBD-induced humoral immunity but also augmented the cellular immune response compared to control groups. These effects were partially attributed to increased antigen uptake and DCs activation. Moreover, sera from mice intranasally vaccinated with RBD and cationic nanocarriers efficiently inhibited RBD binding to cell surface ACE2 receptors and neutralized SARS-CoV-2 pseudovirus infection in 293T/ACE2 cells in vitro.251 Then, in response to waning immunity and the emergence of variant strains, including Omicron, we updated our intranasal RBD vaccine and meticulously assessed its enduring immunogenicity against both wild-type and mutant strains of SARS-CoV-2 in mice. Following a three-dose intranasal immunization regimen, the vaccine elicited and sustained high levels of neutralizing IgG antibodies in the sera for a minimum of one year. Notably, robust mucosal immunity was induced, evidenced by elevated levels of mucosal secretory IgA and the presence of lung TRM cells. Notably, our investigation revealed that the prolonged persistence of lung TRM cells resulted from local T-cell proliferation rather than migration from lymph nodes.252

While the progress in PEI-based intranasal vaccine delivery is noteworthy, challenges persist, requiring careful consideration for the technology’s optimal utilization. One potential concern involves PEI’s cytotoxicity at higher concentrations. PEI with a molecular weight of 25 kDa showed high cytotoxicity in mouse fibroblasts,253 necessitating precise dosage calibration to ensure safety in vivo. Furthermore, the potential immunogenicity of PEI itself could trigger unwanted immune responses, which could affect vaccine efficacy and are associated with potential risks of autoimmune diseases.254 Strategies to address these challenges include the refinement of PEI formulations,255 exploring alternative PEI derivatives with reduced cytotoxicity.256 Additionally, targeted antigen delivery systems can be further modified to minimize PEI exposure to the immune system while maximizing its adjuvant effects targeted antigen delivery systems,257−259 striking a balance between immunogenicity and safety. Classic modifications include acetylation,260 hydroxylation,261 and carboxylation.262 Moreover, a variety of functional groups including protein, PEG, hyaluronic acid, and folic acid could be modified with PEI to optimize the safety and delivery efficiency of the nanoparticle.263 Protein-modified PEI allows the effective binding and condensation of plasmid DNA. For example, it has been demonstrated that PEI modified with histone showed low cytotoxicity and a considerable transfection efficiency.264 Additionally, it was reported that the molecular weight of PEG and degree of PEGylation impose a significant influence on the properties of PEI.265 PEG-modification of PEI has been shown to reduce the surface charges of the polymer, thereby improving its solubility, and also reduced nonspecific ionic interactions between the target cells and the PEGylated PEI.266 However, HA and FA modifications are often used to improve the cancer cell-specific targeting of PEI267−270 and thus are not optimal modifications for delivering immune therapies for respiratory diseases.

3.2.4 Lipid–Polymer Complexs (Lipopolyplexs)

Vaccine antigens can be loaded into hybrid nanoparticles composed of different types of materials, such as lipids, polymers, and peptides. Hybrid nanoparticles typically integrate the potential advantages of their various components. Compared to nonhybrid systems, it provides more flexibility, enhancing both antigen delivery efficiency and adjuvant activity. This section primarily focuses on nanoparticle systems based on polymers and lipids. We discuss the composition and types of interactions within polymer–lipid-based complexes, while also reviewing their applications in nasal vaccines.

Lipid–polymer complexes (lipopolyplexes) are the most common type of hybrid nanoparticle system. Broadly speaking, the interactions of nanoparticles in lipopolyplexes can be divided into three types, including surface interactions, membrane encapsulation, and internal interactions. Surface interactions are predominant types, with polymers and lipids carrying opposite surface charges, leading to a more organized and robust core–shell structure. The properties of the core can be adjusted in response to external stimuli, while the shell part can enhance the stability of the nanoparticles and confer surface tunable properties.271−274 Surface interactions are most employed to design lipid release regulated by the temperature or pH of the target tissue. Moreover, such interactions can impact the physicochemical properties of the hybrid particle system, effectively shielding lipids from chemical, enzymatic, and immune reactions, ensuring their stability in the drug delivery environment.275,276 The inclusion of layered chains of polymers can reinforce the binding within the lipid membrane, rendering it more robust and stable in the face of chemical, enzymatic, and immune reactions. Hydrophobic polymers readily bind with the lipid chains of phospholipids, while hydrophilic polymers typically associate with cholesterol or other substances, allowing them to link to the lipid bilayer. Typically, this form of interaction is combined with surface modifications to regulate the permeability of hybrid nanoparticles and the release of antigens.277,278 Internal interactions can serve as antigen delivery systems that are easily chemically degradable. Due to their compact structure, this system generates more stable liposomes.279 The diverse interactions and compositions between polymers and lipids will yield lipopolyplex properties with varying delivery and release mechanisms, adaptable to different usage conditions.

Numerous studies have demonstrated the use of optimized hybrid lipopolyplex carrier systems to enhance immune stimulation of vaccines on nasal mucosa.146,280 Hyaluronic acid (HA) is an adhesive, biodegradable, and biocompatible polymer that exists in both human and animals. HA dissolves in water at neutral pH and carries a negative charge. As a potent hydrophilic polymer, it is commonly used to form lipopolyplexes with cationic lipids to enhance immune stimulation capability. Fan et al. developed HA and PEG-coated cationic liposomes (DOTAP-HA) for the Yersinia pestis candidate recombinant antigen F1-V.147 The surface modification of DOTAP increased stability, prolonged antigen release (approximately 40% released in vitro over 3 weeks), and reduced the cytotoxicity DCs. Moreover, nasal liposomes loaded with OVA and monophosphorylate lipid A increased the levels of serum IgG and IgG1 as well as OVA-specific CD8+ T cells in mice, compared to mice receiving antigen plus adjuvant solution only. It is worth noting that, compared to conventional liposomes, PEGylated liposomes exhibited better stability within HA, whereas non-PEGylated liposomes demonstrated superior mucosal penetration.281,282 Wang et al. created a targeting ligand lipopolyplex with linked lactose and 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine.283 The encapsulation of OVA into lactosylated liposomes resulted in substantially elevated levels of mucosal IgA and systemic IgG antibodies after nasal immunization in mice. Compared to unmodified liposomes, the targeted lactosylated liposomal carriers exhibited higher macrophage uptake rates and induced elevated levels of TGF-α and IL-6. The research conducted by the same group assessed the capability of lactosylated liposomes as a viable targeted DC mucosal vaccine, demonstrating its potential to induce systemic antitumor immunity and antibody responses.284 In mice, modified intranasal liposomes induced secretory IgA levels in nasal and lung lavage fluids, as well as serum IgG antibody responses. It has been reported that anionic complexes formed by the combination of cationic lipids and polymer-based TriAdj adjuvants (a mixture of innate defense regulator-1002 peptide, poly(I:C), and polyphosphate) are capable of strongly adsorbing immunomodulators or antigens onto their surface, thereby enhancing immune responses, as well as increasing uptake capacity, cytokine release, and antigen presentation on phagocytic cells. This lipopolyplex exhibited lower toxicity and greater Th1/Th2 immune responses compared to mice receiving TriAdj alone.285

Nanoparticle hybrid systems can also be formulated from three or more components. The CAF01 cationic nanoliposome is prepared by mixing squalene, DOTAP, and trehalose 6,6′-dibehenat, then combining the resulting oil phase with the aqueous phase of Tween-80 in a citrate buffer at pH 6.5. Numerous studies have shown that CAF01, as an intranasal vaccine adjuvant delivery system, effectively induces the presentation of antigens to pertinent cell populations and the differentiation of B cells and T cells.286,287 Particularly, CAF01 shifts the effector function of activated CD4+ T cells toward a Th1/Th17 response and provides long-lasting, robust Th1 memory.286 Olsen et al. prepared recombinant proteins based on the VD4 region of the major outer membrane protein of Chlamydia trachomatis and combined these antigens with the liposomal adjuvant CAF01 to induce a robust immune response.287 Following intranasal administration, the vaccine diminished bacterial counts in the vaginal region and averted pathological alterations in the upper genital tract. Mice that received simultaneous intramuscular injection and intranasal administration displayed significantly activated CD4+ T cells, as well as higher levels of IgA in vaginal secretions. CAF09b, with highly surface cationic, is formulated by electrostatically complexing the TLR3 agonist poly(I:C) with a cationic liposomal delivery system.288,289 CAF09b has been extensively tested in clinical trials, integrated with various antigens as a vaccine system against viral infections and tumors (NCT03412786, NCT03715985).290 Notably, the complexation of poly(I:C) prevented the systemic distribution of immune stimulants in the cationic liposomes, negating harmful innate immune responses.291 The research conducted by Bhide et al. indicates that intranasal administration of CAF09b in mice upregulates several genes associated with IFN-I, and pretreatment with CAF09b can prevent mice from succumbing to lethal H1N1 influenza virus challenge.292 Therefore, cationic liposomes may facilitate the localized delivery of complexed poly(I:C) to APCs that produce IFN-I.

3.2.5 Other PNPs

Extensive studies have been done to assess or improve the delivery efficiency of nanocarriers based on chitosan, PLGA, and PEI. Other PNPs such as polyvinylpyrrolidone (PVP), dextran, polymeric micelles, polyalkylcyanoacrylate nanoparticles (PACA), and poly(ethyl cyanoacrylate) (PECA) exhibit distinct features. They represent a diverse range of polymeric nanoparticles that could potentially contribute to intranasal vaccine delivery.

PVP, a water-soluble polymer, offers several advantages in drug and drug delivery due to its biocompatibility and stability.293,294 When formulated into nanoparticles, PVP provides an effective protective barrier for encapsulated antigens and adjuvants, shielding them from degradation in nasal environment. Additionally, PVP-based nanoparticles exhibit controlled release properties, enabling sustained antigen exposure.295 Moreover, the water-solubility of PVP simplifies their preparation and administration, making them attractive candidates for large-scale production.296

Additionally, other than chitosan, natural polysaccharides like dextran and alginate have been utilized for nanoparticle formulations.297 Dextran and its derivatives are hydrophilic and water-soluble natural polymers, inducing robust immune responses. Besides, alginate is also commonly used as adjuvants. Moreover, alginate has been alginate has been employed in the encapsulation of chitosan nanoparticles carrying inactivated influenza virus. Intranasal administration of this virus-based vaccine was shown to increase Th1 immune response.298

Polymeric micelles are usually formed by amphiphilic block copolymers, offering a considerable platform for encapsulating antigens and adjuvants, especially hydrophobic compounds that are traditionally difficult to administer.299,300 Polymeric micelles could provide a protective milieu for the encapsulated vaccine components, shielding them from degradation and enhancing their stability during transit across the nasal mucosa.301 Their nanosized dimensions facilitate efficient cellular uptake and antigen presentation, promoting robust immune responses.302 Furthermore, these nanoparticles can be engineered to incorporate ligands or targeting moieties, enabling site-specific delivery and tailored immunomodulation.303,304 Despite their numerous advantages, challenges such as stability in physiological conditions and optimal encapsulation efficiency necessitate ongoing research to fine-tune their formulations.305

PACA represent another type of biodegradable nanoparticle, derived from alkyl cyanoacrylate polymers, and offer an advantage due to their excellent stability and ability to encapsulate both hydrophobic and hydrophilic antigens and adjuvants effectively. Their relatively small size and versatile surface modifications enable efficient transport across the biological barriers.306,307 Notably, equipped with the property against multidrug resistance (e.g., avoiding efflux proteins highly expressed in hepatocellular carcinoma that pump anticancer chemotherapies out of cells), PACA were often used for the delivery of anticancer therapies.308

In summary, these polymeric nanoparticles offer advantages for intranasal drug delivery, including biocompatibility, controlled release, and enhanced drug stability. However, their limitations, such as potential immunogenicity, stability issues, or complex synthesis procedures, must be carefully addressed to harness their full potential in developing effective intranasal drug delivery systems.

3.3 Inorganic Nanoparticle System

Inorganic nanoparticles stand apart from other extensively studied nanoparticles like LNP and PNP in the vaccine delivery field due to their composition primarily derived from non-natural materials. This distinctive feature results in size-dependent structural, electric, and magnetic properties, offering immense potential for immune therapies.309 These nanoparticles can be harnessed to target various immune signals, enhance stability, and facilitate the transport of antigens. Such attributes make them promising approaches for vaccine delivery.310 In addition, such inorganic nanoparticles that have been used for vaccine delivery could be classified into metallic nanoparticles and nonmetallic nanoparticles. In this section, the current progresses and challenges of these two types of inorganic particles will be discussed.

3.3.1 Metallic Nanoparticles (MNPs)

Metallic nanoparticles (MNPs) exhibit a plethora of properties, particularly in targeted drug delivery systems. MNPs serve as prominent carriers for therapeutic agents. Silver, gold, palladium, titanium, zinc, and copper, among other common MNPs, can undergo convenient surface functionalization through H-bonding, covalent bonding, and electrostatic interactions.311 Additionally, MNPs allow the loading of multiple agents, enhancing therapeutic efficacy.312 Currently, the extensively evaluated metallic nanoparticles for the intranasal delivery include goad nanoparticles (AuNPs) and silver nanoparticles (AgNPs).

AuNPs hold versatile applications, particularly as vaccine platforms enhancing antigen presentation.313,314 Unlike large PNPs or LNPs (>100 nm), AuNPs can be precisely synthesized at immunogenic scales ranging from 1 to 100 nm and in various configurations (sphere, rod, star, and cube), catering to varied immunotherapeutic needs.315 Appropriately sized nanoparticles (∼100 nm) exhibit superior antigen-specific T-cell immunity by efficiently draining into lymph nodes compared to conventional vaccine formulations.316 The chemical and optical properties of AuNPs facilitate the high-density conjugation and characterization of target proteins, vaccines, and adjuvants on their surfaces.317,318 Importantly, being nonliving synthetic materials, AuNPs do not induce carrier-specific immunity upon repeated administration, making them potential candidates for robust and repeated immunotherapeutic interventions.319 It has been reported that AuNPs capped by lyophilized extracellular domain of the M2-ion channel (M2e) of influenza A virus demonstrated stable resuspension in water. Intranasal administration of M2e-AuNP conjugates elicited M2e-specific IgG serum antibodies in mice. Furthermore, the antibody response was significantly heightened when soluble CpG was added as an adjuvant. Mice receiving M2e-AuNP along with soluble CpG as an adjuvant were fully protected from influenza A virus infection. Also, another study found that aged mice vaccinated at approximately 18–21 months old maintain substantial M2e-specific antibody titers in total IgG, IgG1, IgG2a, and IgG2b. This immune response provides significant protection against lethal challenge by influenza A virus. Moreover, it was observed that the antibody titers rise following virus infection and persist at elevated levels for 3 months, indicating the presence of effective M2e-specific memory B cells in elderly mice, and no booster doses were needed to maintain a protective memory response.320 It needs to be emphasized that AuNPs have been used as a carrier for multiantigen intranasal vaccine and exhibit multifunctional protection against the infection.321 This strategy allows the induction of the broad protection against the rapid mutating pathogens, such as SARS-CoV-2.

Studies have illustrated the impact of AgNPs on innate immunity, with evidence of their ability to stimulate the release of proinflammatory cytokines both in vitro, within innate immune cells,322−324 and in vivo after pulmonary administration in rodents.325 Additionally, synthetic nanoparticles possess substantial surface energies, attributed to their elevated surface area ratio, leading to the spontaneous adsorption of proteins on their surfaces, forming the “protein corona”. This inherent property of nanoparticles has been strategically utilized to improve antigen transport and distribution in various vaccine applications.326 Although yet to be used as the delivery system for vaccines, armed with the immune stimulating nature, AgNPs have been used as adjuvants for the intranasal vaccine against influenza.327 It was observed that incorporating AgNPs into virus-inactivated flu vaccines significantly reduced viral loads and prevented excessive lung inflammation after influenza infection. AgNPs boosted the presence of specific IgA-secreting plasma cells and antibody titers. Notably, vaccination in the presence of AgNPs, unlike AuNPs, conferred protection against lethal influenza. Additionally, boosted by the antiviral activity, biocompatibility, and low toxicity, AgNPs were used as a direct intranasal immune therapy against COVID-19 in numerous studies.328 The authors speculate that AgNPs exert antiviral effects on SARS-CoV-2 by disrupting the disulfide bonds on the spike protein and ACE2 receptors. Similarly, the use of Ag as an antiviral agent, given its nonspecific binding to proteins, requires further clarification regarding whether it may lead to some cellular functional impairments. In a clinical trial, mouth and nasal rinsing with AgNPs demonstrated the ability to prevent SARS-CoV-2 infection in healthcare personnel exposed to patients diagnosed with COVID-19.329 Moreover, thus far, 3 clinical trials designed to assess the safety therapeutic effects of intranasal administration of AgNPs have registered on clinical trial. Gov (Table 2), suggesting the translational promise of AgNP-associated intranasal therapies.

Table 2 Immunogenicity of Nanobased Intranasal Vaccines

types of nanoparticles	definition	response of immune system	refs	
Lipid-based nanoparticle system	Lipid nanoparticles	An acellular pertussis vaccine was prepared with antigens combined with a triple-adjuvant system delivered intranasally in a cationic lipid nanoparticle formulation.	Promote a Th1-type response with higher serum antibody titers of IgG2a and IgA. Following a single vaccine dose, lipid nanoparticles vaccines result in elevated nasal sIgA antibodies at 4 weeks postvaccination.	(133)	
mRNA vaccines were constructed against the H1N1 influenza virus with cationic lipid nanoparticle (LNP) or mannose-conjugated LNP (LNP-Man).	Stimulates the production of antibodies (balanced IgG2a/IgG1 isotype ratio) as well as cytokines (IL-4 and IFN-γ), primarily inducing a CD4+ T lymphocyte response. The effect of LNP-Man was better than that of LNP both in vitro and in vivo.	(134)	
Intranasal vaccination with antigen in combination with DOTAP/DC-chol liposomes	Effectively stimulated Th2-mediated nasal immunity and mucosal cellular immune responses; enhanced the uptake of antigen by DCs in nasal-associated lymphoid tissue; induction of Th17 cell cytokine IL-17	(144, 145)	
DOTAP/HA core-PEG shell nanostructures coloaded with ovalbumin/F1-V and monophosphoryl lipid A	NPs coloaded with ovalbumin (OVA) promoted bone marrow derived dendritic cells maturation and upregulation of costimulatory markers, including CD40, CD86, and MHC-II. Generated robust OVA-specific CD8+ T cell and antibody responses; NPs coloaded with F1-V induced potent humoral immune responses with increases IgG, IgG1, and IgG2c titers and balanced Th1/Th2 humoral immune responses.	(147)	
ISCOMs	Intranasally delivered IQB-90 (prepared with QB-90, cholesterol, phospholipids and antigen)	Enhanced local mucosal immunogenicity; exhibited significantly higher levels of antigen-specific serum and mucosal immune responses at distant mucosal sites, such as the nasal cavity, vagina, and intestinal regions; higher and skewed toward Th2 (IgG1 and IgA) antibody isotypes.	(162)	
Combines QS-21 as improved adjuvants and less toxic products	Effectively stimulating the Th1 subtype. Intranasal administration demonstrates a more efficient mucosal immune response with less toxicity compared to the intramuscular injection route.	(180−185)	
Matrix M (composed of two distinct particles, Matrix-A and Matrix-C, along with cholesterol and phospholipids)	Resulted in a robust and cross-reactive serum antibody response, as well as a balanced Th1/Th2 response (IgG1 and IgG2a antibodies, along with cytokines such as IFN-γ, IL-4, IL-5). Induction of Th17 cell cytokine IL-17 and the generation of specific nasal IgA and serum IgG.	(194, 156)	
Polymeric nanoparticle (PNP) system	Chitosan	Antigen adsorbed on the surface of those chitosan nanoparticles	Increased uptake of antigens in nasal epithelium and M cells stimulates humoral and mucosal immune responses, enhancing the secretion of IgA in respiratory mucosa and strengthening systemic IgG and T-cell responses. Generation of antigen-specific systemic antibodies with a Th1 phenotype; high levels of IgG in mucosa and specific immune memory.	(203−210)	
N-Trimethyl chitosan (TMC) nanoparticles as a carrier system for the nasal delivery	Improved nasal mucosal permeability; increases the retention time of encapsulated antigens in the nasal cavity, enhances the uptake of antigens by M cells, and stimulates the maturation of DCs	(217)	
Poly(lactic-co-glycolic acid) (PLGA)	Antigen-loaded PLGA nanoparticles were prepared and coated with material for nasal vaccine delivery	M cells of NALT exhibit significantly enhanced absorption. Compared to uncoated PLGA nanoparticles administered via nasal immunization, it effectively reduces the clearance rate of PLGA particles from the nasal cavity, prolongs their residence time, and enhances their entry into epithelial cells, stimulates the maturation of DCs, resulting in a significant increase in antigen-specific antibodies.	(235, 237, 238)	
polyethyleneimine (PEI)	The gel (consisting of a Schiff base-cross-linked hydrogel between branched polyethyleneimine and oxidized dextran) formulation was designed to increase nasal retention of the antigen and adjuvant to promote a strong mucosal response.	Opening tight junctions disrupts the epithelial barrier, enhances intercellular mRNA delivery, and minimizes toxin absorption in the nasal cavity. The faster generation of serum IgG, IgG1, and IgG2c and significantly greater serum IgG1 levels on day 42 compared to soluble controls. Antigen specific IgA was detected in nasal, vaginal, and fecal samples.	(250)	
PEI-complexed receptor binding domain (RBD) vaccines of SARS-CoV-2 outperformed various delivery systems including DOTAP, chitosan, anionic liposome, and neutral liposome	The SARS-CoV-2 receptor-binding domain (RBD) vaccine complexed with PEI demonstrates superior enhancement of antibody responses compared to various delivery systems. Increased antigen uptake and DC activation. Achieved elevating mucosal IgA secretion levels and promoting proliferation of lung TRM cells. Following a three-dose nasal immunization regimen, high levels of neutralizing IgG antibodies were generated in the serum, persisting for at least one year.	(251, 252)	
Lipid–polymer complexs (Lipopolyplexs)	Encapsulation of ovalbumin into a targeting ligand lipopolyplex with linked lactose and 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine	Levels of mucosal IgA and systemic IgG antibodies significantly increased. Higher macrophage uptake rates compared to unmodified liposomes and induced elevated levels of TGF-α and IL-6	(283)	
A lipidic delivery system of a triple vaccine adjuvant	Strongly adsorbing immune modulators or antigens onto surface; Increased cytokine release on phagocytes, and antigen presentation. Exhibited lower toxicity and a greater Th1/Th2 immune response.	(285)	
Vaccine combined with CAF01	Effectively induced antigen presentation to relevant cell populations, as well as differentiation of B cells and T cells. Shifted the effector function of activated CD4+ T cells toward a Th1/Th17 response and provides enduring, robust Th1 memory.	(286, 287)	
Vaccine combined with CAF09b	Prevented the systemic distribution of immunostimulants in cationic liposomes, counteracting harmful innate immune responses. Upregulated multiple genes associated with IFN-I.	(291, 292)	
Inorganic nanoparticle system	Metallic nanoparticles	Gold nanoparticles (AuNP), which can act as a scaffold for the delivery of various antigens	Effectively trafficking to lymph nodes, it demonstrates outstanding antigen-specific T cell immunity. Upon repeated administration, it did not induce carrier-specific immunity while eliciting specific IgG serum antibodies.	(320, 321)	
Inclusion of silver nanoparticles (AgNPs) in vaccine	Antiviral activity, biocompatibility, and low toxicity; enhanced specific IgA-secreting plasma cells and antibody titers.	(327−329)	
Nonmetallic nanoparticles	Needle-free intranasal HIV-1 vaccine delivery platform based on carbon nanotubes	Enhanced of local IgA and systemic antibody IgG responses	(349)	
An intranasal vaccine containing cationic cross-linked carbon dots and a SARS-CoV-2 antigen, RBD-HR	Powerful systemic cellular immune response stimulation. Induced the proliferation of TRM in the lungs and airways. Activated professional APCs and effectively targeted nasal epithelial cells. Promoted antigen presentation through sialic acid-mediated binding, leading to antigen delivery by nasal epithelial cells.	(124)	
Biomimetic nanoparticle (BNP) system	Virosomes	Virosomes harboring surface HIV-1 gp41-derived P1 lipidated peptides (MYM-V101)	Induced the production of antibodies against conservative motifs in the mucosa, with the ability to inhibit virus transmembrane transport.	(370)	
Virus-like particles (VLPs)	A VLPs vaccine derived from norovirus GI.1 genotype adjuvanted with monophosphoryl lipid A and the mucoadherent chitosan.	Circulating antigen specific IgA and IgG antibody secreting cells were present after nasal administration of the adjuvant virus-like particle vaccine.	(382)	
Outer membrane vesicles (OMVs)	A vaccine based on outer membrane vesicles of pertussis	Induces a robust mucosal immune response, encompassing elevated levels of lung and IgA antibodies. High numbers of IgA and IgG-producing plasma cells, along with lung-resident IgA memory B cells. Only nasal immunization elicited lung Th1/Th17-related cytokine responses. Both pathways, including elevated systemic IgG antibody levels. Only nasal immunization could prevent colonization in both the lungs and nasal cavity.	(388)	
A nasal vaccine OMVs from group B Neisseria meningitidis	Compared to intramuscular injection, all volunteers produced nasal IgA antibodies, and the levels of nasal antibodies remained elevated six months after nasal immunization. Although the serum IgG antibody levels in many recipients were relatively lower, the serum antibodies exhibited bactericidal activity levels equivalent to those of intramuscular injection.	(389)	
Escherichia coli OMV for intranasal vaccination with heterologous antigens	Compared to intranasal administration of adjuvants such as cholera toxin and subcutaneous administration of MF59, it was observed that the humoral and cellular immune responses induced by intranasal OMV adjuvant were comparable to those induced by other adjuvants. Antigen with OMVs alone was sufficient to generate a significant adjuvant effect.	(393)	
RBD-conjugated OMVs were used to immunize COVID-19.	Induced a robust immune response against bacterial outer membrane components and also resulted in detectable antibody titers against the spike protein. High titers of blood anti-RBD IgG as well as detectable mucosal responses.	(394, 395)	

Other than AuNPs and AgNPs, other metallic nanoparticles such as iron and copper nanoparticles have been reported to be used as adjuvants or carriers for immune therapies,330,331 and limited explorations have been done with regard to their application in intranasal delivery. Besides, copper oxide nanoparticles were shown to induces pulmonary toxicity and fibrosis in mice, implying the potential risks of directly exposure of metallic materials to the respiratory system.332 Furthermore, it was recently reported that intranasal administration of cerium oxide nanoparticles could inhibit oxidative stress induced motor manifestations in parkinsonism,333 highlighting the potential antioxidant and inflammation-modulatory roles of nanoparticles based on rare earth metals.

3.3.2 Nonmetallic Nanoparticles

Nonmetallic nanoparticles, in particular, silica- and carbon-based nanoparticles, have been widely used for the delivery of immune therapies.334,335 Silicon and carbon, belonging to group IV elements, represent pivotal nonmetallic substances in human existence due to their abundance and significance. Their intrinsic physical and chemical properties hold importance in the construction of versatile drug delivery systems.336

Silica, extensively employed in numerous pharmaceutical and food applications, has demonstrated its safety profile in various contexts. As researchers explored alternative carriers for encapsulating and safeguarding antigens, mesoporous silica nanoparticles emerged as an option. These silica-based nanostructured materials possess exceptional biocompatibility and chemical stability, making them well-suited candidates for such applications.337,338 So far, the studies of intranasal delivery utilizing silica nanoparticles primarily focus on the nose-to-brain delivery of drugs for the treatment of brain diseases. The delivery efficiency of silica nanoparticles has been confirmed in different mice models.339,340 Notably, it has been demonstrated that intranasal exposure to silica nanoparticles could induce the proinflammatory environment in the brain of rat,341 emphasizing the importance of optimizing the manufacturing and modification procedures of silica nanoparticles to circumvent the potential risks.

Carbon, a fundamental element constituting DNA, is pivotal for life’s origins on Earth. Its inherent flexibility is evident in various allotropes and arrangements. Carbon-based delivery systems have garnered considerable attention across diverse fields owing to their structural dimensions and physicochemical properties.342 These systems, including carbon nanotubes, graphene, mesoporous carbon, and carbon dots, offer exceptional optical activity and extensive multifunctional surface areas. This characteristic translates into higher drug-loading capacities, enhanced biocompatibility, and reduced immunogenicity, marking them as potential materials for the delivery of immune therapies.343

Among the available carbon-based nanodelivery systems, carbon nanotubes and carbon dots are considered as potential candidates for the vaccine delivery platform.344,345 The vaccines delivered by carbon nanotubes have induced the considerable protection against the infections of various virus including largemouth bass ulcerative syndrome virus,346 koi herpesvirus,347 and rhabdovirus.348 Intranasal delivery of HIV-1 glycoprotein vaccine carbon nanotubes also led to the enhanced local IgA and systemic antibody IgG responses against the virus in different animal models.349

Moreover, our team has recently developed an intranasal vaccine incorporating cationic cross-linked carbon dots (CCD) and a SARS-CoV-2 antigen, RBD-HR with spontaneous antigen participation. Intranasal immunization with CCD/RBD-HR generated high levels of antibodies exhibiting broad-spectrum neutralization against authentic Omicron-included variants and pseudoviruses. Despite robust stimulation of systemic cellular immune responses, the intranasal CCD/RBD-HR vaccine also induced potent mucosal immunity, evidenced by the generation of tissue-resident T cells in the lungs and airways. These findings underscore the potential of vaccine in eliciting comprehensive immune responses, both systemic and mucosal, offering valuable insights for advanced vaccine development against SARS-CoV-2 variants.124

3.4 Biomimetic Nanoparticle (BNP) System

In the realm of nanomedicine, the fusion of nanotechnology and biomimetic strategies has led to the development of a diverse array of nanoparticles tailored to drug delivery and vaccine advancement. These BNPs have various advantages, enhancing the efficacy of nanotechnology, including targeted delivery, modulation of biological target activity, and direct cellular impact.

In general, BNP platforms exhibit versatility and offer vast potential for various applications. Recently, BNP has been increasingly used in designing more effective vaccine formulations. Due to its inherent activity, it can function as potent nanovaccine or act as carrier system for targeted therapies and vaccine delivery. This section emphasizes the primary structures of different BNPs and their applications in intranasal vaccine.

3.4.1 Virosomes

Considering the structure, virosomes are single or double-layered spherical recombinant viral vesicles, like liposomes.350 The exterior of the virosome looks like an intact virus. Fundamentally, virosomes are recombinant hollow viral envelopes, with a diameter of approximately 100–200 nm, and unable to replicate.351 The presented antigens are either captured within the cavity or chemically linked to its surface. Its membrane composition comprises approximately 70% naturally phospholipids, with the remaining 30% composed of envelope phospholipids derived from the virus.352−355 Distinguished from liposomes, virosomes incorporate targeted hemagglutinin and neuraminidase glycoproteins into the viral membrane.356−359 This also confers virosomes with distinctive immunostimulatory properties and membrane fusion capabilities, setting them apart from other lipid delivery systems. Due to its delivery effectiveness and demonstrated safety, virosomes are considered capable of directly delivering vaccine antigens into host cells.360 Like intact viruses, virosomes can bind to sialic acid receptors on APCs and enter cells through the endocytosis. Subsequently, the acidic pH within the endosome prompts virosomes to fuse with the endosomal membrane, releasing encapsulated antigens into the cytoplasm. Finally, the degraded antigens are presented to the MHC class I and MHC class II molecules, significantly stimulating the immune system.361−364

Virosomes have been demonstrated to be intranasal carriers for various antigens, which can enhance the binding between NALT and APCs, thereby promoting Th1, Th2, and cytotoxic T lymphocytes cellular immune responses.365,366 In a mice model, Cusi et al. demonstrated that upon intranasal instillation of DOTAP-influenza virosomes, a significant labeled DNA uptake was detected in DCs in draining lymph nodes.367 Inflexal V is a virosomal trivalent influenza vaccine suitable for all age groups, showed significant immune responses in immunocompromised children, adults, and the elderly. It is worth mentioning that the Nasal Flu is a trivalent inactivated influenza vaccine with the same virosomes as Inflexal V and combined with Escherichia coli heat-labile toxins as a mucosal adjuvant, which was launched in Switzerland in 2001. However, it was soon discontinued after the launch due to the increased cases of Bell’s palsy in immunized individuals.368,369 MYM-V101 (virosome exogenously loaded HIV-1 gp41-derived P1 lipidated peptide) can induce the production of antibodies against conserved gp41 motifs in the mucosa, possessing the ability to inhibit HIV-1 transcytosis.370 At the tested concentrations, MYM-V101 is considered a safe intranasal vaccine with good tolerability. Significantly, the study emphasizes that the third intranasal vaccine dose enhances serum IgG antibody levels exclusively in the high dose group, with no discernible effect on IgA levels. Further research is needed to investigate whether intranasal administration in the field of HIV vaccines enhances antibody affinity or antiviral capability. Fernandes et al. developed the insect cells-baculovirus expression vector system (IC-BEVS) to construct a virus-like particle-based COVID-19 candidate vaccine. The study indicates that utilizing IC-BEVS to produce the S protein, covalently coupled via its His tag to a click chemistry lipid present in the virosomal membrane, results in an oriented display of the protein. This display properly exposes its receptor binding domain involved in ACE2 binding on target cells.371 These results indicate excellent prospects for using virosomes as an intranasal vaccine delivery system.

3.4.2 Virus-like Particles (VLPs)

VLPs form through the spontaneous interaction of one or more replicates derived from viral capsids, envelope proteins, or core proteins. Due to VLPs lack viral genetic material, they are incapable of replication, rendering them noninfectious and thus serving as a safe template for vaccine development. Various viral capsid proteins can spontaneously assemble into VLPs exhibiting geometric symmetry, commonly taking the form of icosahedral, helical, or rod-shaped structures.372 The capsid proteins of VLPs can arrange into a single layer, double layer, or triple layer. Furthermore, based on their structural complexity, there are enveloped and nonenveloped VLPs. Nonenveloped VLPs lack a host lipid envelope and are primarily composed of one or more viral capsid proteins, derived from pathogens such as papillomavirus and retroviruses.373,374 These VLPs are smaller in size, making it easier for them to cross tissue barriers and accumulate in lymph nodes.375 Enveloped VLPs consist of a cellular membrane acquired from the host cell, with glycoprotein spikes embedded within their lipid bilayer, serving as target antigens to produce neutralizing antibodies. Enveloped VLPs, highly versatile molecules with enhanced flexibility, can target antigenic epitopes from both similar and dissimilar viruses. It is noteworthy that VLP-based vaccines are primarily designed to stimulate B cells and elicit robust antibody responses by activating T helper cells and being presented by APCs on MHC II molecules. However, VLPs can also be presented to MHC I molecules, effectively delivering and activating genes in CD8+ T cells. These have been confirmed in several clinical trials of VLP-based vaccines, such as targeting hepatitis vaccine, an antimalarial vaccine, and anti-HIV vaccine.73,376,377 VLPs-based vaccines have been successfully utilized in commercial vaccines, including the current market-available human papillomavirus (HPV) vaccines Cervarix and Gardasil, as well as Sci-B-Vac targeting the hepatitis virus.

Overall, VLPs ultimately form repetitive surface structures that resemble live viruses in structure and appearance. Most VLPs range in size from 20 to 200 nm, enabling them to penetrate mucosal barriers. Of note, the size of most enveloped VLPs is greater than 100 nm, making it possible for them to aggregate at the injection site, limiting their application.375 Moreover, due to the polymeric nature of many components of the innate humoral immune system, they are easily taken up by APCs, particularly DCs, enhancing interactions with NALT cells.378 These advantages have made VLP-based vaccines widely utilized, especially in the design of nasal vaccines. The intranasal vaccine based on VLP can effectively enhance the mucosal immune response and help reduce virus shedding and local transmission. Rothen et al. assessed the immune response elicited by an intranasally administered conventional vaccine, utilizing VLPs that presented SARS-CoV-2 RBD in a murine model. The results demonstrated robust systemic RBD antibody generation along with increased levels of IgG and IgA antibodies. Notably, the antibodies generated exhibited the capacity to effectively identify and neutralize various variants of concern.379 Researchers are also aiming toward developing a DNA vaccine prepared using a bacteriophage-based approach. The vaccine can be administered through the nasal cavity, stimulating the generation of VLPs that resemble the structure of SARS-CoV-2, prompting a strong immune response in individuals.380 Offering an alternative approach for generating a wider immune response to influenza subtypes, researchers have developed a mosaic, multisubtype VLP vaccine comprising three or four full-length HA proteins from H5N1, H7N2, and H9N2.381 Tretyakova et al. illustrated that intranasal vaccination using the H5/H7/H9 triple-subtype VLP triggered immune reactions and provided protection to ferrets against experimental infections caused by three avian influenza viruses. In a subsequent phase II clinical study, the efficacy of VLPs administered intranasally was evaluated.382 Dry powder formulations of VLPs derived from rod-shaped viruses were tested with monophosphorylate lipid A and adhesive chitosan as adjuvants. It was well-tolerated, with no vaccine-related serious adverse events, and demonstrated a dose-dependent increase in serum antibody titers.

3.4.3 Outer Membrane Vesicles (OMVs)

Biomimetic design can enhance the practicality of nanoparticle technology by employing natural ligands. Various components from bacterial/fungal membranes have been harnessed for nanoparticle fabrication, partially mimicking their natural traits and facilitating targeted therapies for bacterial or fungal infections, including chitin and others. However, due to the difficulty in replicating the multifaceted biological interactions found in nature, incorporating biomimetic functionalities by decorating nanoparticles with natural ligands faces numerous challenges. To address this issue, based on the properties of cell membranes, a biomimetic strategy employing membrane coating of nanoparticles has been developed. Cell membranes, as the fundamental units of living organisms, participate in numerous biological interactions and possess a rich array of functional regulatory factors and antigenic materials. For vaccine development, cell membranes offer a rich source of multiple antigenic materials, enabling the formulation of vaccines that provide broader protection.

Bacterial outer membrane vesicles (OMVs), a type of bacterial-derived nanoparticle, have garnered growing attention in recent years for their application and development as antibacterial vaccines. OMVs are nanostructures ranging from approximately 20 to 250 nm in size, formed by the wrapping and shedding of bacterial or fungal cells, carrying various proteins resembling those found in bacterial outer membranes (Figure 5).195 OMVs typically are spherical double-layer structures capable of fusing with other cells. In addition to various outer membrane proteins, OMVs can also contain inner membrane and cytoplasmic proteins, rendering them complex antigenic mixtures with outstanding intrinsic immunostimulatory properties. Lipids are also integral structural components of OMVs, working in conjunction with envelope-cross-linking proteins to influence the biogenesis of OMVs. Notably, a higher proportion of fatty acids contributes to increased rigidity in the structure of OMVs. OMVs possess a variety of biological functions, including delivering proteins and toxins to target cells, facilitating the transfer of various effectors between bacterial cells and safeguarding nucleic acids during intercellular transport. Research on OMVs has explored their potential as therapies or biomimetic nanocarriers for precise drug delivery.383−385 With inherent immunogenic properties, including self-adjuvant effects and uptake by immune cells, OMVs serve as an exceptional platform for delivering autologous cell-source vaccines.386 Furthermore, their small size has been demonstrated to enhance their rate of uptake into lymph nodes and APCs, thereby augmenting their immunostimulatory capacity. Containing diverse PAMPs, including lipoproteins, lipopolysaccharides, and pathogenic DNA fragments, they effectively stimulate the host’s innate and adaptive immune systems.387 Due to their multifactorial, nonreplicative, and outstanding immunogenic properties, OMVs are appealing candidates for natural antigen delivery and antibacterial vaccine administration. Similarly, the concept of utilizing OMVs for intranasal vaccine administration has successfully been applied to enhance mucosal immune responses.

Figure 5 Composition of Gram-negative bacterial cell envelope and outer membrane vesicle (OMV). After the cell wall is excised, phospholipids accumulated in the outer membrane leaflets, and the expansion pressure continued to produce, which intensified the further enrichment of outer membrane components. The linkage between the peptidoglycan and the outer membrane layer is disrupted, and finally OMVs are formed. OmpA: outer-membrane protein A. The scheme was generated using Biorender.

Existing research has shown that homologous outer membrane vesicles, as intranasal vaccines, can prevent bacterial diseases caused by their parent strains. Raeven et al. conducted subcutaneous and nasal mucosal immunizations using engineered outer membrane vesicles from Bordetella pertussis that retained pertactin. The results indicated that subcutaneous immunization induced high levels of antibodies and Th1/Th2/Th17 responses, but no mucosal immunity or protection against nasopharyngeal infection was observed. On the contrary, robust mucosal antibody levels were induced through intranasal immunization, encompassing IgA antibodies and memory B cells.388 The Norwegian Institute of Public Health conducted a clinical study on intranasal application. The study administered Neisseria meningitidis OMVs extracted with deoxycholate as a nasal drop or spray. Compared to intramuscularly injected, all volunteers generated nasal IgA antibodies, with nasal antibody levels remaining elevated up to 6 months following nasal immunization. Despite relatively lower levels of serum IgG antibodies in many recipients, the serum antibodies exhibited bactericidal activity levels like those of intramuscular injection.389 In another study, a phase I clinical trial was conducted on the OMVs produced from Shigella strains, using a monovalent vaccine administered via intramuscular, intradermal, and intranasal routes.390 However, the results indicate that the vaccine’s immunogenicity via the intradermal and nasal routes was poor, possibly due to the low dosage used. Further research is needed to assess the results.

Molecular engineering of outer membrane vesicles can design a diverse range of carriers suitable for immune activation, thereby serving as a platform for different types of vaccines. Utilizing the immune-activating properties of OMVs, they can function as adjuvants when combined with diverse antigens, including those associated with viruses, parasites, and tumors.391,392 Pritsch et al. combined Escherichia coli OMVs with the malaria transmission-blocking antigens AnAPN1 and Pfs48/45 for intranasal immunization in mice. Compared with the nasal administration adjuvant cholera toxin and the subcutaneous administration adjuvant MF59, it was found that the humoral and cellular immune intensity induced by the intranasal OMV adjuvant was comparable to the other adjuvants. Notably, the study showed a significant adjuvant effect by simply mixing the antigen with OMVs.393 In recent studies, OMVs have been used as an expression system for the severe acute respiratory SARS-CoV-2 spike protein. Ley et al. utilized Neisseria’s OMVs for the delivery of the SARS-CoV-2 spike protein, coupled with the mCRAMP peptide binding to LPS.29 After the administration of the vaccine via intranasal or intramuscular routes to mice and Syrian hamsters, neutralizing antibodies were detected in the serum following immunization. However, high levels of IgA antibodies were found only in the nasal cavity and lungs after intranasal immunization. Similarly, engineered outer membrane vesicles from Salmonella typhimurium, as well as from Vibrio cholerae and enterotoxigenic Escherichia coli strains, were utilized to express the SARS-CoV-2 spike protein and were administered for intranasal immunization in mice, all of which showed the presence of antibodies neutralizing SARS-CoV-2.394,395 Moreover, a recent clinical study is assessing the safety and effectiveness of intranasal administer with engineered Neisseria meningitidis OMVs as a SARS-CoV-2 subunit antigen (Avacc10) platform (NCT05604690). Interestingly, Pritsch et al. recently reported a method for rapidly obtaining multivalent designed OMV.396 They combined the OMVs obtained from the strain CFT073 of Escherichia coli with OMVs from three clinically isolated multidrug-resistant strains for intranasal vaccination in mice. The findings suggest that the innate humoral immune response (IgM, IgG) was specific to all strains, and no signs of local or systemic toxicity were found.

In conclusion, OMVs represent a versatile vaccine platform. It can be administered nasally, activating innate and adaptive immunity both systemically and at local/distant mucosal. However, only a few studies have been conducted in humans to date,391,392 and there is a need for more robust protocols to scale up OMV production for ensuring reproducibility and stability, facilitating clinical applications.

4 Current Progress in Clinical Trials

The clinical application of intranasal vaccines faces intricate challenges interlinked with the immunological traits of the mucosal system.397 Constantly exposed to diverse environmental irritants, pathogens, and allergens, the mucosal system has evolved robust protective mechanisms.398,399 These mechanisms involve the defense mechanisms of mucosal surface, immune tolerance induction against harmless antigens, and specialized epithelial cells in organized lymphoid tissues.400 Hence, designing an effective mucosal vaccine requires overcoming three key hurdles: stability under harsh mucosal conditions, precise targeting of the sampling site of mucosal immune system, and promoting immune activation rather than tolerance.

Regarding the viral vectors that have been employed for intranasal vaccine development for a period, the limitations of viral vector (such as preexisting immunity and safety concern) may compromise the vaccine efficiency and impair the potential of large-scale clinical use. Therefore, technologies should be rapidly utilized to develop intranasal vaccines. As was discussed in the previous sections, nanoparticles exhibit stronger intranasal immune responses.246 Encapsulating or attaching antigens to nanoparticles shields them from degradation.401 Moreover, nanoparticles can be equipped with targeting moieties or ligands, ensuring specific cell delivery.220 Additionally, materials like liposomes, lipid nanoparticles, chitosan, hyaluronic acid, polyethyleneimine, and poly(lactic-co-glycolic acid) can potentially overcome mucosal barriers. These nanotechnologies enhance antigen recognition by the innate immune system, leading to more potent mucosal immune responses compared to their soluble counterparts. Through these approaches, the hurdles posed by the mucosal environment can be effectively surmounted. Although no nanoparticle-based intranasal vaccine has been registered on clinicaltrials.gov so far, 6 clinical trials have been registered to evaluate intranasal nanoparticle-based antirespiratory disease therapies (Table 3). Among them, 4 trials were designed to assess the intranasal therapies against COVID-19, the other 2 interventions were developed for the treatment of chronic sinusitis and inflammatory disease. Moreover, silver nanoparticles were planned to be used for the attenuation of 3 different disorders. In addition, two trials were designed to assess the therapeutic role of exosomes, a type natural LNPs, on COVID-19. One study released the clinical data obtained from the trial. The results showed that intranasal administration of exosomes did not elicit adverse events in all participants. However, exosome therapy showed negligible efficacy comparing to placebo (NCT04491240, accessed on October 26, 2023). Therefore, although the combination of nanotechnologies with intranasal immune therapy is associated with multiple advancements, extensive research and rigorous testing are still crucially needed to optimize these nanotechnological solutions, ensuring their safety, efficacy, and scalability for widespread application.

Table 3 Intranasal Nanoparticle-Based Antirespiratory Disease Therapies under Clinical Evaluation

NCT Number	phase	condition	form of nanoparticle	
NCT03243201	Phase 1	Chronic sinusitis	Silver nanoparticles	
NCT02408874	Phase 1	Inflammatory disease	Silver nanoparticles	
NCT04894409	NA	COVID-19	Silver nanoparticles	
NCT04491240	Phase 2	COVID-19	Exosome	
NCT04602442	Phase 2	COVID-19	Exosome	
NCT04480333	Phase 1	COVID-19	Not defined	

5 Conclusion and Prospects

This review highlights the landscape of nanobased intranasal vaccines as a noninvasive solution for respiratory infectious diseases. We examined the vulnerabilities of the respiratory system, the challenges of traditional mucosal vaccines, and the transformative role of nanotechnology in overcoming these limitations. By focusing on various nanoparticle-based delivery systems, including lipid nanoparticles, and polymeric nanoparticles, inorganic nanoparticles, and biomimetic nanoparticles, the potential of these approaches in stabilizing vaccines, enhancing mucosal adhesion, and ensuring controlled release was underscored. Through a comprehensive evaluation of current barriers, advancements in delivery technologies, and an exploration of various vaccine formulations, this review also demonstrated that nanobased intranasal vaccines offer a powerful strategy to combat respiratory infections effectively.

Looking forward, several exciting avenues beckon in the field of nanobased intranasal vaccines. Foremost, further research is essential to fine-tune these delivery systems, ensuring their safety, efficacy, and scalability for mass production. Subsequent studies will delve into ways to enhance the systemic immunogenicity and protective effects of nanobased vaccines. For instance, optimizing the efficiency of protein integration into nanoparticles may improve the performance. Additionally, the immunogenic characteristics induced by nanobased intranasal vaccine formulations need further elucidation. Distinct systemic humoral and cellular immune responses play varying protective roles against infections. Certain intranasal vaccines, such as OMVs for intranasal vaccine administration, demonstrate the induction of both systemic neutralizing antibodies and local IgA responses. In contrast, despite the absence of measurable serum neutralizing antibodies induced by some intranasal vaccines, a significant protective effect is observed in the immune host, substantially reducing the viral load challenge in both the upper and lower respiratory tracts. It is noteworthy that an IL-17 induced increase was observed after administration of the nanobased intranasal vaccines. While Th17 responses are associated with autoimmune and inflammatory side effects, their potential risks and benefits in the context of intranasal vaccines induced immune responses remain to be determined. Another crucial aspect is assessing the protective capacity of nasal vaccines against the spread of the virus within the natural sentinel organisms challenged with the nanoparticles. The effectiveness of observed immune responses in preventing infection and disease is not yet clear. While animals immunized with nanobased intranasal vaccines exhibit substantially lower virus titers in nasal and oropharyngeal swabs compared to the control group, they can still transmit the virus to directly exposed sentinel animals if infected. Lastly, the development of personalized vaccines tailored to specific pathogens or individual genetic profiles holds immense potential. Other strategies for nanobased immunization may also yield better results, such as adopting combination therapy, primarily through intramuscular injection, followed by intranasal administration as a mucosal enhancer. As we anticipate future pandemics and emerging infectious threats, the establishment of global platforms for rapid nanobased vaccine development and distribution is crucial. By embracing these future directions, we can usher in an era where nanobased intranasal vaccines not only provide targeted protection against respiratory infectious diseases but also contribute significantly to global health security.

Author Contributions

† Z.B., D.W., and T.L. contributed equally to this work. X.W. and Y.W supervised the project. Z.B., D.W., and T.L. wrote the manuscript. D.W., T.L., W.H., and H.D. were responsible for revising the manuscript and assisted with the writing. All authors discussed the results and commented on the manuscript.

The authors declare no competing financial interest.

Acknowledgments

This work was supported by the National Science Foundation for Excellent Young Scholars (Grant 32122052) and National Natural Science Foundation Regional Innovation and Development (Grant U19A2003).

Vocabulary

Mucosal immune response the immune response that occurs at mucosal surfaces, such as the nasal cavity, involving the activation of immune cells and production of antibodies to defend against pathogens that enter through these surfaces

Nasal-associated lymphoid tissue lymphoid tissue found in the nasal cavity, involved in initiating immune responses against antigens that enter through the nasal mucosa

Adjuvants substances added to vaccines to enhance the immune response, often by promoting antigen presentation or stimulating innate immune cells

Intranasal vaccine vaccine administered through the nasal route, designed to induce immune responses at mucosal surfaces in the nasal cavity for protection against pathogens

Immunogenicity the ability of a substance, such as a vaccine or antigen, to provoke an immune response in the body, leading to the production of antibodies or activation of immune cells
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