Current Situation and Prospects of Nano-vaccine Technology Development

Looking back at the history of human development, vaccines are an unprecedented medical milestone that has saved countless lives by harnessing the human immune system
.

During the 2019 COVID-19 pandemic, vaccination remains the most effective defense

Compared with traditional vaccines, nanovaccines have advantages in lymph node accumulation, antigen assembly and antigen presentation; they also have unique pathogen biomimetic properties due to the ordered combination of multiple immune factors
.

In addition to infectious diseases, nanovaccine technology also shows great potential to treat cancer

Types of Nanomaterial-Based Vaccines

Types of Nanomaterial-Based Vaccines

In recent years, various nanomaterials for vaccine development have been explored, including lipid nanoparticles, protein nanoparticles, polymer nanoparticles, inorganic nanocarriers, and biomimetic nanoparticles
.

Different types of nanocarriers have different physicochemical characteristics and behaviors in vivo, which affect vaccination

Self-assembled protein nanoparticles

Self-assembled protein nanoparticles

Natural nanomaterials have good biocompatibility and biodegradability
.

Several types of protein nanoparticles made from proteins of natural origin have been used to deliver antigens

VLPs are self-assembled complexes composed of viral proteins and are considered to be safe and efficient antigen delivery platforms
.

VLPs have favorable immunological properties because they are self-adjuvant and can be recognized immunologically based on virus size and repetitive surface geometry

polymer nanoparticles

polymer nanoparticles

Polymer nanoparticles are colloidal systems with a wide size range (10–1000 nm)
.

Polymer nanoparticles are highly immunogenic and stable, and can effectively encapsulate and display antigens

For the development of nanovaccine, both natural polymer nanomaterials (such as chitosan and dextran) and synthetic polymer nanomaterials (such as PLA and PLGA) are useful tools
.

Naturally derived polymer nanoparticles are highly biocompatible, water-soluble, and low-cost

lipid nanoparticles

lipid nanoparticles

Lipid nanoparticles are nanoscale lipid vesicles formed by self-assembly of amphiphilic phospholipid molecules
.

With low toxicity, high biocompatibility, and controlled release properties, LNPs are promising nanocarriers for nucleic acid delivery

LNP is also an important component of mRNA drugs and vaccines
.
LNPs have controllable size, shape, and charge, which are important properties that may affect the effect of immune activation
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Modified LNPs can achieve optimal immune responses
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As nanovaccine, LNPs can realize the combined delivery of multiple antigens and adjuvants
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In addition, the membrane surface of LNPs can display antigens, enhancing the expression of the native conformation
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LNPs have shown great potential for nanovaccine development in many preclinical and clinical applications
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In addition to the COVID-19 mRNA vaccine, many other LNP-mRNA vaccines are in clinical trials for the prevention and treatment of major human health threats, including viral infections, cancer, and genetic diseases
.

Inorganic Nanomaterials

Inorganic Nanomaterials

Inorganic materials commonly used in nanomedicine include metals and oxides, non-metal oxides and inorganic salts
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Inorganic materials have low biodegradability and are structurally stable
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Many inorganic nanoformulations have inherent adjuvant activity
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However, for the application of nanovaccine, the physicochemical properties of inorganic nanomaterials need to be modified to improve their biocompatibility
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The most widely used inorganic materials for antigen delivery include gold, iron and silica nanoparticles
.

Biomimetic Nanomaterials

Biomimetic Nanomaterials

Biomimetic nanomaterials are versatile enough to enable efficient targeted delivery or effective interaction with biological systems
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Bioinspired nanoparticles with high biocompatibility and unique antigenicity can be used to develop effective vaccine formulations
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A simple biomimetic design uses natural ligands or peptides, such as RGD and CDX peptides, to modify nanoparticles and enhance binding for improved targeting for efficient delivery
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In addition, molecularly imprinted polymers can also be used to mimic antibodies to develop biomimetic nanoparticles
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Several other biomimetic strategies have emerged in the design of nanovaccine against infection and cancer
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Virosomes are liposomal haploid nanocarriers (60–200 nm) that utilize the liposome concept but are structurally similar to enveloped viruses with nucleocapsids removed
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Virosomes are an emerging class of biomimetic nanoparticles for the development of nanovaccines against viral infections
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Outer membrane vesicles (OMVs) are bacterial-derived nanovesicles that carry various proteins similar to the bacterial outer membrane
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OMV is a natural antibacterial vaccine because of its multi-antigen properties
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Strategies to improve immune response to nanovaccine

Strategies to improve immune response to nanovaccine

The flexible design of nanomaterials endows nanovaccine with better specific immune response, which is mainly due to the unique drug/antigen delivery properties and nanoimmunomodulation of nanomedicines
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Targeted delivery of antigens to key cells and tissues

Targeted delivery of antigens to key cells and tissues

One of the most promising areas of nanotechnology application is drug delivery
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As for vaccination, it's also very important to deliver the antigen to the right place in the immune system
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Unlike other types of precise cell-type drug delivery, antigen vaccine delivery involves spatiotemporal interactions of multiple cell types, including antigen-presenting cells (APCs), B cells, various T cells, macrophages, and neutrophils
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Furthermore, the aforementioned interactions tend to occur in specific tissues or locations, further complicating antigen delivery
.
Therefore, some promising strategies have been used to design nanovaccines, such as crossing biological barriers, lymph node (LN) transport, controlled release of antigens, APC targeting, cross-presentation,
etc.

For example, 20–200 nm nanoparticles are more readily internalized by a common APC, dendritic cells (DCs)
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Targeted nanoparticle delivery to DCs can be achieved by modifying affinity-based specific ligands that target DC subsets, such as the C-type lectin receptor
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In addition, multivalent antigenic structures were also found to enhance antigen recognition and activation of B cells, another APCs
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Multivalent effect of nanovaccine

Multivalent effect of nanovaccine

There is evidence that multivalent effects can elicit stronger humoral and cellular immune responses in self-assembling polypeptide nanoparticles, multi-antigen-binding nanoparticles, and other multivalent combinations
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Encouragingly, nanotechnology has absolute advantages in manipulating antigen density and orientation, providing a good platform to study the underlying mechanisms of multivalent effects and their optimization strategies
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For example, liposomes containing multivalent HIV trimers have been found to increase the strength of antibody responses to target antigenic protein regions
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Further studies have shown that antibody responses can be formed by programming specific epitopes; vaccine specificity can be improved by burying unwanted epitopes and exposing required epitopes, thereby reducing immunodominant non-immunity to HIV trimers Neutralize the reaction in the region
.

Carry nucleic acid to express antigen in vivo

Carry nucleic acid to express antigen in vivo

The successful application of COVID-19 vaccines has demonstrated the unlimited potential of mRNA vaccines.
The efficacy of nucleic acid-based vaccines mainly depends on the delivery of DNA or RNA molecules that upregulate the expression of target-encoded antigens and prime them in target immune cells Specific, strong immune response
.

DNA vaccines are simple, stable, and inexpensive to mass produce
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However, the inefficient delivery of plasmid DNA (pDNA) in vivo compromises its effectiveness and limits further preclinical applications
.
In contrast, mRNA vaccines have more significant advantages, with better antigen expression and faster clearance, in which nanotechnology plays an important role
.
Cationic lipids are the most commonly used nanomaterials that help protect mRNA from degradation and immune recognition
.

In situ triggers tumor antigen release

In situ triggers tumor antigen release

In addition to the introduction of antigens through vaccination, the release of tumor antigens in vivo can also be triggered
.
One of these mechanisms is the triggering of immunogenic cell death (ICD), leading to the release of tumor-associated antigens (TAAs), damage-associated molecular patterns (DAMPs), and pro-inflammatory factors, which trigger adaptive anti-tumor immunity
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By exploiting the superior delivery capabilities of nanomedicines, the effects of ICD inducers can be synergistically amplified with other immunotherapeutic agents, such as immune checkpoint inhibitors, indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitors, and Interferon gene-stimulating protein (STING) agonists to combat immunosuppression
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Therefore, the co-delivery of ICD inducers and immunotherapeutics is a promising design strategy for nanovaccine treatment of solid tumors
.

Immune Adjuvants and Other Immune Stimulation Strategies

Immune Adjuvants and Other Immune Stimulation Strategies

Immune adjuvants are an integral part of vaccines and play an auxiliary role in enhancing the immune system's response to antigens
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Some nanomaterials have inherent adjuvant properties that promote cytokine secretion and activate immune signaling pathways
.
Furthermore, nanomaterials with phototherapy or reactive oxygen species generation properties can also induce ICD effects in cancer immunotherapy
.
These self-adjuvant nanomaterials offer more possibilities and potentials for the application of nanomedicines in vaccines
.

dosing strategy

dosing strategy

Currently, most vaccines take the parenteral route, which is invasive and has limited compliance
.
The development of nanomedicine has provided multiple options for vaccine routes, including postoperative, intradermal/subcutaneous, intranasal, inhalation, and oral administration, for infectious diseases and cancer treatment
.

Postoperative medication

Postoperative medication

Currently, surgery remains the primary treatment option for solid tumors
.
However, tumor recurrence remains a challenge, and nanomedicine strategies for drug delivery and immunotherapy after tumor surgery are emerging
.

For example, in order to improve the efficiency of postoperative T cell immunity, a hydrogel of thermoresponsive curcumin-loaded polymer nanoparticles assembled with antigenic peptides and CpG ODNs was developed
.
This strategy can induce ICD, thereby enhancing antitumor immunity
.
This immunotherapy strategy promoted CTL infiltration and suppressed local recurrence and lung metastasis
.
In another study, an implantable 3D porous scaffold was designed to deplete myeloid-derived suppressor cells and presented whole tumor lysates with nanogel-based adjuvants to promote CTLs
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This immune niche strategy modulates the immunosuppressive environment and can prevent postoperative tumor recurrence and metastasis
.

Intradermal/subcutaneous administration

Intradermal/subcutaneous administration

Intradermal/subcutaneous injection is a common route of immunization for DNA vaccines
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Both the epidermis and dermis of the skin contain resident APCs that are immune targets
.
Since the skin is painless, intradermal/subcutaneous injection has been widely used for vaccination
.

In recent years, this drug delivery strategy has also been used in anticancer therapy
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Subcutaneous immunization with VLPs that bind human EGFR 2 epitopes has been reported to induce elevated titers of specific antibodies against HER2-positive malignancies
.
Further, multifunctional microneedle systems for tumor and infectious disease vaccination have also been explored
.
In addition, transdermal vaccines can be used for topical and intratumoral anti-melanoma immunotherapy
.

intranasal administration

intranasal administration

Nasal administration is an important way to treat respiratory infectious diseases
.
Nasal immunization via nanovaccine holds promise for preventing disease by primarily affecting the infected respiratory tract, such as tuberculosis, and could be used in cancer treatment
.

Chitosan nanoparticles are a water-soluble platform for nasal delivery of tuberculosis vaccine antigens
.
Thio-OVA conjugated to N-trimethylaminoethyl methacrylate chitosan showed higher cellular uptake, deep cervical lymph node transport efficiency and immune response after nasal administration
.
For intranasal cancer nanovaccine delivery, a recent study developed a self-assembled nanovaccine loaded with multiple OVA peptide antigens
.
This nanovaccine through intranasal administration prolongs the residence time and improves the efficiency of antigen uptake, thereby enhancing the antigen-specific immune response
.

Inhalation administration

Inhalation administration

Inhalation administration is also a promising route of vaccination for pulmonary infectious diseases such as tuberculosis
.
Synthetic nanoparticles are effective tools for inhaled formulations
.
Polymer nanocapsules with oil cores and polymer shells have been developed for pulmonary delivery of imiquimod, TLR-7 agonists, and fusion antigen proteins
.
Vaccination of such polymer nanocapsules induced a strong immune response
.

In addition, inhalation administration can also be used for cancer nanovaccine, such as lung metastases
.
Inhaled VLPs have been reported to promote neutrophil infiltration in tumors and increase cytokine and chemokine production as well as macrophage inflammatory protein 1α in tumor-bearing mice
.
This nanovaccine treatment significantly reduced the metastatic tumor burden across various tumor types
.

Oral administration

Oral administration

Oral administration is a non-invasive route with good compliance
.
Oral vaccines are the best option for administration, immunization, safety, and storage
.

Some nanocarriers have been developed into oral tuberculosis vaccines
.
Liposome-encapsulated DNA vaccines induce potent immune responses against TB
.
VLPs can also be used to carry HIV envelope cDNA for enhanced stability in the gastric environment
.
This strategy resulted in higher antigen concentrations in the gut after oral administration
.

Oral administration strategies can also be used for cancer vaccines
.
Nanoemulsions have been reported to have high encapsulation capacity for co-delivery of melanoma antigen, heat shock protein, and staphylococcal toxin
A.
This oral administration strategy showed an immune response comparable to subcutaneous immunization
.

Clinical application of nano-vaccine technology

Clinical application of nano-vaccine technology

Nanovaccines have been developed to treat various diseases
.
Including cancer and various infectious diseases such as AIDS, malaria and tuberculosis (TB)
.
There are a number of nanovaccine currently in clinical stage
.

Prevention and treatment of infectious diseases

Prevention and treatment of infectious diseases

There are some similarities in the development of vaccines for infectious diseases, antigen delivery remains the key to vaccination, and self-assembling protein nanoparticles are an effective means of antigen delivery
.
RTS,S is the first and currently only malaria vaccine on the market that uses VLPs to deliver antigens
.
In addition, VLPs have also been tested to display HIV envelope proteins, such as the V1V2 loop, and can generate specific IgG in mice
.

Polymer nanomaterials have received extensive attention as vaccine platforms due to their synthetic feasibility, low immunogenicity, and high biodegradability
.
Recently, HIV-1-derived gp140 immunogen with 3M-052, a TLR-7/8 agonist, was loaded into PLGA nanoparticles and induced high frequency and sustained HIV envelope specificity in rhesus monkeys Sexual immune response
.

Inorganic nanoparticles and biomimetic nanoparticles are also effective platforms for the development of anti-infective nanovaccine
.
For example, HIV's gag p17 increases CD8+ T cell proliferation by binding to highly mannoside-modified GNPs; virion vaccines developed from the HIV-1 gp41 subunit induce strong mucosal antibodies against HIV
.

Inhibit tumor recurrence and metastasis

Inhibit tumor recurrence and metastasis

Various nanomaterials have been explored as efficient tumor vaccine delivery platforms
.
VLPs have been used directly for the delivery of tumor-associated antigens, and VLPs vaccines can be used in combination with radiation therapy, chemotherapy, or immunotherapy
.
To comprehensively stimulate antitumor immune responses, we designed HDL-mimicking nanodiscs for antigen and adjuvant delivery to lymphoid organs
.
Nanodisc treatment showed a significant increase in the frequency of neoantigen-specific CTLs and tumor eradication in combination with immune checkpoint blockade therapy
.

Traditional LNPs are also efficient platforms for delivering tumor vaccines
.
In a recent study, mRNAs encoding tumor antigens were incorporated into cationic C1 LNPs with adjuvant properties for efficient delivery and presentation to dendritic cells
.
The c1 mRNA nanovaccine has significant preventive and therapeutic effects on tumors
.

Outlook

Outlook

Rapid advances in nanotechnology over the past few decades have laid the foundation for the development of nanomedicine and vaccines
.
Compared with traditional vaccines, nanovaccine utilizes a variety of nanoparticles and has significant advantages in delivery efficiency, dosage regimen, route of administration, adjuvant and vaccination effect
.
In addition to nanomaterial design, the development of novel immunogens is of great significance for achieving ideal infectious disease preventive immune responses; while for cancer nanovaccine development, the safety, targeting, and vaccine integrity of the effective cascade is important for therapeutic immune responses critical
.

Regarding the safety of nanovaccines, immunogenicity and toxicity are two major concerns
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Nanoparticles may activate host immune responses after administration, and furthermore, nanoparticle derivatives may elicit unexpected nonspecific immune responses following biodegradation
.
Both cationic and ionizable nanoparticles may be immunogenic by increasing proinflammatory cytokine levels
.
The cytotoxicity of nanoparticles is closely related to the type and dose of nanomaterials
.
Therefore, the selection of biodegradable components for the development of nanovaccine with better biocompatibility is the future direction
.

At present, liposomes and lipid nanoparticles have played a leading role in the clinical application of nanovaccine, indicating that the good biocompatibility and biosafety of nanomaterials are still indicators that cannot be ignored in the competition for next-generation nanovaccine
.
It is worth mentioning that diseases with different underlying immune mechanisms will further drive the development of nanovaccine subtypes
.
Looking at vaccine nanotechnology currently under clinical development, mRNA-based nanovaccine holds great promise in cancer treatment and infectious disease prevention
.

Many issues, including physicochemical properties, biointerfaces, and quality control, remain to be borne by the successful clinical translation of nanovaccine
.
In addition, the implementation population and cost-effectiveness of nanovaccine should also be considered; while for cancer nanovaccines, patient-specific antigens are a challenge for personalized vaccines
.

In conclusion, nanovaccine technology has shown encouraging results in experimental studies, and further efforts in nanomaterials, immunology, virology, oncology and pharmaceutical industries will jointly promote the clinical translation and application of nanovaccine technology, Ultimately benefiting more infectious disease and oncology patients
.

references:

references:

1.
Emerging vaccine nanotechnology: Fromdefense against infection to sniping cancer.
Acta Pharm Sin B.
2022 Jan 4

1.
Emerging vaccine nanotechnology: Fromdefense against infection to sniping cancer.
Acta Pharm Sin B.
2022 Jan 4