Current Situation of Nanovaccines Technology Development

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Current Situation of Nanovaccines 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 COVID-19 pandemic, vaccination remains the most effective defense. The success of the lipid nanoparticles COVID-19 mRNA vaccine provides a broad prospect for the application of nanotechnology in vaccine development.

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, nanovaccines technology also shows great potential for treating cancer. The ultimate goal of cancer vaccines is to fully mobilize the potency of the immune system to recognize tumor antigens and eliminate tumor cells, and nanotechnology has the properties necessary to achieve this goal. As one of the cancer immunotherapy candidates with customizable components and orderly integration, nanovaccine technology will likely become a strategy and platform for more effective activation of antitumor immunity.

Types of Nanomaterial-Based Vaccines In recent years, various nanomaterials have been explored for vaccine development, including lipid nanoparticles, protein nanoparticles, polymer nanoparticles, inorganic nanocarriers and biomimetic nanoparticles. Different types of nanocarriers have different physicochemical characteristics and behaviors in vivo, thus affecting vaccination.

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Self-assembled protein nanoparticles Natural nanomaterials have good biocompatibility and biodegradability. Several types of protein nanoparticles made from naturally sourced proteins have been used to deliver antigens. Self-assembled protein nanoparticles are promising candidate materials for nanovaccines. Typical examples of self-assembled protein nanoparticles include the ferritin family of proteins, pyruvate dehydrogenase (E2), and virus-like particles (VLP), which have shown great potential in the development of nanovaccines.

Polymer nanoparticles Polymer nanoparticles are colloidal systems with a wide size range (10 -1000nm). Polymer nanoparticles have high immunogenicity and stability and can effectively encapsulate and display antigens. Polymer nanoparticles can improve the efficiency of APC antigen uptake by phagocytosis or endocytosis. Both natural

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polymer nanomaterials (e.g., chitosan and dextran) and synthetic polymer nanomaterials (e.g., PLA and PLGA) are useful tools for nano-vaccine development.

Lipid nanoparticles Lipid nanoparticles are nanoscale lipid vesicles formed by self-assembly of amphiphilic phospholipid molecules. LNPs is a promising nucleic acid delivery nanocarrier with low toxicity, high biocompatibility and controlled release properties.

LNP is also an important component of mRNA drugs and vaccines. LNP has controllable size, shape and charge, which are important properties that may affect immune activation. Modified LNPs can achieve optimal immune response. As nanovaccines, LNPs can deliver multiple antigens and adjuvants together. In addition, the membrane surface of LNPs can display antigens, enhancing the expression of natural conformation.

LNPs have shown great potential for nanovaccines development in many preclinical and clinical applications. In addition to the COVID-19 mRNA vaccines, there are many other LNP-mRNA vaccines in clinical trials for the prevention and treatment of major human health threats, including viral infections, cancer and genetic diseases.

Inorganic Nanomaterials Inorganic materials commonly used in nanomedicine include metals and oxides, non-metal oxides and inorganic salts. Inorganic materials have low biodegradability and stable structure. Many inorganic nano-preparations have inherent adjuvant activity.

However, for the application of nanovaccines, the physicochemical properties of inorganic nanomaterials need to be modified to improve their biocompatibility. The most widely used inorganic materials for antigen delivery include gold, iron and silica nanoparticles.

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Dosing strategies for nanovaccines Currently, most vaccines use the parenteral route, which is invasive and has limited compliance. The development of nanomedicine offers a variety of options for vaccine routes, including postoperative, intradermal/subcutaneous, intranasal, inhaled and oral administration, for the treatment of infectious diseases and cancer.

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 a nanogel-based adjuvant to promote CTLs. This immune niche strategy modulates the immunosuppressive environment and can prevent postoperative tumor recurrence and metastasis.

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

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In recent years, this drug delivery strategy has also been used in anti-cancer therapy.

Subcutaneous immunization with VLPs that bind human EGFR 2 epitopes has been reported to induce elevated titers of specific antibodies against HER2-positive malignancies. Furthermore, 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 is an important way to treat respiratory infectious diseases.

Intranasal immunization via nanovaccines is expected to prevent disease by primarily affecting the infected respiratory tract, such as tuberculosis, and could be used in cancer treatment.

For intranasal cancer nanovaccine delivery, a recent study developed a self-assembled nanovaccine loaded with multiple OVA peptide antigens. The nanovaccines are administered intranasally with extended residence time and improved antigen uptake efficiency, thereby enhancing antigen-specific immune responses.

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 nanovaccines, such as lung metastases.

Oral administration

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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 TB vaccines. DNA vaccines coated with liposomes induce an effective immune response against TB. VLP can also be used to carry HIV envelope cDNA to enhance stability in the gastric environment. This strategy results in higher concentrations of intestinal antigens after oral administration.

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

Clinical application of nanovaccines technology Nanovaccines have been developed to treat a variety of diseases, including cancer and multiple infectious diseases such as AIDS, malaria, and tuberculosis (TB). There are a number of nanovaccines currently in clinical stage.

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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-assembled protein nanoparticles are an effective means of antigen delivery. RTS,S, the first and currently only malaria vaccine on the market, uses VLP to deliver antigens. In addition, VLP has also been tested to demonstrate HIV envelope proteins, such as the V1V2 ring, and can produce specific IgG in mice.

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Polymer nanomaterials have attracted wide attention as vaccine platforms due to their feasibility of synthesis, low immunogenicity and high biodegradability. Inorganic and biomimetic nanoparticles are also effective platforms for developing anti-infection nanovaccines.

Inhibit tumor recurrence and metastasis Various nanomaterials have been explored as effective tumor vaccine delivery platforms.

VLPs has been used directly for the delivery of tumor-associated antigens and VLPs vaccines can be used in combination with radiotherapy, chemotherapy or immunotherapy.

In order to fully stimulate the anti-tumor immune response, nanodisks simulating HIGH-DENSITY lipoprotein were designed to deliver antigens and adjuvants to lymphatic organs. Nanodisk therapy showed a significant increase in the frequency of neoantigen specific CTL and tumor elimination in combined immune checkpoint blocking 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

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adjuvant properties for efficient delivery and presentation to dendritic cells. The c1 mRNA nanovaccine has significant preventive and therapeutic effects on tumors.

Conclusion Rapid advances in nanotechnology over the past few decades have laid the foundation for the development of nanomedicine and vaccines. Compared with traditional vaccines, nanovaccines utilize a variety of nanoparticles and has significant advantages in delivery efficiency, dosage regimen, route of administration, adjuvant and vaccination effect.

Currently, liposomes and lipid nanoparticles play 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.

Looking at vaccine nanotechnology currently under clinical development, mRNA-based nanovaccines hold great promise in cancer treatment and infectious disease prevention.

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

Related articles: [1] Lipid Nanoparticles: Key Technology For mRNA Delivery [2] Lipid Nanoparticles for Drug and Vaccine Delivery [3] Overview of mRNA-Lipid Nanoparticle COVID-19 Vaccines [4] Current Nanomedicines for the Treatment of Cancer​