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.

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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.
As a reliable PEG supplier, Biopharma PEG has been focusing on the development of a
full range of medical applications and technologies for nanocarrier systems, including
various types of nanoparticles, liposomes, micelles, etc. We also provide PEG products
that can use in COVID-19 mRNA vaccines.
Reference:
1. Emerging vaccine nanotechnology: Fromdefense against infection to sniping cancer. Acta Pharm Sin
B. 2022 Jan 4
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[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​