key: cord-0955920-izspimrb
authors: Feng, Chan; Li, Yongjiang; Ferdows, Bijan Emiliano; Patel, Dylan Neal; Ouyang, Jiang; Tang, Zhongmin; Kong, Na; Chen, Enguo; Tao, Wei
title: Emerging vaccine nanotechnology: From defense against infection to sniping cancer
date: 2022-01-04
journal: Acta Pharm Sin B
DOI: 10.1016/j.apsb.2021.12.021
sha: 935287e8a4c43500ad721661bbbd3e0d20d13aae
doc_id: 955920
cord_uid: izspimrb

Looking retrospectively at the development of humanity, vaccination is an unprecedented medical landmark that saves lives by harnessing the human immune system. During the ongoing coronavirus disease 2019 (COVID-19) pandemic, vaccination is still the most effective defense modality. The successful clinical application of the lipid nanoparticle-based Pfizer/BioNTech and Moderna mRNA COVID-19 vaccines highlights promising future of nanotechnology in vaccine development. Compared with conventional vaccines, nanovaccines are supposed to have advantages in lymph node accumulation, antigen assembly, and antigen presentation; they also have, unique pathogen biomimicry properties because of well-organized combination of multiple immune factors. Beyond infectious diseases, vaccine nanotechnology also exhibits considerable potential for cancer treatment. The ultimate goal of cancer vaccines is to fully mobilize the potency of the immune system as a living therapeutic to recognize tumor antigens and eliminate tumor cells, and nanotechnologies have the requisite properties to realize this goal. In this review, we summarize the recent advances in vaccine nanotechnology from infectious disease prevention to cancer immunotherapy and highlight the different types of materials, mechanisms, administration methods, as well as future perspectives.

The key principle of vaccination is how to trigger the proper immune response to target antigens. Underlying this process is a complicated network responding to exogenous and endogenous danger stimuli, which are involved in various immune cell types and concerted by innate and adaptive immune responses. The flexible design of nanomaterials endows nanovaccines with improved specific immune responses. The vaccines mainly benefit from the unique drug/antigen delivery properties and nano-enabled immunomodulation of nanomedicine. In this section, we focus on these strategies for evoking the immune response.

One of the most promising areas in which nanotechnology is applied is drug delivery.

As for vaccination, delivering an antigen to the right place in the immune system is also of great importance. Unlike other types of drug delivery to precise cell types, the antigen vaccine delivery process involves spatiotemporal interactions of several cell types, including antigen-presenting cells (APCs), B cells, various T cells, macrophages, and neutrophils. In addition, the above interactions tend to occur in a specific tissue or location, further complicating antigen delivery. Therefore, several promising strategies have been employed to design nanovaccines, such as crossing the biological barrier, lymph node (LN) trafficking, the controlled release of antigen, APCs targeting, cross-presentation, among others 10, 11 .

Researchers widely hypothesized that prolonged persistence of antigen or minimized unnecessary degradation of antigen would enhance immune response.

Therefore, nanomedicine researchers were devoted to increasing the persistence of antigens at the injection sites, in lymphoid tissues, and even in APCs by conjugating or encapsulating antigens in nanomaterials 12, 13 . Beyond the precondition of antigen persistence in the internal environment, LN delivery is highly sought after for its design because of the large population of immune cells residing in LNs. Currently, only a small amount of the antigen at the injection site can be delivered to the LNs by APCs; to J o u r n a l P r e -p r o o f enhance LN delivery methods, researchers need to further adjust multiple physical properties of nanoparticles, such as their charge, shape, size, and flexibility [14] [15] [16] [17] .

Researchers demonstrated that nanoparticles smaller than 100 nm tend to drain to the LNs and that different nanomaterials may have different optimal sizes for LN delivery 18, 19 . Given the increasing interest in the mucosal immune response, delivery methods that effectively cross the mucosal barrier are also considered highly in vaccine design. Owing to the negatively charged porous mucin glycopolymer structure, mucosal delivery efficacy depends largely on the size and surface charge of nanoparticles 20, 21 . Thus, nanoparticles smaller than the cut-offs of mucosal and cationic nanoparticles (below about 200 nm) can achieve promising mucosal delivery 22 .

Following the delivery of antigens in the appropriate tissues and locations, the internalization, processing, and presentation of antigens by APCs is critical to evoke a strong immune response. Hence, researchers manipulate the physical characteristics of nanoparticles (e.g., their charge, shape, and size) to promote APC uptake of antigens and a consequent strong immune response 23, 24 . For example, 20-200nm nanoparticles are more easily internalized by a common type of APC, dendritic cells (DCs) 25 .

Targeted nanoparticle delivery to DCs can be achieved by modifying specific ligands for affinity-based targeting DC subsets, such as C-type lectin receptors 26 . Moreover, it was revealed that multivalent antigen structures can enhance antigen recognition and activation of B cells-another type of APCs 27 .

Most viruses and bacteria have unique repetitive structures that the immune system can detect. It is revolutionary to consider this repetitive antigen structure in vaccine design.

There is evidence to suggest that the multivalency effect elicits a stronger humoral and cellular immune response in self-assembled polypeptide nanoparticles 28 , multiple antigen conjugated nanoparticles 29 , and other multivalent assemblies 30, 31 . And most encouragingly, nanotechnology has an absolute advantage in manipulating antigen density and orientation, providing great platforms for investigating the underlying mechanisms of multivalency effect and its optimizing strategies. Puffer and J o u r n a l P r e -p r o o f colleagues 32 found that the multivalency of hapten induced higher levels of antibodies, correlated with increased Ca 2+ signaling in B cells. Moreover, multivalent hapten even confers immunogenicity to low-affinity epitopes 33 . With more in-depth research, the multivalency of antigens can be programmed to activate immune cells by several pathways, such as complement activation 34 , during which B cell receptors crosslink through tyrosine-based activation motifs (ITAMs) 29 . Although the mechanism behind this phenomenon is elusive, virus-like particles (VLPs) with the multivalency effect can enhance B cell activation and downstream immune responses. The studies of nanomaterial-multivalent antigens for combating infectious diseases have exhibited great promise. For example, liposomes with multivalent HIV trimers have been found to increase antibody response breadths against target antigen protein regions, suggesting that multivalency can influence the antibody reservoir 35 . Further studies suggest that antibody responses can be shaped by programming specific epitopes; the specificity of the vaccine can be improved by burying undesirable epitopes and exposing desirable epitopes, which reduces responses to the immunodominant, non-neutralizing regions of HIV trimers 36 . Protein-based nanomaterials display alteration was also applied in screening neutralizing region for binding neutralizing antibodies 37 . Although questions about how antigen orientation influences immune responses remain, nanomaterial platforms are advantageous experimental tools for deeper investigation.

The successful application of mRNA vaccines to combat the COVID-19 pandemic has demonstrated the limitless potential of nucleic acid-based vaccines. The efficacy of nucleic acid-based vaccines depends predominately on the delivery of DNA or RNA molecules, which upregulate the expression of target encoding antigens and evoke a specific, strong immune response in target immune cells. DNA vaccines were supposed to have great promise in infectious diseases prophylaxis and treatment because they are simple, stable, and inexpensive to mass produce 38, 39 . However, inefficient plasmid DNA (pDNA) delivery in vivo impaired the effectiveness and limited the further J o u r n a l P r e -p r o o f preclinical application. For example, traditional DNA vaccines tend to spread rapidly after injection, resulting in a diminished probability of pDNA interacting with APCs. In addition, the inherent risk of traditional viral delivery pushed nonviral vectors, which are relatively safe, into focus. Among the promising nonviral vectors are nanomaterials, which stand out due to their specific delivery advantages; the need to efficiently deliver novel mRNA-based vaccines further advanced the development of nanomedicine in vaccine design. As previously mentioned, nanoparticles can be programmed with specific LN and APC targeting abilities, which may apply to nucleic acid-based vaccines too 40,41 . Unlike protein/peptide antigen, nucleic acids are more susceptible to degradation by endonucleases. Additionally, the nonspecific immune response to foreign nucleic acids is a nonnegligible hindrance for clinical translation 42 . Therefore, when designing nucleic acid nano delivery systems, researchers must consider an encapsulating element to protect the nucleic acids from endonuclease enzymes 43-45 .

In addition to the double-stranded DNA located in the nucleus, there is single-stranded mRNA, which the ribosomes translate codon-by-codon for protein production in the cytoplasm. Thus, mRNA vaccines can upregulate the expression of antigens in the cytoplasm directly without having to cross the nuclear envelope 42, 46 .

Moreover, the undesirable immune response to foreign mRNA can be assuaged by incorporating modified nucleosides, such as pseudouridine and 5-methylcytidine, into the mRNA transcript 47, 48 . Considering these advantages, the mRNA vaccine was supposed to exhibit better antigen expression efficiency and faster clearance, which are conducive to clinical translation. And most encouragingly, this hypothesis was largely confirmed by the approval of the Pfizer/BioNTech and Moderna mRNA COVID-19 vaccines. It is worth mentioning that nanotechnology plays an important role in mRNA COVID-19 vaccines 4-6 . The two vaccines are cationic lipid nanoparticles, consisting of a cholesterol, an ionizable cationic lipid, a PEGylated lipid, and a phospholipid distearoylphosphatidylcholine (DSPC) helper lipid 6 . Cationic lipids, the most commonly employed nanomaterials, are often prepared by prepared by complexing cationic polymers/lipids with negatively charged nucleic acids; this structure, helps protect mRNA from degradation and immunorecognition.

Beyond treating infectious diseases, nucleic acid-based vaccines have long been promising candidates for cancer treatment. However, due to immunosuppression in the tumor microenvironment, vaccine design should involve numerous pathways to activate a sufficient antitumor immune response. It was revealed that nucleic acid molecules also participate in tumor immunomodulation 49, 50 . For example, some nucleic acids can function as immune adjuvants 51 , and small interfering RNA (siRNA) can inhibit PD-L1 expression for tumor suppression 52 . Besides, nucleic acids can also be used as vaccine vectors. Liu and co-workers 53 developed a DNA nanodevice with a tubular structure that loads molecular adjuvants and antigen peptides, inducing a strong antitumor immune response. Instead of introducing an antigen via vaccination, it is possible to trigger the release of tumor antigens in vivo. One such mechanism is to trigger immunogenic cell death (ICD), which results in the release of tumor-associated antigens (TAAs), the danger-associated molecular patterns (DAMPs), and proinflammatory factors to evoke J o u r n a l P r e -p r o o f adaptive antitumor immunity 55 . The ICD process can be triggered by a series of antitumor therapies, including certain chemotherapies, phototherapies, radiotherapies, sonodynamic therapies, and local hyperthermia treatments 55-58 . The aforementioned therapies are also supposed to reverse "cold tumors" to "hot tumors" behind which the mechanisms could involve ICD induction, promoting immune cells infiltration and macrophage phenotype transition from M2 to M1. Moreover, by harnessing the superior delivery capabilities of nanomedicines, the effect of ICD inducers can be amplified synergistically with other immunotherapeutic agents, such as immune checkpoint inhibitors, indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitors, and stimulator of interferon genes (STING), for combating immunosuppression 56 .

Therefore, besides the classical co-delivery of antigens and immune adjuvants, the co-delivery of ICD inducers and immunotherapeutic agents is a promising design strategy for nanovaccines in solid tumor treatment. 

Currently, most vaccines employed the parenteral route, which is invasive and has limited compliance, for delivery. The development of nanomedicine provided various options for vaccine routes including postoperative, intradermal/subcutaneous, intranasal, inhalation, and oral administration for both cancer therapy and infectious diseases. hydrogel. This nanomedicine can be prepared feasible to boost personalized immunotherapy 76 . Besides, specific autologous cancer cells can be combined with non-specific immune activation such as bacterial-derived membranes 77 . Postoperative nanovaccines are rising for the treatment of cancer.

Intradermal/subcutaneous administration is a common route of immunization for DNA vaccines. Both epidermis and dermis layers of the skin contain resident APCs that are targeted for immunization. As the skin is painless, intradermal/subcutaneous administration has been widely applied for prophylactic vaccination.

In recent years, this administration strategy was also explored for anticancer therapy. It has been reported that subcutaneous immunizations using VLPs conjugated with human EGFR 2 epitopes induced elevated HER2-specific antibody titers against the HER2 positive malignancies 78 79 . Microneedles can also be dissolvable for vaccine delivery. Plasmodium falciparum surface protein P47 and CpG were loaded into microneedles and showed potent activation of TLR9 signaling for malaria vaccine 80 . Recently, a vaccine core and PLGA shell microneedle patch was developed for the long-last and programmed burst release of the vaccine 81 . This strategy may be used for both prophylactic and therapeutic purposes without repeated vaccination.

Intranasal administration is an important route for respiratory infectious diseases 82 .

Nasal immunization via nanovaccines is promising for preventing diseases through mainly affecting infected respiratory tracts such as TB and for the treatment of cancers.

Chitosan nanoparticles are water-soluble platforms that can be explored for intranasal delivery of antigen for TB vaccination. Thiolated OVA conjugated to N-trimethylaminoethylmethacrylate chitosan showed elevated cellular uptake, deep cervical lymph nodes transport efficiency, and immune responses after intranasal administration 83 . Recently, inulin acetate, a natural polymer, was developed as an intranasal nanovaccine delivery system for its inherent adjuvant (TLR4 activation) ability 84 . This nanocarrier has the potential for mucosal vaccination via intranasal administration. For synthetic nanoparticles, a "self-healing microencapsulation" technology has been developed by Bailey and colleagues for the stable loading of antigens in PLGA particles. They used calcium phosphate adjuvant gel as a trapping agent for antigen encapsulation, leading to sustained release of OVA antigen and proliferation of CD8 + T cell via intranasal delivery 85 and could be used as a single-dose vaccination platform 86 . More recently, for the controllable particle size, PLGA nanoparticle was used for intranasal delivery of all trans-Retinoic acid and J o u r n a l P r e -p r o o f prolonged the drug release for targeted treatment of TB in the lung 87 . For intranasal cancer nanovaccine delivery, a recent study developed a self-assembled nanovaccine loaded with multiple OVA peptide antigens. This nanovaccine is safe through nasal administration and prolonged residence time and increased the antigen uptake efficiency, which led to enhanced antigen-specific immune response 88 .

Inhalation administration is also a promising vaccination route for pulmonary infectious diseases such as TB. Synthetic nanoparticles are useful tools for inhalation formulations.

Polymeric nanocapsules with oily core and polymer shell have been developed for pulmonary delivery of imiquimod, a TLR-7 agonist, and a fusion antigen protein 89 .

Vaccination of this polymeric nanocapsule induced strong immune responses. The development of biomimetic nanotechnology offered strategies for developing nanovaccines by imitating respiratory droplets. In a recent study, a bionic-virus nanovaccine that mimics the structure of SARS-CoV-2 was developed by using liposomes as capsid structure and the receptor binding domains as "spike" 90 . This inhalable nanovaccine induced strong mucosal immunity and this nanovaccine strategy can also be used for other respiratory infectious diseases.

In addition, inhalation administration can also be applied for cancer nanovaccines such as lung metastasis. It has been reported that inhalation of the VLPs can facilitate the neutrophils infiltration in tumor, and increase cytokines and chemokines production and macrophage inflammatory protein 1α in tumor-bearing mice 91 . This nanovaccine treatment significantly reduced metastatic tumor burden for various tumor types.

Oral administration is a noninvasive route with excellent compliance 92 . Oral vaccines are optimal formulations for administration, immunization, safety, and storage. During the process, antigens may degrade in the gastrointestinal tract resulting in a small number of antigens exposed to the mucosal tissue and limited intestinal uptake.

Several nanocarriers have been developed as TB vaccines that can be orally administrated. Liposome-encapsulated DNA vaccines can induce effective immune responses against TB 93 . VLP can also be used to carry HIV envelope cDNA with enhanced stability in the gastric environment. This strategy leads to high antigen concentration across intestinal lumen after oral administration 94 . In another example, polyethyleneimine-coated SPIONs loaded with malarial DNA showed high DNA binding and transfection efficiency even in the acidic environment 95 .

Oral administration strategy may also be used for cancer vaccines. It has been reported that nanoemulsions have high encapsulation capacity for co-delivery of melanoma antigen, heal shock protein, and staphylococcal toxin A for oral administration. This oral delivery strategy showed comparable immune responses to subcutaneous immunization 96 .

Recently, various nanomaterials for developing vaccines have been explored, including lipid-based nanoparticles, protein nanoparticles, polymeric nanoparticles, inorganic nanocarriers, and biomimetic nanoparticles. Different types of nanocarriers have distinct physicochemical profiles and behaviors in vivo, that influence vaccination accordingly. Here, we will briefly discuss the different types of nanomaterials for nanovaccines and their features. VLPs are self-assembled complexes composed of viral proteins, which are supposed to be safe and highly efficient delivery platforms for antigen delivery without genetic components and replication ability 98 In contrast to exogenous viral proteins, several endogenous self-assembled proteins can also be explored as nanovaccine platforms, those protein nanoparticles are also called caged protein nanoparticles for their highly organized structures 100 .

Ferritin is a typically caged protein nanoparticle that has widely been used for antigen delivery, drug delivery, imaging, and diagnostic applications 101 . Classical ferritin is comprised of 24 subunits, forming a central hollow cavity structure (12 nm ×8 nm) that stores iron. Antigen proteins can be genetically modified as subunits to form ferritins or can be incorporated onto ferritins to be efficiently phagocytosed by APCs.

It has been reported that ferritin can passively target lymph nodes with a high retention time and induce strong immune responses 79 .

Polymeric nanoparticles are colloidal systems with a wide size range (10-1000 nm) 102 .

Polymeric nanoparticles have high immunogenicity and stability for efficient encapsulation and display of antigen, which can be loaded within the core and Compared to natural polymers, synthetic polymeric nanoparticles generally have higher reproducibility and are more controllable for molecular weight compositions and degradation rates 107 . For example, PLGA nanoparticle is highly biodegradable and its properties can be fine-tuned. PLGA can be coupled with PEG and then self-assembled into a polymeric micelle for hydrophobic peptide antigens delivery with better T cell responses 108 . 

Commonly used inorganic materials in nanomedicine include metals and oxides, non-metal oxides, and inorganic salts. Inorganic materials have low biodegradability but are stable in structure. Many inorganic nanoformulations have inherent adjuvant activity 115 . However, for nanovaccine application, 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 116 , iron 117 , and silica nanoparticles 118 .

Gold nanoparticles (GNPs) are spherical and positively charged. GNPs have good biocompatibility, low immunogenicity, and high antigen loading capacity. GNPs have size-dependent toxicity 119 ; however, GNPs also have a high affinity to sulfhydryl groups 120 , which can be utilized for surface engineering to couple with cysteine residues to produce polypeptide antigens with improved safety and pharmacokinetic profiles. In addition, GNPs have intrinsic immunostimulatory effects to induce inflammatory cytokines production 121 . Therefore, GNPs can be used not only as a transport carrier for antigens but also for stimulating immune responses 122 . Silica nanoparticles are also potent candidates for nanovaccine carrier materials 123 . Recent studies have shown that controlling the morphology 124 

Nanovaccines have been developed for various diseases. Here, we provide examples of how nanovaccines are being employed against cancers and infectious diseases, including HIV/AIDS, malaria and tuberculosis (TB). The most cutting-edge strategies of developing nanovaccines and their design aspects are included and discussed.

HIV/AIDS, malaria, and TB are impacting global health and causing millions of deaths worldwide, highlighting the need for prevention and treatment strategies 145 Self-assembled protein nanoparticles are useful platforms for antigen delivery.

RTS,S, the first and currently the only malaria vaccine in the market 147 , uses VLP to deliver antigen. VLP has been tested to display HIV envelope proteins such as V1V2

loop for vaccination and generated specific IgG in mice ( Fig. 2A ) 112148 . Ferritin nanoparticles have also been employed to display HIV envelope trimers on particle surfaces to increase immunogenicity 148, 149 . Other larger proteins such as dihydrolipoyl acetyltransferase (E2) 150 

Cancer remains a leading cause of human death. Developing an anticancer vaccine is a vital step in reaching personalized medicine to treat this prolific disease. Despite tremendous efforts, full elucidation of the cancer pathogenesis is challenging 162 .

Generally, cancerous cells result from the mutation of healthy cells involving multiple environmental and genetic factors. Therefore, unlike infectious diseases, cancer is J o u r n a l P r e -p r o o f highly heterologous in cases and the prevention of cancer is extremely difficult 163 in combined immune checkpoint blockade therapy (Fig. 2B) 167 . Traditional LNPs are also highly effective platforms for tumor vaccine delivery. In a recent study, mRNA encoding tumor antigens were incorporated into cationic C1 LNP, which has adjuvant properties, for efficient delivery and presentation to dendritic cells ( Fig. 4B and C) 168 .

The C1 mRNA nanovaccine showed significant prevention and therapeutic effects on tumors.

Membrane-coating technology has been extensively explored for nanovaccine development. RBC-NPs with mannose modification and MPLA as the adjuvant were used to deliver B16F10 melanoma-associated antigen glycoprotein 100 to dendritic cells and inhibited significantly tumor growth 169 As tumor cells are highly heterologous, a single tumor antigen vaccine may have insufficient immune responses to eliminate tumors 176 . Therefore, the whole tumor cell lysate may be loaded into nanoparticles such as chitosan 177 and nanovesicles ( Fig. 5A and B) 178 for enhanced antigens presentation. Besides, native tumor antigens may have low immunogenicity and induce limited immune responses to combat the tumor.

In recent years, artificial antigen-presenting cells (aAPC) technology 179 has emerged to stimulate tumor-specific T cells by engineering nanomaterials equipped with peptide epitope and costimulatory molecules, replicating the immune-activation functions of APCs. Nanoscale aAPCs may have core material such as iron oxide 180 

In the past decades, the rapid development of nanotechnology provided avenues for Focus on the typical clinical approved nanovaccines and vaccine nanotechnology under clinical development, we would get inspirations to find out the direction of next-generation vaccine nanotechnology. As shown in Table 1 [190] [191] [192] [193] [194] 

The authors have no conflicts of interest to declare. 

Biomaterials as tools to decode immunity

Materials for Immunotherapy

Nano-bio interfaces effect of two-dimensional nanomaterials and their applications in cancer immunotherapy

Insights from nanotechnology in COVID-19 treatment

A materials-science perspective on tackling COVID-19

Role of nanotechnology behind the success of mRNA vaccines for COVID-19

Uncoupling resistance to cancer immunotherapy

Assessment of adverse events and their ability to discriminate response to anti-PD-1/PD-L1 antibody immunotherapy

Oncology meets immunology: the cancer-immunity cycle

Nanobiomaterial-based vaccination immunotherapy of cancer

Eliciting B cell immunity against infectious diseases using nanovaccines

Role of sustained antigen release from nanoparticle vaccines in shaping the T cell memory phenotype

Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand Tfh cells and promote germinal center induction

Programmable multistage drug delivery to lymph nodes

Exploiting lymphatic transport and complement activation in nanoparticle vaccines

The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node

Flexible macromolecule versus rigid particle retention in the injected skin and accumulation in draining lymph nodes are differentially influenced by hydrodynamic size

Drug Delivery for Cancer Immunotherapy and Vaccines

Structure-based programming of lymph-node targeting in molecular vaccines

Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues

Nanoparticle diffusion in respiratory mucus from humans without lung disease

Chitosan-based particulate systems for the delivery of mucosal vaccines against infectious diseases

Role of target geometry in phagocytosis. Proc Arsenene-mediated multiple independently targeted reactive oxygen species burst for cancer therapy

Pnictogens in medicinal chemistry: evolution from erstwhile drugs to emerging layered photonic nanomedicine

In situ sprayed NIR-responsive, analgesic black phosphorus-based gel for diabetic ulcer treatment

Navigating 2D Monoelemental Materials (Xenes) for Cancer Nanomedicine

ROS-mediated selective killing effect of black phosphorus: mechanistic understanding and its guidance for safe biomedical applications

Synthesis of ultrathin biotite nanosheets as an intelligent theranostic platform for combination cancer therapy

Bioinorganic hybrid bacteriophage for modulation of intestinal microbiota to remodel tumor-immune microenvironment against colorectal cancer

Postoperative cancer treatments: In-situ delivery system 75

The systematic evaluation of size-dependent toxicity and multi-time biodistribution of gold nanoparticles

Engineering autologous tumor cell vaccine to locally mobilize antitumor immunity in tumor surgical bed

Bacterial cytoplasmic membranes synergistically enhance the antitumor activity of autologous cancer vaccines

Plant viral nanoparticles-based HER2 vaccine: Immune response influenced by differential transport, localization and cellular interactions of particulate carriers

Active microneedle administration of plant virus nanoparticles for cancer in situ vaccination improves immunotherapeutic efficacy

Design of Dissolvable microneedles for delivery of a Pfs47-based malaria transmission-blocking vaccine

Transdermal microneedles for the programmable burst release of multiple vaccine payloads

Nasal nanovaccines

Preparation and evaluation of antigen/N-trimethylaminoethylmethacrylate chitosan conjugates for nasal immunization

Toll-like receptor-4 (TLR4) agonist-based intranasal nanovaccine delivery system for inducing mucosal immunity

Self-encapsulating poly(lactic-co-glycolic acid) (PLGA) microspheres for intranasal vaccine delivery

Toward a single-dose vaccination strategy with self-encapsulating plga microspheres

Inhalable poly(lactic-co-glycolic acid) (PLGA) microparticles encapsulating all-trans-Retinoic acid (ATRA) as a host-directed, adjunctive treatment for Mycobacterium tuberculosis infection

A novel self-assembled epitope peptide nanoemulsion vaccine targeting nasal mucosal epithelial cell for reinvigorating CD8 + T cell immune activity and inhibiting tumor progression

Design of polymeric nanocapsules for intranasal vaccination against mycobacterium tuberculosis: influence of the polymeric shell and antigen positioning

Liposomal oral DNA vaccine (mycobacterium DNA) elicits immune response

DNA vaccine-encapsulated virus-like particles derived from an orally transmissible virus stimulate mucosal and systemic immune responses by oral administration

Superparamagnetic nanoparticles for effective delivery of malaria DNA vaccine

The antitumor immune responses induced by nanoemulsion-encapsulated MAGE1-HSP70/SEA complex protein vaccine following peroral administration route

Peptide-based supramolecular vaccine systems

Engineering virus-like particles as vaccine platforms

Major findings and recent advances in virus-like particle (VLP)-based vaccines

Protein-based nanoparticles in cancer vaccine development

Taking advantage of cellular uptake of ferritin nanocages for targeted drug delivery

Nanovaccine: an emerging strategy

Chitosan-based colloidal polyelectrolyte complexes for drug delivery: a review

Advancements in protein nanoparticle vaccine platforms to combat infectious disease

Biodegradable polymeric nanoparticles for therapeutic cancer treatments

Antigen delivery via hydrophilic PEG-b-PAGE-b-PLGA nanoparticles boosts vaccination induced T cell immunity

Lipid nanoparticles for nucleic acid delivery: Current perspectives

Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns

Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults

Safety and efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Lipid nanoparticles for mRNA delivery

Tools for translation: non-viral materials for therapeutic mRNA delivery

Designing inorganic nanomaterials for vaccines and immunotherapies

Gold nanoparticles for preparation of antibodies and vaccines against infectious diseases

Iron Oxide Nanoparticles-Based Vaccine Delivery for Cancer Treatment

The pore size of mesoporous silica nanoparticles regulates their antigen delivery efficiency

Cell-Membrane Immunotherapy Based on Natural Killer Cell Membrane Coated Nanoparticles for the Effective Inhibition of Primary and Abscopal Tumor Growth

Gold nanoparticles induce transcriptional activity of NF-kappaB in a B-lymphocyte cell line

Immunostimulant and biocompatible gold and silver nanoparticles synthesized using the Ulva intestinalis L. aqueous extract

Gold nanoparticle-based platforms for vaccine development

Mesoporous silica nanoparticles as antigen carriers and adjuvants for vaccine delivery

Hollow mesoporous silica nanoparticles with extra-large mesopores for enhanced cancer vaccine

Serum albumin nanoparticles vaccine provides protection against a lethal Pseudomonas aeruginosa challenge

Silica Nanoparticle as a Lymph Node Targeting Platform for Vaccine Delivery

A versatile and robust platform for the scalable manufacture of biomimetic nanovaccines

Biologically modified nanoparticles as theranostic bionanomaterials

Biomimetic strategies for targeted nanoparticle delivery

Molecularly imprinted polymer nanoparticles: an emerging versatile platform for cancer therapy

Biomembrane-based nanostructures for cancer targeting and therapy: From synthetic liposomes to natural biomembranes and membrane-vesicles

Cancer cell membrane-coated nanoparticles for personalized therapy in patient-derived xenograft models

Immune cell membrane-coated biomimetic nanoparticles for targeted cancer therapy

Nanomaterial biointerfacing via mitochondrial membrane coating for targeted detoxification and molecular detection

A Trojan horse biomimetic delivery strategy using mesenchymal stem cells for PDT/PTT therapy against lung melanoma metastasis

Homologous-targeting biomimetic nanoparticles for photothermal therapy and Nrf2-siRNA amplified photodynamic therapy against oral tongue squamous cell carcinoma

Virosome-based nanovaccines; a promising bioinspiration and biomimetic approach for preventing viral diseases: A review

Liposomes and virosomes as delivery systems for antigens, nucleic acids and drugs

Designer outer membrane vesicles as immunomodulatory systems-reprogramming bacteria for vaccine delivery

Bacterial outer membrane vesicles engineered with lipidated antigens as a platform for Staphylococcus aureus vaccine

Nanotechnology approaches for global infectious diseases

Advances in nanomaterial vaccine strategies to address infectious diseases impacting global health

S malaria vaccine pilots in three African countries

Design and characterization of a self-assembling protein nanoparticle displaying HIV-1 Env V1V2 loop in a native-like trimeric conformation as vaccine antigen

Presenting native-like HIV-1 envelope trimers on ferritin nanoparticles improves their immunogenicity

Viral-mimicking protein nanoparticle vaccine for eliciting anti-tumor responses

Rational HIV immunogen design to target specific germline B cell receptors

Enhancing and shaping the immunogenicity of native-like HIV-1 envelope trimers with a two-component protein nanoparticle

envelope-specific plasma cells and humoral immunity in nonhuman primates

A malaria vaccine adjuvant based on recombinant antigen binding to liposomes

Vaccination with glycan-modified HIV NFL envelope trimer-liposomes elicits broadly neutralizing antibodies to multiple sites of vulnerability

Loading dendritic cells with gold nanoparticles (GNPs) bearing HIV-peptides and mannosides enhance HIV-specific T cell responses

Nanoparticle-based adjuvant for enhanced protective efficacy of DNA vaccine Ag85A-ESAT-6-IL-21 against Mycobacterium tuberculosis infection

Co-adsorption of synthetic Mincle agonists and antigen to silica nanoparticles for enhanced vaccine activity: A formulation approach to co-delivery

Immunization with HIV-1 gp41 subunit virosomes induces mucosal antibodies protecting nonhuman primates against vaginal SHIV challenges

An Engineered biomimetic mper peptide vaccine induces weakly hiv neutralizing antibodies in mice

Mimicking nanoparticles can neutralize hiv infectivity

Advances in the development of personalized neoantigen-based therapeutic cancer vaccines

Resolving genetic J o u r n a l P r e -p r o o f heterogeneity in cancer

Radiation therapy combined with cowpea mosaic virus nanoparticle in situ vaccination initiates immune-mediated tumor regression

Combination of plant virus nanoparticle-based in situ vaccination with chemotherapy potentiates antitumor response

Potentiating cancer immunotherapy using papaya mosaic virus-derived nanoparticles

Designer vaccine nanodiscs for personalized cancer immunotherapy

Enhanced immune memory through a constant photothermal-metabolism regulation for cancer prevention and treatment

Erythrocyte membrane-enveloped polymeric nanoparticles as nanovaccine for induction of antitumor immunity against melanoma

Nanoparticulate delivery of cancer cell membrane elicits multiantigenic antitumor immunity

Immunogenic cell death in cancer and infectious disease

Immunogenic cell death amplified by co-localized adjuvant delivery for cancer immunotherapy

Myeloid-derived suppressor cell membrane-coated magnetic nanoparticles for cancer theranostics by inducing macrophage polarization and synergizing immunogenic cell death

Supramolecular assembled programmable nanomedicine as in situ cancer vaccine for cancer immunotherapy

Tumour heterogeneity and resistance to cancer therapies

Enhanced antitumor immunity by targeting dendritic cells with tumor cell lysate-loaded chitosan nanoparticles vaccine

PEGylated tumor cell membrane vesicles as a new vaccine platform for cancer immunotherapy

Towards efficient cancer immunotherapy: advances in developing artificial antigen-presenting cells

Nanoscale artificial antigen presenting cells for T cell immunotherapy

Biomimetic magnetosomes as versatile artificial antigen-presenting cells to potentiate T-cell-based anticancer therapy

Biodegradable nanoellipsoidal artificial antigen presenting cells for antigen specific T-cell activation

Separating T cell targeting components onto magnetically clustered nanoparticles boosts

Activation and expansion of human T cells using artificial antigen-presenting cell scaffolds

Rapid Expansion of highly functional antigen-specific T cells from patients with melanoma by nanoscale artificial antigen-presenting cells

Bacterial outer membrane vesicles suppress tumor by interferon-gamma-mediated antitumor response

Biomineralized bacterial outer membrane vesicles potentiate safe and efficient tumor microenvironment reprogramming for anticancer therapy

Safety evaluation of lipid nanoparticle-formulated modified mrna in the sprague-dawley rat and cynomolgus monkey

Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics

Mosquirix™): an overview

Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis

Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy

A phase I study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding J o u r n a l P r e -p r o o f human OX40L, IL-23, and IL-36γ, for intratumoral (iTu) injection alone and in combination with durvalumab

A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors

The authors acknowledged the support from the US METAvivor Early Career J o u r n a l P r e -p r o o f