ArticleLiterature Review

Nanodimensions/adjuvants dans les vaccins COVID-19
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Une issue favorable à la crise du COVID-19 pourrait être obtenue grâce à une vaccination massive. Les vaccins proposés contiennent plusieurs principes actifs vaccinaux différents (VAP), tels que le virus inactivé, l'antigène, l'ARNm et l'ADN, qui sont associés à des adjuvants standard ou à des nanomatériaux (NM) tels que les liposomes dans les vaccins de Moderna et BioNTech/Pfizer. Les adjuvants du vaccin COVID-19 peuvent être choisis parmi des liposomes ou d'autres types de NM composés par exemple d'oxyde de graphène, de nanotubes de carbone, de micelles, d'exosomes, de vésicules membranaires, de polymères ou de NM métalliques, en s'inspirant des nano-vaccins anticancéreux, dont les adjuvants peuvent partager certaines de leurs propriétés avec celles des vaccins viraux. Les mécanismes d'action des nano-adjuvants reposent sur la facilitation par les NM du ciblage de certaines régions d'intérêt immunitaire telles que le mucus, les ganglions lymphatiques et les zones d'infection ou d'irrigation sanguine, la modulation éventuelle du type d'attachement de la VAP à NM, en particulier le positionnement du VAP sur la surface externe du NM pour favoriser la présentation du VAP aux cellules présentatrices d'antigène (APC) ou l'encapsulation du VAP dans le NM pour empêcher la dégradation du VAP, et la possibilité d'ajuster la nature de la réponse immunitaire en ajustant les propriétés physico-chimiques de NM tels que leur taille, leur charge de surface ou leur composition. L'utilisation de NM comme adjuvants ou la présence de nano-dimensions dans les vaccins COVID-19 ont non seulement le potentiel d'améliorer le rapport bénéfice/risque du vaccin, mais également de réduire la dose de vaccin nécessaire pour atteindre une efficacité totale. Cela pourrait donc faciliter la propagation globale des vaccins COVID-19 au sein d'une partie suffisamment importante de la population mondiale pour sortir de la crise actuelle.

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Due to the high prevalence and long incubation periods often without symptoms, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected millions of individuals globally, causing the coronavirus disease 2019 (COVID-19) pandemic. Even with the recent approval of the anti-viral drug, remdesivir, and Emergency Use Authorization of monoclonal antibodies against S protein, bamlanivimab and casirimab/imdevimab, efficient and safe COVID-19 vaccines are still desperately demanded not only to prevent its spread but also to restore social and economic activities via generating mass immunization. Recent Emergency Use Authorization of Pfizer and BioNTech’s mRNA vaccine may provide a pathway forward, but monitoring of long-term immunity is still required, and diverse candidates are still under development. As the knowledge of SARS-CoV-2 pathogenesis and interactions with the immune system continues to evolve, a variety of drug candidates are under investigation and in clinical trials. Potential vaccines and therapeutics against COVID-19 include repurposed drugs, monoclonal antibodies, antiviral and antigenic proteins, peptides, and genetically engineered viruses. This paper reviews virology and immunology of SARS-CoV-2, alternative therapies for COVID-19 to vaccination, principles and design considerations in COVID-19 vaccine development, and the promises and roles of vaccine carriers in addressing the unique immunopathological challenges presented by the disease.
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Metastasis is one of the main causes of failure in the treatment of triple-negative breast cancer (TNBC). Immunotherapy brings hope and opportunity to solve this challenge, while its clinical applications are greatly inhibited by the tumor immunosuppressive environment. Here, an intelligent biomimetic nanoplatform was designed based on dendritic large-pore mesoporous silica nanoparticles (DLMSNs) for suppressing metastatic TNBC by combining photothermal ablation and immune remodeling. Taking advantage of the ordered large-pore structure and easily chemically modified property of DLMSNs, the copper sulfide (CuS) nanoparticles with high photothermal conversion efficiency were in situ deposited inside the large pores of DLMSNs, and the immune adjuvant resiquimod (R848) was loaded controllably. A homogenous cancer cell membrane was coated on the surfaces of these DLMSNs, followed by conjugation with the anti-PD-1 peptide AUNP-12 through a polyethylene glycol linker with an acid-labile benzoic-imine bond. The thus-obtained AM@DLMSN@CuS/R848 was applied to holistically treat metastatic TNBC in vitro and in vivo. The data showed that AM@DLMSN@CuS/R848 had a high TNBC-targeting ability and induced efficient photothermal ablation on primary TNBC tumors under 980 nm laser irradiation. Tumor antigens thus generated and increasingly released R848 by response to the photothermal effect, combined with AUNP-12 detached from AM@DLMSN@CuS/R848 in the weakly acidic tumor microenvironment, synergistically exerted tumor vaccination, and T lymphocyte activation functions on immune remodeling to prevent TNBC recurrence and metastasis. Taken together, this study provides an intelligent biomimetic nanoplatform to enhance therapeutic outcomes in metastatic TNBC.
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COVID-19, coronavirus disease 2019, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic. At the time of writing this (October 14, 2020), more than 38.4 million people have become affected, and 1.0 million people have died across the world. The death rate is undoubtedly correlated with the cytokine storm and other pathological pulmonary characteristics, as a result of which the lungs cannot provide sufficient oxygen to the body's vital organs. While diversified drugs have been tested as a first line therapy, the complexity of fatal cases has not been reduced so far, and the world is looking for a treatment to combat the virus. However, to date, and despite such promise, we have received very limited information about the potential of nanomedicine to fight against COVID-19 or as an adjunct therapy in the treatment regimen. Over the past two decades, various therapeutic strategies, including direct-acting antiviral drugs, immunomodulators, a few non-specific drugs (simple to complex), have been explored to treat Acute Respiratory Distress Syndrome (ARDS), Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), influenza, and sometimes the common flu, thus, correlating and developing specific drugs centric to COVID-19 is possible. This review article focuses on the pulmonary pathology caused by SARS-CoV-2 and other viral pathogens, highlighting possible nanomedicine therapeutic strategies that should be further tested immediately.
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Immunotherapy is the newest approach to combat cancer. It can be achieved using several strategies, among which is the dendritic cell (DC) vaccine therapy. Several clinical trials are ongoing using DC vaccine therapy either as a sole agent or in combination with other interventions to tackle different types of cancer. Immunotherapy can offer a potential treatment to coronavirus disease 2019 (COVID-19) the worst pandemic facing this generation, a disease with deleterious effects on the health and economic systems worldwide. We hypothesize that DC vaccine therapy may provide a potential treatment strategy to help combat COVID-19. Cancer patients are at the top of the vulnerable population owing to their immune-compromised status. In this review, we discuss DC vaccine therapy in the light of the body’s immunity, cancer, and newly emerging infections such as COVID-19 in hopes of better-customized treatment options for patients with multiple comorbidities.
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Humanity is experiencing a catastrophic pandemic. SARS-CoV-2 has spread globally to cause significant morbidity and mortality, and there still remain unknowns about the biology and pathology of the virus. Even with testing, tracing, and social distancing, many countries are struggling to contain SARS-CoV-2. COVID-19 will only be suppressible when herd immunity develops, either because of an effective vaccine or if the population has been infected and is resistant to reinfection. There is virtually no chance of a return to pre-COVID-19 societal behavior until there is an effective vaccine. Concerted efforts by physicians, academic laboratories, and companies around the world have improved detection and treatment and made promising early steps, developing many vaccine candidates at a pace that has been unmatched for prior diseases. As of August 11, 2020, 28 of these companies have advanced into clinical trials with Moderna, CanSino, the University of Oxford, BioNTech, Sinovac, Sinopharm, Anhui Zhifei Longcom, Inovio, Novavax, Vaxine, Zydus Cadila, Institute of Medical Biology, and the Gamaleya Research Institute having moved beyond their initial safety and immunogenicity studies. This review analyzes these frontrunners in the vaccine development space and delves into their posted results while highlighting the role of the nanotechnologies applied by all the vaccine developers.
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A painless skin delivery of vaccine for disease prevention is of great advantage in improving compliance in patients. To test this idea as a proof of concept, we utilized a pDNA vaccine construct, pDNAg333-2GnRH that has a dual function of controlling rabies and inducing immunocontraception in animals. The pDNA was administered to mice in a nanoparticulate form delivered through the skin using the P.L.E.A.S.E.® (Precise Laser Epidermal System) microporation laser device. Laser application was well tolerated, and mild skin reaction was healed completely in 8 days. We demonstrated that adjuvanted nanoparticulate pDNA vaccine significantly upregulated the expression of co-stimulatory molecules in dendritic cells. After topical administration of the adjuvanted nano-vaccine in mice, the high avidity serum for GnRH antibodies were induced and maintained up to 9 weeks. The induced immune response was of a mixed Th1/Th2 profile as measured by IgG subclasses (IgG2a and IgG1) and cytokine levels (IFN-γ and IL-4). Using flow cytometry, we revealed an increase of CD8+ T-cells and CD45R B cells upon the administration of the adjuvanted vaccine. Our previous study used the same pDNA nanoparticulate vaccine through an IM route, and a comparable immune response was induced using P.L.E.A.S.E. However, the vaccine dose in the current study was four-fold less than what was applied through the IM route. We concluded that laser-assisted skin vaccination has a potential of becoming a safe and reliable vaccination tool for rabies vaccination in animals or even in humans for pre- or post-exposure prophylaxis.
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Therapeutic cancer vaccines require robust cellular immunity for the efficient killing of tumor cells, and recent advances in neoantigen discovery may provide safe and promising targets for cancer vaccines. However, elicitation of T cells with strong antitumor efficacy requires intricate multi-step processes that have been difficult to attain with traditional vaccination approaches. Here, a multi-functional nano-vaccine platform has been developed for direct delivery of neoantigens and adjuvants to lymph nodes (LNs) and highly efficient induction of neoantigen-specific T cell responses. PEGylated reduced graphene oxide nanosheet (RGO-PEG, 20-30 nm in diameter) is a highly modular and biodegradable platform for facile preparation of neoantigen vaccines within 2 h. RGO-PEG exhibits rapid, efficient (15-20% ID/g) and sustained (up to 72 h) accumulation in LNs, achieving > 100-fold improvement in LN-targeted delivery, compared with soluble vaccines. Moreover, RGO-PEG induces intracellular reactive oxygen species (ROS) in dendritic cells (DCs), guiding antigen processing and presentation to T cells. Importantly, a single injection of RGO-PEG vaccine elicits potent neoantigen-specific T cell responses lasting up to 30 days and eradicates established MC-38 colon carcinoma. Further combination with anti-PD-1 therapy achieved great therapeutic improvements against B16F10 melanoma. RGO-PEG may serve a powerful delivery platform for personalized cancer vaccination.
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Since its eruption in China, novel coronavirus disease (Covid‐19) has been reported in most of the countries and territories (>200) of the world with ~ 18 million confirmed cases (as of August 3, 2020). In most of the countries, Covid‐19 upsurge is uncontrolled with a significant mortality rate. Currently no treatment effective for Covid‐19 is available in the form of vaccines or antiviral drugs and patients are currently treated symptomatically. Although majority of the patients develop mild symptoms and recover without mechanical ventilation for respiratory management, severe respiratory illness develops in a significant portion of affected patients and may result in death. While the scientific community is working to develop vaccines and drugs against Covid‐19 pandemic, novel alternative therapies may reduce mortality rate. Recent use of stem cells for critically ill Covid‐19 patients in a small group of patients in China and subsequent Emergency Use Authorization (EUA) of stem cells by Food and Drug Administration (FDA) to GIOSTAR (Global Institute of Stem Cell Therapy and Research) and Athersys has created excitement among medical community. As a result, several clinical trials have been registered using stem cells for Covid‐19 treatment that aim to use different cell sources, dosage and importantly diverse targeted patient groups. In this brief review the possibilities of stem cell use in Covid‐19 patients and relevant challenges in their use have been discussed. This article is protected by copyright. All rights reserved.
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There is a need for effective vaccine delivery systems and vaccine adjuvants without extraneous excipients that can compromise or minimize their efficacy. Vaccine adjuvants cytosine–phosphate–guanosine oligodeoxynucleotides (CpG ODNs) can effectively activate immune responses to secrete cytokines. However, CpG ODNs are not stable in serum due to enzymatic cleavage and are difficult to transport through cell membranes. Herein, DNA microcapsules made of CpG ODNs arranged into 3D nanostructures are developed to improve the serum stability and immunostimulatory effect of CpG. The DNA microcapsules allow encapsulation and co‐delivery of cargoes, including glycogen. The DNA capsules, with >4 million copies of CpG motifs per capsule, are internalized in cells and accumulate in endosomes, where the Toll‐like receptor 9 is engaged by CpG. The capsules induce up to 10‐fold and 20‐fold increases in tumor necrosis factor (TNF)‐α and interleukin (IL)‐6 secretion, respectively, in RAW264.7 cells compared with CpG ODNs. Furthermore, the microcapsules stimulate TNF‐α and IL‐6 secretion in a concentration‐ and time‐dependent manner. The immunostimulatory activity of the capsules correlates to their intracellular trafficking, endosomal confinement, and degradation, assessed by confocal and super‐resolution microscopy. These DNA capsules can serve as both adjuvants to stimulate an immune reaction and vehicles to encapsulate vaccine peptides/genes to achieve synergistic immune effects. DNA capsules that combine carrier and cargo are synthesized using Y‐shaped DNA (containing cytosine–phosphate–guanosine, CpG, sequences) as building blocks. After cellular internalization, DNA capsules accumulate in endosomes, inducing the production of high levels of cytokines. More than 4 million copies of CpG can be delivered to a cell with the internalization of a single DNA capsule.
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Compared with subcutaneous or intramuscular routes for vaccination, vaccine delivery via gastrointestinal mucosa has tremendous potential as it is easy to administer and pain free. Robust immune responses can be triggered successfully once vaccine carried antigen reaches the mucosal associated lymphoid sites (e.g., Peyer’s patches). However, the absence of an efficient delivery method has always been an issue for successful oral vaccine development. In our study, inspired by mammalian orthoreovirus (MRV) transport into gut mucosal lymphoid tissue via Microfold cells (M cells), artificial virus-like nanocarriers (AVN), consisting of gold nanocages functionalized with the s1 protein from mammalian reovirus (MRV), were tested as an effective oral vaccine delivery vehicle targeting M cells. AVN was shown to have a significantly higher transport compared to other experimental groups across mouse organoid monolayers containing M cells. These findings suggest that AVN has the potential to be an M cell-specific oral vaccine/drug delivery vehicle.
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The current global health threat by the Novel coronavirus disease (COVID-19) requires an urgent deployment of available advanced therapeutic options available. The role of nanotechnology is highly relevant to counter this “virus” nano enemy. Nano intervention is discussed in terms of designing effective nanocarriers to counter the conventional limitations of antiviral and biological therapeutics. This strategy directs the safe and effective delivery of available therapeutic options using engineered nanocarriers, blocking the initial interactions of viral spike glycoprotein with host cell surface receptors, and disruption of virion construction. Controlling and eliminating the spread and reoccurrence of this pandemic demands a safe and effective vaccine strategy. Nanocarriers have potential to design risk-free and effective immunization strategies for SARS-CoV-2 vaccine candidates such as protein constructs and nucleic acids. We discuss recent as well as ongoing nanotechnology-based therapeutic and prophylactic strategies to fight against this pandemic, outlining the key areas for Nanoscientists to step-in.
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Cellular uptake of antigens (Ags) by antigen-presenting cells (APCs) is vital for effective functioning of the immune system. Intramuscular or subcutaneous administration of vaccine Ags alone is not sufficient to elicit optimal immune responses. Thus, adjuvants are required to induce strong immunogenicity. Here, we developed nanoparticulate adjuvants that assemble into a bilayer spherical polymersome (PSome) to promote the cellular uptake of Ags by APCs. PSomes were synthesized by using a biodegradable and biocompatible block copolymer methoxy-poly(ethylene glycol)-b-poly(D,L-lactide) to encapsulate both hydrophilic and lipophilic biomacromolecules, such as ovalbumin (OVA) as a model Ag and monophosphoryl lipid A (MPLA) as an immunostimulant. After co-encapsulation of OVA and MPLA, the PSome synthetic vehicle exhibited the sustained release of OVA in cell environments and allowed efficient delivery of cargos into APCs. The administration of PSomes loaded with OVA and MPLA induced the production of interleukin-6 and tumor necrosis factor-alpha cytokines by macrophage activation in vitro and elicited effective Ag-specific antibody responses in vivo. These findings indicate that the nano-sized PSome may serve as a potent adjuvant for vaccine delivery systems to modulate enhanced immune responses.
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Vaccine is one of the most effective strategies for preventing and controlling infectious diseases and some noninfectious diseases, especially cancers. Adjuvants and carriers have been appropriately added to the vaccine formulation to improve the immunogenicity of the antigen and induce long-lasting immunity. However, there is an urgent need to develop new all-purpose adjuvants because some adjuvants approved for human use have limited functionality. Graphene oxide (GO), widely employed for the delivery of biomolecules, excels in loading and delivering antigen and shows the potentiality of activating the immune system. However, GO aggregates in biological liquid and induces cell death, and it also exhibits poor biosolubility and biocompatibility. To address these limitations, various surface modification protocols have been employed to integrate aqueous compatible substances with GO to effectively improve its biocompatibility. More importantly, these modifications render functionalized-GO with superior properties as both carriers and adjuvants. Herein, the recent progress of physicochemical properties and surface modification strategies of GO for its application as both carriers and adjuvants is reviewed. Statement of Significance Due to its unique physicochemical properties, graphene oxide is widely employed in medicine for purposes of photothermal treatment of cancer, drug delivery, antibacterial therapy, and medical imaging. Our work describes the surface modification of graphene oxide and for the first time summarizes that functionalized graphene oxide serves as a vaccine carrier and shows significant adjuvant activity in activating cellular and humoral immunity. In the future, it is expected to be introduced into vaccine research to improve the efficacy of vaccines.
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Nanovaccines need to be transported to lymph node follicles to induce humoral immunity and generate neutralized antibody. Here we discovered that subcapsular sinus macrophages play a barrier role to prevent nanovaccines from accessing lymph node follicles. This is illustrated by measuring the humoral immune responses after removing or functionally altering these cells in the nanovaccine transport process. We achieved up to 60 times more antigen-specific antibody production after suppressing subcapsular sinus macrophages. The degree of the enhanced antibody production is dependent on the nanovaccine dose and size, formulation, and administration time. We further found that pharmacological agents that disrupt the macrophage uptake function can be considered as adjuvants in vaccine development. Immunizing mice using nanovaccines formulated with these agents can induce more than 30 times higher antibody production compared to nanovaccines alone. These findings suggest that altering transport barriers to enable more of the nanovaccine to be delivered to the lymph node follicles for neutralized antibody production is an effective strategy to boost vaccination.
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In the past few decades, cancer immunotherapy has developed rapidly. Cancer immunotherapy, either used alone or in combination with a variety of immunotherapies (such as cancer therapeutic vaccines, adoptive cell therapy, or immune checkpoint blocking therapy), is a very attractive class of cancer therapy. However, so far, the clinical effect of most cancer immunotherapy is not satisfactory. It has been widely recognized that nanotechnology can enhance the efficacy of cancer immunotherapy. A variety of biogenic nanoparticles have been developed, which have excellent immunogenicity and modifiability, and can carry tumor therapeutic drugs to achieve combined therapy, so as to improve the effectiveness and durability of antitumor immunity while reducing adverse side effects. In this review, we summarized the key parameters and futures of three kinds of biogenic nanomaterials in cancer immunotherapy; we highlighted the progress of cancer immunotherapy based on outer membrane vesicles, virus‐like particles, and exosomes. This article is categorized under: • Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease • Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
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Cancer vaccines for prevention and treatment of tumors have attracted tremendous interests as a type of cancer immunotherapy strategy. A major challenge in achieving robust T-cell responses to destruct tumor cells after vaccination is the abilities of antigen cross-presentation for antigen-presenting cells (APCs) such as dendritic cells (DCs). Herein, we demonstrate that a polyamidoamine dendrimer modified with guanidinobenzoic acid (DGBA) could serve as an effective protein carrier to enable delivery of protein antigen, thereby leading to effective antigen cross-presentation by DCs. With ovalbumin (OVA) as the model antigen and unmethylated cytosine-guanine dinucleotides (CpG) as the adjuvant, a unique type of tumor vaccine is formulated. Importantly, such DGBA-OVA-CpG nanovaccine can induce robust antigen-specific cellular immunities and further demonstrates outstanding prophylactic efficacy against B16-OVA melanoma. More significantly, the nanovaccine shows excellent therapeutic effect to treat established B16-OVA melanoma when used in combination with the programmed cell death protein 1 (PD-1) checkpoint-blockade immunotherapy. This study presents the great promises of employing rationally engineered cytosolic protein carriers for the development of tumor vaccines to achieve effective cancer immunotherapy.
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The surface of the mucosa is the biggest path through which pathogens enter the human body. We need an understanding of mucosal immune systems to use vaccines that generate protective mucosal and systemic immunity to regulate the outbreak of various infectious diseases. The better impact of the mucosal vaccine over traditional injectable vaccines are that not only do they induce efficient immune reactions to the mucosa but they are also comfortable in physical aspect & psychological aspect. The material of the vaccine includes pathogens antigens and adjuvants, which enable vaccination to be effective. Vaccines are classified into different criteria, including the used vaccine material and method of administration. Vaccines have traditionally been injected through a needle. However, as most of the pathogens first infect the mucosal surfaces, and growing interest is expressed in establishing protective immunity from the mucosa, which is accomplished through mucosal paths through vaccinosis. To improve the existing vaccines further, innovative strategies derived from interdisciplinary scientific research will need to develop new vaccine production, storage, and delivery systems. A distinctive & vast research and development platform has been set up for the growth of the next generation of mucosal vaccinations. The latest science and technological advancement in the areas of molecular biology, bio and chemical engineering, genome and system biology has provided accumulated understanding of the inborn and acquired multi-dimensional immune system. This review summarizes recent developments in the use of mucosal vaccines and their associated nanoadjuvants for the control of infectious diseases.
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Biodegradable nanomaterials can protect antigens from degradation, promote cellular absorption, enhance immune responses. We constructed a eukaryotic plasmid [pCAGGS-opti441-hemagglutinin (HA)] by inserting the optimized HA gene fragment of H9N2 AIV into the pCAGGS vector. The pCAGGS-opti441-HA/DGL was developed through packaging the pCAGGS-opti441-HA with dendrigraft poly-l-lysines (DGLs). DGL not only protected the pCAGGS-opti441-HA from degradation, but also exhibited high transfection efficiency. Strong cellular immune responses were induced in chickens immunized with the pCAGGS-opti441-HA/DGL. The levels of IFN-γ and IL-2, and lymphocyte transformation rate of the vaccinated chickens increased at the third week post the immunization. For the vaccinated chickens, T lymphocytes were activated and proliferated, the numbers of CD3 + CD4+ and CD4+/CD8+ increased, and the chickens were protected completely against H9N2 AIV challenge. This study provides a method for the development of novel AIV vaccines, and a theoretical basis for the development of safe and efficient gene delivery carriers.
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Nanotechnology-based drug delivery platforms have been explored for cancer treatments and resulted in several nanomedicines in clinical uses and many in clinical trials. However, current nanomedicines have not met the expected clinical therapeutic efficacy. Thus, improving therapeutic efficacy is the foremost pressing task of nanomedicine research. An effective nanomedicine must overcome biological barriers to go through at least five steps to deliver an effective drug into the cytosol of all the cancer cells in a tumor. Of these barriers, nanomedicine extravasation into and infiltration throughout the tumor are the two main unsolved blockages. Up to now, almost all the nanomedicines are designed to rely on the high permeability of tumor blood vessels to extravasate into tumor interstitium, i.e., the enhanced permeability and retention (EPR) effect or so-called "passive tumor accumulation"; however, the EPR features are not so characteristic in human tumors as in the animal tumor models. Following extravasation, the large size nanomedicines are almost motionless in the densely packed tumor microenvironment, making them restricted in the periphery of tumor blood vessels rather than infiltrating in the tumors and thus inaccessible to the distal but highly malignant cells. Recently, we demonstrated using nanocarriers to induce transcytosis of endothelial and cancer cells to enable nanomedicines to actively extravasate into and infiltrate in solid tumors, which led to radically increased anticancer activity. In this perspective, we make a brief discussion about how active transcytosis can be employed to overcome the difficulties, as mentioned above, and solve the inherent extravasation and infiltration dilemmas of nanomedicines.
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Engineered nanoparticles could trigger inflammatory responses and potentiate desired innate immune response for efficient immunotherapy. Here we report size-dependent activation of innate immune signaling pathways by gold (Au) nanoparticles. The ultrasmall-size (<10 nm) Au nanoparticles preferentially activate NLRP3 inflammasome for Caspase-1 maturation and interleukin-1β production, while the larger-size Au nanoparticles (>10 nm) trigger NF-κB signaling pathway. Ultrasmall (4.5 nm) Au nanoparticles (Au4.5) activate NLRP3 inflammasome through directly penetrating into cell cytoplasm to promote robust ROS production and target autophagy protein-LC3 (microtubule-associated protein 1-light chain 3) for proteasomal degradation in endocytic/phagocytic-independent manner. LC3-dependent autophagy is required for inhibiting NLRP3 inflammasome activation and plays a critical role in the negative control of inflammasome activation. Finally, we show that Au4.5 nanoparticles could function as vaccine adjuvants to markedly enhance ovalbumin (OVA)-specific antibody production in an NLRP3-dependent pattern. Our findings have provided molecular insights into size-dependent innate immune signaling activation by cell-penetrating nanoparticles, and identified LC3 as a potential regulatory target for efficient immunotherapy.
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Efficient cancer vaccines not only require the co-delivery of potent antigens and highly immunostimulatory adjuvants to initiate robust tumor-specific host immune response, but also solve the spatiotemporal consistency of host immunity and tumor microenvironment (TME) immunomodulation. Here, we designed a biomaterials-based strategy for converting tumor-derived antigenic microparticles (T-MPs) into a cancer vaccine to meet this conundrum and demonstrated its therapeutic potential in multiple murine tumor models. The internal cavity of T-MPs was employed to store nano-Fe3O4 (Fe3O4/T-MPs) and then dense adjuvant CpG-loaded liposome arrays (CpG/Lipo) were tethered on the surface of Fe3O4/T-MP through mild surface engineering to get a vaccine (Fe3O4/T-MPs-CpG/Lipo), demonstrating that co-delivery of Fe3O4/T-MPs and CpG/Lipo to antigen presenting cells (APCs) could elicit strong tumor antigen-specific host immune response. Meanwhile, vaccines distributed in TME could reverse infiltrated tumor-associated macrophages (TAMs) into a tumor-suppressive M1 phenotype by nano-Fe3O4, amazingly induce abundant infiltration of cytotoxic T lymphocytes and transform “cold” tumor into “hot” tumor. Furthermore, amplified antitumor immunity was realized by the combination of Fe3O4/T-MPs-CpG/Lipo vaccine and immune checkpoint PD-L1 blockade, specifically inhibiting ∼83% progression of B16F10-bearing mice and extending the median survival time to 3 months. Overall, this study synergistically modulates tumor immunosuppressive network and host antitumor immunity in a spatiotemporal manner, which suggests a general cell-engineering strategy tailored to personalized vaccine from autologous cancer cell materials of each individual patient.