Currently,the cancer immunotherapy has made great progress while antitumor vaccine attracts substantial attention.Still,the selection of adjuvants as well as antigens are always the most crucial issues for better vacc...Currently,the cancer immunotherapy has made great progress while antitumor vaccine attracts substantial attention.Still,the selection of adjuvants as well as antigens are always the most crucial issues for better vaccination.In this study,we proposed a biomimetic antitumor nanovaccine based on biocompatible nanocarriers and tumor cell membrane antigens.Briefly,endogenous calcium pyrophosphate nanogranules with possible immune potentiating effect are designed and engineered,both as delivery vehicles and adjuvants.Then,these nanocarriers are coated with lipids and B16-OVA tumor cell membranes,so the biomembrane proteins can serve as tumor-specific antigens.It was found that calcium pyrophosphate nanogranules themselves were compatible and possessed adjuvant effect,while membrane proteins including tumor associated antigen were transferred onto the nanocarriers.It was demonstrated that such a biomimetic nanovaccine could be well endocytosed by dendritic cells,promote their maturation and antigen-presentation,facilitate lymph retention,and trigger obvious immune response.It was confirmed that the biomimetic vaccine could induce strong T-cell response,exhibit excellent tumor therapy and prophylactic effects,and simultaneously possess nice biocompatibility.In general,the present investigation might provide insights for the further design and application of antitumor vaccines.展开更多
The study of tumor nanovaccines(NVs)has gained interest because they specifically recognize and eliminate tumor cells.However,the poor recognition and internalization by dendritic cells(DCs)and insufficient immunogeni...The study of tumor nanovaccines(NVs)has gained interest because they specifically recognize and eliminate tumor cells.However,the poor recognition and internalization by dendritic cells(DCs)and insufficient immunogenicity restricted the vaccine efficacy.Herein,we extracted two molecular-weight Astragalus polysaccharides(APS,12.19 k D;APSHMw,135.67 k D)from Radix Astragali and made them self-assemble with OVA257–264directly forming OVA/APS integrated nanocomplexes through the microfluidic method.The nanocomplexes were wrapped with a sheddable calcium phosphate layer to improve stability.APS in the formed nanocomplexes served as drug carriers and immune adjuvants for potent tumor immunotherapy.The optimal APS-NVs were approximately 160 nm with uniform size distribution and could remain stable in physiological saline solution.The FITC-OVA in APS-NVs could be effectively taken up by DCs,and APS-NVs could stimulate the maturation of DCs,improving the antigen cross-presentation efficiency in vitro.The possible mechanism was that APS can induce DC activation via multiple receptors such as dectin-1 and Toll-like receptors 2 and 4.Enhanced accumulation of APS-NVs both in draining and distal lymph nodes were observed following s.c.injection.Smaller APS-NVs could easily access the lymph nodes.Furthermore,APS-NVs could markedly promote antigen delivery efficiency to DCs and activate cytotoxic T cells.In addition,APS-NVs achieve a better antitumor effect in established B16-OVA melanoma tumors compared with the OVA+Alum treatment group.The antitumor mechanism correlated with the increase in cytotoxic T cells in the tumor region.Subsequently,the poor tumor inhibitory effect of APS-NVs on the nude mouse model of melanoma also confirmed the participation of antitumor adaptive immune response induced by NVs.Therefore,this study developed a promising APS-based tumor NV that is an efficient tumor immunotherapy without systemic side effects.展开更多
Mucosal vaccines that stimulate both mucosal and systemic immune responses are desirable,as they could prevent the invading pathogens at their initial infection sites in a convenient and userfriendly way. Nanovaccines...Mucosal vaccines that stimulate both mucosal and systemic immune responses are desirable,as they could prevent the invading pathogens at their initial infection sites in a convenient and userfriendly way. Nanovaccines are receiving increasing attention for mucosal vaccination due to their merits in overcoming mucosal immune barriers and in enhancing immunogenicity of the encapsulated antigens.Herein, we summarized several nanovaccine strategies that have been reported for enhancing mucosal immune responses, including designing nanovaccines that have superior mucoadhesion and mucus penetration capacity, designing nanovaccines with better targeting efficiency to M cells or antigen-presenting cells, and co-delivering adjuvants by using nanovaccines. The reported applications of mucosal nanovaccines were also briefly discussed, including prevention of infectious diseases, and treatment of tumors and autoimmune diseases. Future research progresses in mucosal nanovaccines may promote the clinical translation and application of mucosal vaccines.展开更多
The rise of nanotechnology has opened new horizons for cancer immunotherapy.However,most nano vaccines fabricated with nanomaterials suffer from carrier-related concerns,including low drug loading capacity,unpredictab...The rise of nanotechnology has opened new horizons for cancer immunotherapy.However,most nano vaccines fabricated with nanomaterials suffer from carrier-related concerns,including low drug loading capacity,unpredictable metabolism,and potential systemic toxicity,which bring obstacles for their clinical translation.Herein,we developed an antigen self-assembled nanovaccine,which was resulted from a simple acryloyl modification of the antigen to induce self-assembly.Furthermore,a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid(Zol)were integrated or absorbed onto the nanoparticles(denoted as MEAO-Z)to intensify the immune response.The synthesized nano vaccine with a diameter of around 70 nm showed successful lymph node transportation,high dendritic cell internalization,promoted costimulatory molecule expression,and preferable antigen cross-presentation.In virtue of the above superiorities,MEAO-Z induced remarkably higher titers of serum antibody,stronger cytotoxic T lymphocyte immune responses and IFN-γsecretion than free antigen and adjuvants.In vivo,MEAO-Z significantly suppressed EG7-OVA tumor groth and prolonged the survival time of tumor-bearing mice.These results indicated the translation promise of our self-assembled nano vaccine for immune potentiation and cancer immunotherapy.展开更多
The chirality of bioactive molecules is closely related to their functions.D-amino acids commonly distributed in the bacterial cell walls trigger a robust anti-infective immune response.Inspired by that,two kinds of c...The chirality of bioactive molecules is closely related to their functions.D-amino acids commonly distributed in the bacterial cell walls trigger a robust anti-infective immune response.Inspired by that,two kinds of chiral polypeptides,poly(L-phenylalanine)-block-poly(L-lysine)(PL-K)and poly(Lphenylalanine)-block-poly(D-lysine)(PD-K),were synthesized and used as nanoadjuvants of nanovaccines for cancer prevention and therapy.The amphiphilic polypeptides self-assembled into nanoparticles with a diameter of about 30 nm during ultrasonic-assisted dissolution in phosphate-buffered saline.The nanovaccines PL-K-OVA and PD-K-OVA were easily prepared by mixing solutions of PL-K or PD-K and the model antigen chicken ovalbumin(OVA),respectively,with loading efficiencies of almost 100%.Compared to PL-K-OVA,PD-K-OVA more robustly induced dendritic cell maturation,antigen cross-presentation,and adaptive immune response.More importantly,it effectively prevented and treated the OVA-expressed B16-OVA melanoma model.PD-K-OVA achieved a tumor inhibition rate of 94.9%and even 97.0%by combining with anti-PD-1 antibody.Therefore,the chiral polypeptide nanoparticles represent simple,efficient,and extensively applicable nanoadjuvants for various nanovaccines.展开更多
Current seasonal influenza vaccines confer only limited coverage of virus strains due to the frequent genetic and antigenic variability of influenza virus(IV).Epitope vaccines that accurately target conserved domains ...Current seasonal influenza vaccines confer only limited coverage of virus strains due to the frequent genetic and antigenic variability of influenza virus(IV).Epitope vaccines that accurately target conserved domains provide a promising approach to increase the breadth of protection;however,poor immunogenicity greatly hinders their application.The protruding(P)domain of the norovirus(NoV),which can self-assemble into a 24-mer particle called the NoV P particle,offers an ideal antigen presentation platform.In this study,a multiepitope nanovaccine displaying influenza epitopes(HMN-PP)was constructed based on the NoV P particle nanoplatform.Large amounts of HMN-PP were easily expressed in Escherichia coli in soluble form.Animal experiments showed that the adjuvanted HMN-PP nanovaccine induced epitope-specific antibodies and haemagglutinin(HA)-specific neutralizing antibodies,the antibodies could persist for at least three months after the last immunization.Furthermore,HMN-PP induced matrix protein 2 extracellular domain(M2e)-specific antibody-dependent cell-mediated cytotoxicity,CD4^(+)and CD8^(+)T-cell responses,a nucleoprotein(NP)-specific cytotoxic T lymphocyte(CTL)response.These results indicated that the combination of a multiepitope vaccine and self-assembled NoV P particles may be an ideal and effective vaccine strategy for highly variable viruses such as IV and SARS-CoV-2.展开更多
Tumor vaccines trigger tumor-specific immune responses to prevent or treat tumors by activating the hosts’immune systems,and therefore,these vaccines have potential clinical applications.However,the low immunogenicit...Tumor vaccines trigger tumor-specific immune responses to prevent or treat tumors by activating the hosts’immune systems,and therefore,these vaccines have potential clinical applications.However,the low immunogenicity of the tumor antigen itself and the low efficiency of the vaccine delivery system hinder the efficacy of tumor vaccines that cannot produce high-efficiency and long-lasting antitumor immune effects.Here,we constructed a nanovaccine by integrating CD47KO/CRT dual-bioengineered B16F10 cancer cell membranes and the unmethylated cytosine-phosphate-guanine(CpG)adjuvant.Hyperbranched PEI25k was used to load unmethylated cytosine-phosphate-guanine(CpG)through electrostatic adsorption to prepare PEI25k/CpG nanoparticles(PEI25k/CpG-NPs).CD47KO/CRT dual-bioengineered cells were obtained by CRISPR-Cas9 gene editing technology,followed by the cell surface translocation of calreticulin(CRT)to induce immunogenic cell death(ICD)in vitro.Finally,the extracted cell membranes were coextruded with PEI25k/CpG-NPs to construct the CD47KO/CRT dual-bioengineered cancer cell membrane-coated nanoparticles(DBE@CCNPs).DBE@CCNPs could promote endocytosis of antigens and adjuvants in murine bone marrow derived dendritic cells(BMDCs)and induce their maturation and antigen cross-presentation.To avoid immune checkpoint molecule-induced T cell dysfunction,the immune checkpoint inhibitor,the anti-PD-L1 antibody,was introduced to boost tumor immunotherapy through a combination with the DBE@CCNPs nanovaccine.This combination therapy strategy can significantly alleviate tumor growth and may open up a potential strategy for clinical tumor immunotherapy.展开更多
Herein,we firstly developed a non-covalent glycosylated gold nanoparticles/peptides nanovaccine which is assembled byβ-cyclodextrin(β-CD)based host-guest recognitions.This nanovaccine can generate significant titers...Herein,we firstly developed a non-covalent glycosylated gold nanoparticles/peptides nanovaccine which is assembled byβ-cyclodextrin(β-CD)based host-guest recognitions.This nanovaccine can generate significant titers of antibodies and improve the therapeutic effect against melanoma,suggesting the immunogenicity of peptide antigens can be improved by loading with this carrier.The novel vaccine carrier provides a platform for the transport of various antigens especially T cell-independent antigens.展开更多
Tumor nanovaccines have potential applications in the prevention and treatment of malignant tumors.However,it remains a longstanding challenge in exploiting efficient nanocarriers for inducing potent specifically cell...Tumor nanovaccines have potential applications in the prevention and treatment of malignant tumors.However,it remains a longstanding challenge in exploiting efficient nanocarriers for inducing potent specifically cellular immune responses.Toward this objective,we herein explore an intensive tumor immunotherapeutic strategy by combining mannosylated nanovaccines and gene regulated PD-L1 blockade for immune stimulation and killing activity.Here,we fabricate a mannose modified PLL-RT(Man-PLL-RT)mediated nanovaccines with dendritic cells(DCs)targeting capacity.Man-PLL-RT is capable of co-encapsulating with antigen(ovalbumin,OVA)and adjuvant(unmethylated cytosine-phosphate-guanine,CpG)by electrostatic interaction.This positively charged Man-PLL-RT/OVA/CpG nanovaccines can facilitate the endocytosis,maturation and cross presentation in DCs.However,the nanovaccines arouse limited inhibition of tumor growth,which is mainly due to the immunosuppressed microenvironment of tumors.Combining tumor nanovaccines with gene regulated PD-L1 blockade leads to an obvious tumor remission in B16F10 melanoma bearing mice.The collaborative strategy provides essential insights to boost the benefits of tumor vaccines by regulating the checkpoint blockade with gene therapy.展开更多
Vaccines can improve the quality of human life by preventing the burden of infectious diseases.Also,vaccination is becoming a powerful medication for preventing and treating tumors.Various vaccines have been developed...Vaccines can improve the quality of human life by preventing the burden of infectious diseases.Also,vaccination is becoming a powerful medication for preventing and treating tumors.Various vaccines have been developed based on the origin of the antigens.Herein,we focus on the subunit vaccines whose antigens are proteins or peptides.The advantage of subunit vaccines is safety for recipients;however,the immunogenicity of subunit antigens is relatively low.Nanoparticular delivery systems have been applied to improve the immunocompetence of subunit vaccines by targeting lymph nodes,and effectively present antigens to immune cells.Moreover,adding appropriate molecular adjuvants may strengthen the antigens to elicit immune response.In this perspective article,we first elucidate the characteristics of immunity induced by subunit nanovaccines and then summarize the strategies to fabricate subunit nanovaccines with delivering materials.Herein we highlight non-covalent interaction to fabricate nanoparticular subunit vaccines.展开更多
Cancer therapeutic nanovaccines are ideal tools to inhibit tumor growth and provide the body with continuous protecting immune surveillance.However,the conventional subcutaneous(SC)vaccination normally induces limited...Cancer therapeutic nanovaccines are ideal tools to inhibit tumor growth and provide the body with continuous protecting immune surveillance.However,the conventional subcutaneous(SC)vaccination normally induces limited anti-tumor immune responses with low therapeutic efficacy.Herein,we devised clay-based nanovaccines and directly delivered them to the spleen via intravenous(IV)injection to induce the stronger anti-tumor immunity with higher efficacy for tumor prevention and treatment.The clay,i.e.,layered double hydroxide(LDH)was prepared as nanoadjuvant with the average size from 77 to 285 nm and co-loaded with the model antigen ovalbumin(OVA)and bioadjuvant CpG to form CpG/OVA-LDH(CO-LDH)nanovaccines.We found that CO-LDH-215(the size of LDH was 215 nm)promoted dendritic cells to present the most antigen,and moreover showed the highest spleen enrichment(~1.67%of CO-LDH-215 enriched in the spleen at 24 h post IV injection).The in vivo immunologic data showed that CO-LDH-215 induced the most potent anti-tumor immune responses and completely prevented the growth of E.G7-OVA tumor in the mouse model.Furthermore,IV injected CO-LDH-215 nanovaccine more effectively delayed tumor growth than that SC injected,largely due to the direct and quick delivery of more nanovaccines to the spleen.This study demonstrates that the therapeutic efficacy of nanovaccines can be greatly enhanced by targeted delivery of nanovaccines to the spleen via the proper vaccination route.展开更多
The clinical outcomes of cancer nanovaccine have been largely impeded owing to the low antigen-specific T cell response rate and acquired resistance caused by the immunosuppressive tumor microenvironment(TME).Here,we ...The clinical outcomes of cancer nanovaccine have been largely impeded owing to the low antigen-specific T cell response rate and acquired resistance caused by the immunosuppressive tumor microenvironment(TME).Here,we reported a tumor acidity-responsive nanovaccine to remodel the immunosuppressive TME and expand the recruitment of tumor infiltrating lymphocytes(TILs)using hybrid micelles(HM),which encapsulated colony stimulating factor 1 receptor(CSF1-R)inhibitor BLZ-945 and indoleamine 2,3-dioxygenase(IDO)inhibitor NLG-919 in its core and displayed a model antigen ovalbumin(OVA)on its surface(denoted as BN@HM-OVA).The bioactive nanovaccine is coated with a polyethylene glycol(PEG)shell for extending nanoparticle circulation.The shell can be shed in response to the weakly acidic tumor microenvironment.The decrease in size and the increase in positive charge may cause the deep tumor penetration of drugs.We demonstrated that the bioactive nanovaccine dramatically enhance antigen presentation by dendritic cells(DCs)and drugs transportation into M1-like tumor-associated macrophages(TAMs)and tumor cells via size reduction and increasing positive charge caused by the weakly acidic TME.Such bioactive nanovaccine could remodel the immunosuppressive TME into an effector T cells favorable environment,leading to tumor growth inhibition in prophylactic and therapeutic E.G7-OVA tumor models.Furthermore,combining the bioactive nanovaccine with simultaneous anti-PD-1 antibody treatment leads to a long-term tumor inhibition,based on the optimal timing and sequence of PD-1 blockade against T cell receptor.This research provides a new strategy for the development of efficient cancer immunotherapy.展开更多
Currently,the incorporation of multiple epitopes into vaccines is more desirable than the incorporation of a single antigen for universal influenza vaccine development.However,epitopes induce poor immune responses.Alt...Currently,the incorporation of multiple epitopes into vaccines is more desirable than the incorporation of a single antigen for universal influenza vaccine development.However,epitopes induce poor immune responses.Although the use of adjuvants can overcome this obstacle,it may raise new problems.Effective antigen delivery vehicles that can function as both antigen carriers and intrinsic adjuvants are highly desired for vaccine development.Here,we report a biepitope nanovaccine that provides complete protection in mice against H3N2 virus as well as partial protection against H1N1 virus.This vaccine(3MCD-f)consists of two conserved epitopes(matrix protein 2 ectodomain(M2e)and CDhelix),and these epitopes were presented on the surface of ferritin in a sequential tandem format.Subcutaneous immunization with 3MCD-f in the absence of adjuvant induces robust humoral and cellular immune responses.These results provide a proof of concept for the 3MCD-f nanovaccine that might be an ideal candidate for future influenza pandemics.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),with several antigenic variants,has grown into a global challenge,and the rapid establishment of an immune barrier is crucial to achieving long-term control ...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),with several antigenic variants,has grown into a global challenge,and the rapid establishment of an immune barrier is crucial to achieving long-term control of the virus.This has led to a great demand for easy preparation and scalable vaccines,especially in low-income countries.Here,we present an inhalable nanovaccine comprising chitosan and SARS-CoV-2 spike protein.The chitosan-mediated nanovaccine enabled a strong spike-specific antibody immune response and augmented local mucosal immunity in bronchoalveolar lavage and lungs,which might be capable of protecting the host from infection without systemic toxicity.In addition,the enhanced adaptive immunity stimulated by chitosan showed potential protection against SARS-CoV-2.Furthermore,inhalation of the nanovaccine induced a comparable antibody response compared to intramuscular injection.This inhalable nanovaccine against SARS-CoV-2 offers a convenient and compliant strategy to reduce the use of needles and the need for medical staff.展开更多
Immunostimulatory therapies based on pattern recognition receptors(PRRs)have emerged as an effective approach in the fight against cancer,with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity ...Immunostimulatory therapies based on pattern recognition receptors(PRRs)have emerged as an effective approach in the fight against cancer,with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity tumor environment.The agonist cyclic dinucleotides(CDNs)of the stimulator of interferon gene(STING)are a group of very promising anticancer molecules that increase tumor immunogenicity by activating innate immunity.However,the tumor immune efficacy of CDNs is limited by several factors,including relatively narrow cytokine production,inefficient delivery to STING,and rapid clearance.In addition,a single adjuvant molecule is unable to elicit a broad cytokine response and thus cannot further amplify the anticancer effect.To address this problem,two or more agonist molecules are often used together to synergistically enhance immune efficacy.In this work,we found that a combination of the STING agonist CDGSF and the Toll-like receptor 7/8(TLR7/8)agonist 522 produced a broader cytokine response.Subsequently,we developed multicomponent nanovaccines(MCNVs)consisting of a PC7A polymer as a nanocarrier encapsulating the antigen OVA and adjuvant molecules.These MCNVs activate bone marrow-derived dendritic cells(BMDCs)to produce multiple proinflammatory factors that promote antigen cross-presentation to stimulate specific antitumor Tcell responses.In in vivo experiments,we observed that MCNVs triggered a strong T-cell response in tumor-infiltrating lymphocytes,resulting in significant tumor regression and,notably,a 100%survival rate in mice through 25 days without other partnering therapies.These data suggest that our nanovaccines have great potential to advance cancer immunotherapy with increased durability and potency.展开更多
During the last decades,the use of nanotechnology in med icine has effectively been translated to the design of drug delivery systems,nanostructured tissues,diagnostic platforms,and novel nanomaterials against several...During the last decades,the use of nanotechnology in med icine has effectively been translated to the design of drug delivery systems,nanostructured tissues,diagnostic platforms,and novel nanomaterials against several human diseases and infectious pathogens.Nanotechnology-enabled vaccines have been positioned as solutions to mitigate the pandemic outbreak caused by the novel pathogen severe acute respiratory syndrome coronavirus 2.To fast-track the development of vaccines,unprecedented industrial and academic collaborations emerged around the world,resulting in the clinical translation of effective vaccines in less than one year.In this article,we provide an overview of the path to translation from the bench to the clinic of nanotechnology-enabled messenger ribonucleic acid vaccines and examine in detail the types of delivery systems used,their mechanisms of action,obtained results during each phase of their clinical development and their regulatory approval process.We also analyze how nanotechnology is impacting global health and economy during the COVID-19 pandemic and beyond.展开更多
Activating humoral and cellular immunity in lymph nodes(LNs)of nanoparticle-based vaccines is critical to controlling tumors.However,how the physical properties of nanovaccine carriers orchestrate antigen capture,lymp...Activating humoral and cellular immunity in lymph nodes(LNs)of nanoparticle-based vaccines is critical to controlling tumors.However,how the physical properties of nanovaccine carriers orchestrate antigen capture,lymphatic delivery,antigen presentation and immune response in LNs is largely unclear.Here,we manufactured gold nanoparticles(AuNPs)with the same size but different shapes(cages,rods,and stars),and loaded tumor antigen as nanovaccines to explore their disparate characters on above four areas.Results revealed that star-shaped AuNPs captured and retained more repetitive antigen epitopes.On lymphatic delivery,both rods and star-shaped nanovaccines mainly drain into the LN follicles region while cage-shaped showed stronger paracortex retention.A surprising finding is that the star-shaped nanovaccines elicited potent humoral immunity,which is mediated by CD4^(+)T helper cell and follicle B cell cooperation significantly preventing tumor growth in the prophylactic study.Interestingly,cage-shaped nanovaccines preferentially presented peptide-MHC I complexes to evoke robust CD8^(+)T cell immunity and showed the strongest therapeutic efficacy when combined with the PD-1 checkpoint inhibitor in established tumor study.These results highlight the importance of nanoparticle shape on antigen delivery and presentation for immune response in LNs,and our findings support the notion that different design strategies are required for prophylactic and therapeutic vaccines.展开更多
Vaccine-based cancer immunotherapy has demonstrated a significant potential for cancer treatment in clinics.Although the efficiencies of vaccines are limited,they can be enhanced by a well-designed antigen delivery sy...Vaccine-based cancer immunotherapy has demonstrated a significant potential for cancer treatment in clinics.Although the efficiencies of vaccines are limited,they can be enhanced by a well-designed antigen delivery system that promotes sufficient antigen presentation of dendritic cells(DCs)for initiating high T cell immunity.Herein,antigen-loaded manganese oxide(Mn_(3)O_(4))triangular-shaped ultrasmall nanoparti-cles were prepared to stimulate DC-based immunotherapy under the guidance of T_(1)magnetic resonance imaging.The FDA-approved triblock copolymer Pluronic^(■)F-68 wasused not onlyto transferthe phase from hydrophobic to hydrophilic but also to enrich antigen loading and improve the biocompatibility of the prepared nanoparticles.Ovalbumin(OVA),a model antigen,was adsorbed on the surface of polymer-coated nanoparticles through electrostatic interaction to form Mn_(3)O_(4)@PF68-OVA nanoparticle-antigen complexes to stimulate DC-based immunization and antigen-specific T cell immunity.The Mn_(3)O_(4)@PF68-OVA nanovaccine(NV)induces negligible toxicity effects against 4T1 and bone marrow-derived dendritic cells(BMDCs)by conventional methods supports the proliferation of intestine organoids,which are an innovative three-dimensional cytotoxicity evaluation system,thereby indicating their potential safety for in vivo cancer therapies.The designed paramagnetic nanovaccine possessed excellent OVA delivery to dendritic-regulated antigen-specific T cells in vitro by stimulating the maturation level of BMDCs.In ad-dition,Mn_(3)O_(4)@PF68-OVA NVs enhance immunity in vivo by increasing the T-cells and M1 macrophages,which suggests improved immunity.Excitingly,vaccination with Mn_(3)O_(4)@PF68-OVA offer complete pro-tection in the prophylactic group and significant tumor inhibition in the therapeutic group against B16-OVA tumor.In addition,the designed nanovaccine demonstrated high T_(1)-MR imaging in the tumor,fur-ther justifying enhanced tumor accumulation and capability to real-time monitor the treatment proce-dure.This study presents a promising nanosystem to design an effective nanovaccine for T_(1)-MR imaging-guided tumor immunotherapy.展开更多
Chiral materials with the same atomic compositions exhibit different chemical,physical,and biological properties because of their distinct spatial structures.Herein,a chiral strategy was proposed to develop poly(lacti...Chiral materials with the same atomic compositions exhibit different chemical,physical,and biological properties because of their distinct spatial structures.Herein,a chiral strategy was proposed to develop poly(lactic acid)(PLA)nanoparticle as an efficient nanoadjuvant to activate adaptive anticancer immunity.Two chiral nanovaccines were prepared by directly mixing amino-terminated PLA(PLLA-NH2 or PDLA-NH2)with the model protein antigen ovalbumin(OVA).After being injected into mice subcutaneously,both nanovaccines efficiently migrated to the lymph nodes to initiate the sequential anticancer immune responses.Compared with the PLLA nanovaccine(PLLA-OVA),the PDLA one(PDLA-OVA)contributed to more robust dendritic cell(DC)maturation,antigen presentation,and T lymphocyte activation.In addition to the activation of cellular immunity,PDLA-OVA also triggered a more vigorous activation of humoral immunity,which induced the production of more anti-OVA immunoglobulin G(IgG)than PLLA-OVA.When used as prophylactic or therapeutic nanovaccine toward murine melanoma models,PDLA-OVA triggered more potent adaptive anticancer immune responses that more effectively inhibited the cancer genesis and progression,indicating the significant potential of immunologically effective PDLA nanoadjuvant in cancer immunotherapy.展开更多
Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in...Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in combination with immune checkpoint blockade(ICB).Current cancer ICB benefits only a small subset of patients,largely due to a lack of pre-existing target cells and checkpoint targets for ICB,tumor antigenic heterogeneity,and tumor immunosuppression.Therapeutic vaccines hold the potential to enhance ICB therapeutic efficacy by expanding antitumor cell repertoires,upregulating immune checkpoint levels and hence sensitizing ICB,and reducing tumor immunosuppression.Chemically defined peptide vaccines are attractive,but their current therapeutic efficacy has been limited due to 1)poor vaccine delivery to immunomodulatory lymph nodes(LNs)and antigen(Ag)-presenting cells(APCs),2)poor immunostimulant adjuvant efficacy with restricted target cell subsets in humans,3)limited adjuvant/Ag codelivery to enhance Ag immunogenicity,and 4)limited ability to overcome tumor antigenic heterogeneity.Here,we developed nanovaccines(NVs)using pH-responsive polymeric micellular nanoparticles(NPs)for the codelivery of bi-adjuvant[Toll-like receptor(TLR)7/8 agonist R848 and TLR9 agonist CpG]and peptide neoantigens(neoAgs)to draining LNs for efficient Ag presentation in a broad range of APC subsets.These NVs potentiated the immunogenicity of peptide Ags and elicits robust antitumor T cell responses with memory,and remodeled the tumor immune milium with reduced tumor immunosuppression.As a result,NVs significantly enhanced ICB therapeutic efficacy for murine colorectal tumors and orthotopic glioblastoma multiforme(GBM).These results suggest marked potential of bi-adjuvant/neoAg-codelivering NVs for combination cancer immunotherapy.展开更多
基金supported by the National Key R&D Program of China(2017YFA0205600)the National Natural Science Foundation of China(81690264,81821004).
文摘Currently,the cancer immunotherapy has made great progress while antitumor vaccine attracts substantial attention.Still,the selection of adjuvants as well as antigens are always the most crucial issues for better vaccination.In this study,we proposed a biomimetic antitumor nanovaccine based on biocompatible nanocarriers and tumor cell membrane antigens.Briefly,endogenous calcium pyrophosphate nanogranules with possible immune potentiating effect are designed and engineered,both as delivery vehicles and adjuvants.Then,these nanocarriers are coated with lipids and B16-OVA tumor cell membranes,so the biomembrane proteins can serve as tumor-specific antigens.It was found that calcium pyrophosphate nanogranules themselves were compatible and possessed adjuvant effect,while membrane proteins including tumor associated antigen were transferred onto the nanocarriers.It was demonstrated that such a biomimetic nanovaccine could be well endocytosed by dendritic cells,promote their maturation and antigen-presentation,facilitate lymph retention,and trigger obvious immune response.It was confirmed that the biomimetic vaccine could induce strong T-cell response,exhibit excellent tumor therapy and prophylactic effects,and simultaneously possess nice biocompatibility.In general,the present investigation might provide insights for the further design and application of antitumor vaccines.
基金supported by Key Project at Central Government Level:the ability establishment of sustainable use for valuable Chinese medicine resources(2060302-2305-04)CAMS Innovation Fund for Medical Sciences(2021-1-I2M-031,2022-I2M-1-018,2022-I2M-2-002)+1 种基金Jilin Provincial Fiscal Construction Program for High-Tech Industries and Technologies(2022C041-5,20220401117YY)Hohhot Science and Technology Program(2021-Social-4)。
文摘The study of tumor nanovaccines(NVs)has gained interest because they specifically recognize and eliminate tumor cells.However,the poor recognition and internalization by dendritic cells(DCs)and insufficient immunogenicity restricted the vaccine efficacy.Herein,we extracted two molecular-weight Astragalus polysaccharides(APS,12.19 k D;APSHMw,135.67 k D)from Radix Astragali and made them self-assemble with OVA257–264directly forming OVA/APS integrated nanocomplexes through the microfluidic method.The nanocomplexes were wrapped with a sheddable calcium phosphate layer to improve stability.APS in the formed nanocomplexes served as drug carriers and immune adjuvants for potent tumor immunotherapy.The optimal APS-NVs were approximately 160 nm with uniform size distribution and could remain stable in physiological saline solution.The FITC-OVA in APS-NVs could be effectively taken up by DCs,and APS-NVs could stimulate the maturation of DCs,improving the antigen cross-presentation efficiency in vitro.The possible mechanism was that APS can induce DC activation via multiple receptors such as dectin-1 and Toll-like receptors 2 and 4.Enhanced accumulation of APS-NVs both in draining and distal lymph nodes were observed following s.c.injection.Smaller APS-NVs could easily access the lymph nodes.Furthermore,APS-NVs could markedly promote antigen delivery efficiency to DCs and activate cytotoxic T cells.In addition,APS-NVs achieve a better antitumor effect in established B16-OVA melanoma tumors compared with the OVA+Alum treatment group.The antitumor mechanism correlated with the increase in cytotoxic T cells in the tumor region.Subsequently,the poor tumor inhibitory effect of APS-NVs on the nude mouse model of melanoma also confirmed the participation of antitumor adaptive immune response induced by NVs.Therefore,this study developed a promising APS-based tumor NV that is an efficient tumor immunotherapy without systemic side effects.
基金supported by National Natural Science Foundation of China (Grant Nos. 81925036 & 82003684)China Postdoctoral Science Foundation Grant (2019M663534, China)+3 种基金the Key Research and Development Program of Science and Technology Department of Sichuan Province (No. 2020YFS0570, China)Sichuan Veterinary Medicine and Drug Innovation Group of China Agricultural Research System (CARS-SVDIP, China)the Fundamental Research Funds for the Central UniversitiesSichuan University Postdoctoral Interdisciplinary Innovation Fund。
文摘Mucosal vaccines that stimulate both mucosal and systemic immune responses are desirable,as they could prevent the invading pathogens at their initial infection sites in a convenient and userfriendly way. Nanovaccines are receiving increasing attention for mucosal vaccination due to their merits in overcoming mucosal immune barriers and in enhancing immunogenicity of the encapsulated antigens.Herein, we summarized several nanovaccine strategies that have been reported for enhancing mucosal immune responses, including designing nanovaccines that have superior mucoadhesion and mucus penetration capacity, designing nanovaccines with better targeting efficiency to M cells or antigen-presenting cells, and co-delivering adjuvants by using nanovaccines. The reported applications of mucosal nanovaccines were also briefly discussed, including prevention of infectious diseases, and treatment of tumors and autoimmune diseases. Future research progresses in mucosal nanovaccines may promote the clinical translation and application of mucosal vaccines.
基金financially supported by the National Natural Science Foundation of China(81925036&81872814)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2020YFS0570,China)+2 种基金Sichuan Veterinary Medicine and Drug Innovation Group of China Agricultural Research System(CARS-SVDIP)111 project(b18035,China)the Fundamental Research Funds for the Central Universities(China)。
文摘The rise of nanotechnology has opened new horizons for cancer immunotherapy.However,most nano vaccines fabricated with nanomaterials suffer from carrier-related concerns,including low drug loading capacity,unpredictable metabolism,and potential systemic toxicity,which bring obstacles for their clinical translation.Herein,we developed an antigen self-assembled nanovaccine,which was resulted from a simple acryloyl modification of the antigen to induce self-assembly.Furthermore,a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid(Zol)were integrated or absorbed onto the nanoparticles(denoted as MEAO-Z)to intensify the immune response.The synthesized nano vaccine with a diameter of around 70 nm showed successful lymph node transportation,high dendritic cell internalization,promoted costimulatory molecule expression,and preferable antigen cross-presentation.In virtue of the above superiorities,MEAO-Z induced remarkably higher titers of serum antibody,stronger cytotoxic T lymphocyte immune responses and IFN-γsecretion than free antigen and adjuvants.In vivo,MEAO-Z significantly suppressed EG7-OVA tumor groth and prolonged the survival time of tumor-bearing mice.These results indicated the translation promise of our self-assembled nano vaccine for immune potentiation and cancer immunotherapy.
基金supported by the National Key Research and Development Program(2022YFC2603500,2022YFC2603501,2021YFC2400600,2021YFC2400603,and 2021YFC2400604)the National Natural Science Foundation of China(52273158,52273159,U21A2099,52022095,and 52073280)+2 种基金the Science and Technology Development Program of Jilin Province(20210509005RQ,20210504001GH,20200404182YY,and 20200201322JC)the Special Project for City-Academy Scientific and Technological Innovation Cooperation of Changchun(21SH14)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2019230).
文摘The chirality of bioactive molecules is closely related to their functions.D-amino acids commonly distributed in the bacterial cell walls trigger a robust anti-infective immune response.Inspired by that,two kinds of chiral polypeptides,poly(L-phenylalanine)-block-poly(L-lysine)(PL-K)and poly(Lphenylalanine)-block-poly(D-lysine)(PD-K),were synthesized and used as nanoadjuvants of nanovaccines for cancer prevention and therapy.The amphiphilic polypeptides self-assembled into nanoparticles with a diameter of about 30 nm during ultrasonic-assisted dissolution in phosphate-buffered saline.The nanovaccines PL-K-OVA and PD-K-OVA were easily prepared by mixing solutions of PL-K or PD-K and the model antigen chicken ovalbumin(OVA),respectively,with loading efficiencies of almost 100%.Compared to PL-K-OVA,PD-K-OVA more robustly induced dendritic cell maturation,antigen cross-presentation,and adaptive immune response.More importantly,it effectively prevented and treated the OVA-expressed B16-OVA melanoma model.PD-K-OVA achieved a tumor inhibition rate of 94.9%and even 97.0%by combining with anti-PD-1 antibody.Therefore,the chiral polypeptide nanoparticles represent simple,efficient,and extensively applicable nanoadjuvants for various nanovaccines.
基金the Department of Science and Technology of Jilin Province(Nos.20220204008YY and 20210204197YY)Changchun Science and Technology Bureau(No.21ZY15).
文摘Current seasonal influenza vaccines confer only limited coverage of virus strains due to the frequent genetic and antigenic variability of influenza virus(IV).Epitope vaccines that accurately target conserved domains provide a promising approach to increase the breadth of protection;however,poor immunogenicity greatly hinders their application.The protruding(P)domain of the norovirus(NoV),which can self-assemble into a 24-mer particle called the NoV P particle,offers an ideal antigen presentation platform.In this study,a multiepitope nanovaccine displaying influenza epitopes(HMN-PP)was constructed based on the NoV P particle nanoplatform.Large amounts of HMN-PP were easily expressed in Escherichia coli in soluble form.Animal experiments showed that the adjuvanted HMN-PP nanovaccine induced epitope-specific antibodies and haemagglutinin(HA)-specific neutralizing antibodies,the antibodies could persist for at least three months after the last immunization.Furthermore,HMN-PP induced matrix protein 2 extracellular domain(M2e)-specific antibody-dependent cell-mediated cytotoxicity,CD4^(+)and CD8^(+)T-cell responses,a nucleoprotein(NP)-specific cytotoxic T lymphocyte(CTL)response.These results indicated that the combination of a multiepitope vaccine and self-assembled NoV P particles may be an ideal and effective vaccine strategy for highly variable viruses such as IV and SARS-CoV-2.
基金The authors are thankful to the National Key R&D Program of China(2021YFB3800900)National Natural Science Foundation of China(51925305,51873208,51973217)+2 种基金Taishan Scholar Foundation of Shandong Province(qnts20161035)Natural Science Foundation of Shandong Province(ZR2019ZD24,ZR2019YQ30)Jilin Province Science and Technology Development Program(20200201075JC,20210509005RQ).
文摘Tumor vaccines trigger tumor-specific immune responses to prevent or treat tumors by activating the hosts’immune systems,and therefore,these vaccines have potential clinical applications.However,the low immunogenicity of the tumor antigen itself and the low efficiency of the vaccine delivery system hinder the efficacy of tumor vaccines that cannot produce high-efficiency and long-lasting antitumor immune effects.Here,we constructed a nanovaccine by integrating CD47KO/CRT dual-bioengineered B16F10 cancer cell membranes and the unmethylated cytosine-phosphate-guanine(CpG)adjuvant.Hyperbranched PEI25k was used to load unmethylated cytosine-phosphate-guanine(CpG)through electrostatic adsorption to prepare PEI25k/CpG nanoparticles(PEI25k/CpG-NPs).CD47KO/CRT dual-bioengineered cells were obtained by CRISPR-Cas9 gene editing technology,followed by the cell surface translocation of calreticulin(CRT)to induce immunogenic cell death(ICD)in vitro.Finally,the extracted cell membranes were coextruded with PEI25k/CpG-NPs to construct the CD47KO/CRT dual-bioengineered cancer cell membrane-coated nanoparticles(DBE@CCNPs).DBE@CCNPs could promote endocytosis of antigens and adjuvants in murine bone marrow derived dendritic cells(BMDCs)and induce their maturation and antigen cross-presentation.To avoid immune checkpoint molecule-induced T cell dysfunction,the immune checkpoint inhibitor,the anti-PD-L1 antibody,was introduced to boost tumor immunotherapy through a combination with the DBE@CCNPs nanovaccine.This combination therapy strategy can significantly alleviate tumor growth and may open up a potential strategy for clinical tumor immunotherapy.
基金the Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine(No.20188030322011)the National Natural Science Foundation of China(No.81773580)。
文摘Herein,we firstly developed a non-covalent glycosylated gold nanoparticles/peptides nanovaccine which is assembled byβ-cyclodextrin(β-CD)based host-guest recognitions.This nanovaccine can generate significant titers of antibodies and improve the therapeutic effect against melanoma,suggesting the immunogenicity of peptide antigens can be improved by loading with this carrier.The novel vaccine carrier provides a platform for the transport of various antigens especially T cell-independent antigens.
基金This work was supported by the National Natural Science Foundation of China(51925305,51873208,51973217,51520105004 and 51803210)National Science and Technology Major Projects for Major New Drugs Innovation and Development(2018ZX09711003-012)and Jilin Province Science and Technology Development Program(20180414027GH and 20200201075JC).
文摘Tumor nanovaccines have potential applications in the prevention and treatment of malignant tumors.However,it remains a longstanding challenge in exploiting efficient nanocarriers for inducing potent specifically cellular immune responses.Toward this objective,we herein explore an intensive tumor immunotherapeutic strategy by combining mannosylated nanovaccines and gene regulated PD-L1 blockade for immune stimulation and killing activity.Here,we fabricate a mannose modified PLL-RT(Man-PLL-RT)mediated nanovaccines with dendritic cells(DCs)targeting capacity.Man-PLL-RT is capable of co-encapsulating with antigen(ovalbumin,OVA)and adjuvant(unmethylated cytosine-phosphate-guanine,CpG)by electrostatic interaction.This positively charged Man-PLL-RT/OVA/CpG nanovaccines can facilitate the endocytosis,maturation and cross presentation in DCs.However,the nanovaccines arouse limited inhibition of tumor growth,which is mainly due to the immunosuppressed microenvironment of tumors.Combining tumor nanovaccines with gene regulated PD-L1 blockade leads to an obvious tumor remission in B16F10 melanoma bearing mice.The collaborative strategy provides essential insights to boost the benefits of tumor vaccines by regulating the checkpoint blockade with gene therapy.
基金supported by the National Natural Science Foundation of China(Grant Nos.22075324,51820105004)the Key Areas Research and Development Program of Guangzhou(Grant No.202007020006)。
文摘Vaccines can improve the quality of human life by preventing the burden of infectious diseases.Also,vaccination is becoming a powerful medication for preventing and treating tumors.Various vaccines have been developed based on the origin of the antigens.Herein,we focus on the subunit vaccines whose antigens are proteins or peptides.The advantage of subunit vaccines is safety for recipients;however,the immunogenicity of subunit antigens is relatively low.Nanoparticular delivery systems have been applied to improve the immunocompetence of subunit vaccines by targeting lymph nodes,and effectively present antigens to immune cells.Moreover,adding appropriate molecular adjuvants may strengthen the antigens to elicit immune response.In this perspective article,we first elucidate the characteristics of immunity induced by subunit nanovaccines and then summarize the strategies to fabricate subunit nanovaccines with delivering materials.Herein we highlight non-covalent interaction to fabricate nanoparticular subunit vaccines.
基金This work was financially supported by the International Partnership Program of Chinese Academy of Sciences(No.122111KYSB20180005)the Australian Research Council(ARC)Discovery Project(No.DP190103486)+2 种基金Zhejiang Provincial Natural Science Foundation of China(No.LY19H160011)Ningbo Digestive System Clinical Medicine Research Center(No.2019A21003)We also thank the Support from the Dey Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Povince。
文摘Cancer therapeutic nanovaccines are ideal tools to inhibit tumor growth and provide the body with continuous protecting immune surveillance.However,the conventional subcutaneous(SC)vaccination normally induces limited anti-tumor immune responses with low therapeutic efficacy.Herein,we devised clay-based nanovaccines and directly delivered them to the spleen via intravenous(IV)injection to induce the stronger anti-tumor immunity with higher efficacy for tumor prevention and treatment.The clay,i.e.,layered double hydroxide(LDH)was prepared as nanoadjuvant with the average size from 77 to 285 nm and co-loaded with the model antigen ovalbumin(OVA)and bioadjuvant CpG to form CpG/OVA-LDH(CO-LDH)nanovaccines.We found that CO-LDH-215(the size of LDH was 215 nm)promoted dendritic cells to present the most antigen,and moreover showed the highest spleen enrichment(~1.67%of CO-LDH-215 enriched in the spleen at 24 h post IV injection).The in vivo immunologic data showed that CO-LDH-215 induced the most potent anti-tumor immune responses and completely prevented the growth of E.G7-OVA tumor in the mouse model.Furthermore,IV injected CO-LDH-215 nanovaccine more effectively delayed tumor growth than that SC injected,largely due to the direct and quick delivery of more nanovaccines to the spleen.This study demonstrates that the therapeutic efficacy of nanovaccines can be greatly enhanced by targeted delivery of nanovaccines to the spleen via the proper vaccination route.
基金by the National Natural Science Foundation of China(U19A2006,12132004,12032007,11972111,31900940,32071304,32171309,32171395)the Sichuan Science and Technology Program(21YJ0130)+1 种基金the Joint Funds of Center for Engineering Medicine(ZYGX2021YGLH010,ZYGX2021YGLH017,ZYGX2021YGLH023)the technical support from the Public Experiment Centre of State Bioindustrial Base(Chongqing).
文摘The clinical outcomes of cancer nanovaccine have been largely impeded owing to the low antigen-specific T cell response rate and acquired resistance caused by the immunosuppressive tumor microenvironment(TME).Here,we reported a tumor acidity-responsive nanovaccine to remodel the immunosuppressive TME and expand the recruitment of tumor infiltrating lymphocytes(TILs)using hybrid micelles(HM),which encapsulated colony stimulating factor 1 receptor(CSF1-R)inhibitor BLZ-945 and indoleamine 2,3-dioxygenase(IDO)inhibitor NLG-919 in its core and displayed a model antigen ovalbumin(OVA)on its surface(denoted as BN@HM-OVA).The bioactive nanovaccine is coated with a polyethylene glycol(PEG)shell for extending nanoparticle circulation.The shell can be shed in response to the weakly acidic tumor microenvironment.The decrease in size and the increase in positive charge may cause the deep tumor penetration of drugs.We demonstrated that the bioactive nanovaccine dramatically enhance antigen presentation by dendritic cells(DCs)and drugs transportation into M1-like tumor-associated macrophages(TAMs)and tumor cells via size reduction and increasing positive charge caused by the weakly acidic TME.Such bioactive nanovaccine could remodel the immunosuppressive TME into an effector T cells favorable environment,leading to tumor growth inhibition in prophylactic and therapeutic E.G7-OVA tumor models.Furthermore,combining the bioactive nanovaccine with simultaneous anti-PD-1 antibody treatment leads to a long-term tumor inhibition,based on the optimal timing and sequence of PD-1 blockade against T cell receptor.This research provides a new strategy for the development of efficient cancer immunotherapy.
基金the National Natural Science Foundation of China(No.31770996).
文摘Currently,the incorporation of multiple epitopes into vaccines is more desirable than the incorporation of a single antigen for universal influenza vaccine development.However,epitopes induce poor immune responses.Although the use of adjuvants can overcome this obstacle,it may raise new problems.Effective antigen delivery vehicles that can function as both antigen carriers and intrinsic adjuvants are highly desired for vaccine development.Here,we report a biepitope nanovaccine that provides complete protection in mice against H3N2 virus as well as partial protection against H1N1 virus.This vaccine(3MCD-f)consists of two conserved epitopes(matrix protein 2 ectodomain(M2e)and CDhelix),and these epitopes were presented on the surface of ferritin in a sequential tandem format.Subcutaneous immunization with 3MCD-f in the absence of adjuvant induces robust humoral and cellular immune responses.These results provide a proof of concept for the 3MCD-f nanovaccine that might be an ideal candidate for future influenza pandemics.
基金This work was supported by the National Key R&D Program of China(Nos.2019YFA0904200 and 2018YFA0507600)Tsinghua University Spring Breeze Fund(No.2020Z99CFY042)+1 种基金the National Natural Science Foundation of China(No.92053108)Applications for Chinese patents related to chitosan-mediated inhalable nanovaccine has been submitted(Patent No.202111130951.7)。
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),with several antigenic variants,has grown into a global challenge,and the rapid establishment of an immune barrier is crucial to achieving long-term control of the virus.This has led to a great demand for easy preparation and scalable vaccines,especially in low-income countries.Here,we present an inhalable nanovaccine comprising chitosan and SARS-CoV-2 spike protein.The chitosan-mediated nanovaccine enabled a strong spike-specific antibody immune response and augmented local mucosal immunity in bronchoalveolar lavage and lungs,which might be capable of protecting the host from infection without systemic toxicity.In addition,the enhanced adaptive immunity stimulated by chitosan showed potential protection against SARS-CoV-2.Furthermore,inhalation of the nanovaccine induced a comparable antibody response compared to intramuscular injection.This inhalable nanovaccine against SARS-CoV-2 offers a convenient and compliant strategy to reduce the use of needles and the need for medical staff.
基金supported by the National Key R&D Program of China(Nos.2019YFA0904200 and 2018YFA0507600)Tsinghua University Spring Breeze Fund(No.2020Z99CFY042)the National Natural Science Foundation of China(No.92053108).
文摘Immunostimulatory therapies based on pattern recognition receptors(PRRs)have emerged as an effective approach in the fight against cancer,with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity tumor environment.The agonist cyclic dinucleotides(CDNs)of the stimulator of interferon gene(STING)are a group of very promising anticancer molecules that increase tumor immunogenicity by activating innate immunity.However,the tumor immune efficacy of CDNs is limited by several factors,including relatively narrow cytokine production,inefficient delivery to STING,and rapid clearance.In addition,a single adjuvant molecule is unable to elicit a broad cytokine response and thus cannot further amplify the anticancer effect.To address this problem,two or more agonist molecules are often used together to synergistically enhance immune efficacy.In this work,we found that a combination of the STING agonist CDGSF and the Toll-like receptor 7/8(TLR7/8)agonist 522 produced a broader cytokine response.Subsequently,we developed multicomponent nanovaccines(MCNVs)consisting of a PC7A polymer as a nanocarrier encapsulating the antigen OVA and adjuvant molecules.These MCNVs activate bone marrow-derived dendritic cells(BMDCs)to produce multiple proinflammatory factors that promote antigen cross-presentation to stimulate specific antitumor Tcell responses.In in vivo experiments,we observed that MCNVs triggered a strong T-cell response in tumor-infiltrating lymphocytes,resulting in significant tumor regression and,notably,a 100%survival rate in mice through 25 days without other partnering therapies.These data suggest that our nanovaccines have great potential to advance cancer immunotherapy with increased durability and potency.
基金supported by NIH Grants R01DK072381,R37DK039773,and TR-002155.
文摘During the last decades,the use of nanotechnology in med icine has effectively been translated to the design of drug delivery systems,nanostructured tissues,diagnostic platforms,and novel nanomaterials against several human diseases and infectious pathogens.Nanotechnology-enabled vaccines have been positioned as solutions to mitigate the pandemic outbreak caused by the novel pathogen severe acute respiratory syndrome coronavirus 2.To fast-track the development of vaccines,unprecedented industrial and academic collaborations emerged around the world,resulting in the clinical translation of effective vaccines in less than one year.In this article,we provide an overview of the path to translation from the bench to the clinic of nanotechnology-enabled messenger ribonucleic acid vaccines and examine in detail the types of delivery systems used,their mechanisms of action,obtained results during each phase of their clinical development and their regulatory approval process.We also analyze how nanotechnology is impacting global health and economy during the COVID-19 pandemic and beyond.
基金supported by the National Natural Science Foundation of China(Nos.81901878,U1804183,and 82202318)Key Scientific Research Project(Education Department of Henan Province,China,20HASTIT049)China Postdoctoral Science Foundation(2019M662553,2020T130611,and 2022TQ0310)。
文摘Activating humoral and cellular immunity in lymph nodes(LNs)of nanoparticle-based vaccines is critical to controlling tumors.However,how the physical properties of nanovaccine carriers orchestrate antigen capture,lymphatic delivery,antigen presentation and immune response in LNs is largely unclear.Here,we manufactured gold nanoparticles(AuNPs)with the same size but different shapes(cages,rods,and stars),and loaded tumor antigen as nanovaccines to explore their disparate characters on above four areas.Results revealed that star-shaped AuNPs captured and retained more repetitive antigen epitopes.On lymphatic delivery,both rods and star-shaped nanovaccines mainly drain into the LN follicles region while cage-shaped showed stronger paracortex retention.A surprising finding is that the star-shaped nanovaccines elicited potent humoral immunity,which is mediated by CD4^(+)T helper cell and follicle B cell cooperation significantly preventing tumor growth in the prophylactic study.Interestingly,cage-shaped nanovaccines preferentially presented peptide-MHC I complexes to evoke robust CD8^(+)T cell immunity and showed the strongest therapeutic efficacy when combined with the PD-1 checkpoint inhibitor in established tumor study.These results highlight the importance of nanoparticle shape on antigen delivery and presentation for immune response in LNs,and our findings support the notion that different design strategies are required for prophylactic and therapeutic vaccines.
基金financially supported by the National Natural Science Foundation of China(No.51672250 and 51902289)the Zhejiang International Science and Technology Cooperation Project(Nos.2021C01180 and 2019C04020)the Research Foundation of ZSTU(No.18012134-Y).
文摘Vaccine-based cancer immunotherapy has demonstrated a significant potential for cancer treatment in clinics.Although the efficiencies of vaccines are limited,they can be enhanced by a well-designed antigen delivery system that promotes sufficient antigen presentation of dendritic cells(DCs)for initiating high T cell immunity.Herein,antigen-loaded manganese oxide(Mn_(3)O_(4))triangular-shaped ultrasmall nanoparti-cles were prepared to stimulate DC-based immunotherapy under the guidance of T_(1)magnetic resonance imaging.The FDA-approved triblock copolymer Pluronic^(■)F-68 wasused not onlyto transferthe phase from hydrophobic to hydrophilic but also to enrich antigen loading and improve the biocompatibility of the prepared nanoparticles.Ovalbumin(OVA),a model antigen,was adsorbed on the surface of polymer-coated nanoparticles through electrostatic interaction to form Mn_(3)O_(4)@PF68-OVA nanoparticle-antigen complexes to stimulate DC-based immunization and antigen-specific T cell immunity.The Mn_(3)O_(4)@PF68-OVA nanovaccine(NV)induces negligible toxicity effects against 4T1 and bone marrow-derived dendritic cells(BMDCs)by conventional methods supports the proliferation of intestine organoids,which are an innovative three-dimensional cytotoxicity evaluation system,thereby indicating their potential safety for in vivo cancer therapies.The designed paramagnetic nanovaccine possessed excellent OVA delivery to dendritic-regulated antigen-specific T cells in vitro by stimulating the maturation level of BMDCs.In ad-dition,Mn_(3)O_(4)@PF68-OVA NVs enhance immunity in vivo by increasing the T-cells and M1 macrophages,which suggests improved immunity.Excitingly,vaccination with Mn_(3)O_(4)@PF68-OVA offer complete pro-tection in the prophylactic group and significant tumor inhibition in the therapeutic group against B16-OVA tumor.In addition,the designed nanovaccine demonstrated high T_(1)-MR imaging in the tumor,fur-ther justifying enhanced tumor accumulation and capability to real-time monitor the treatment proce-dure.This study presents a promising nanosystem to design an effective nanovaccine for T_(1)-MR imaging-guided tumor immunotherapy.
基金supported by the National Natural Science Foundation of China(52273159,52273158,U21A2099,52173149,52073280,52022095,51973216,51873207,51833010)the Science and Technology Development Program of Jilin Province(20210509005RQ,20210504001GH,20200404182YY)+1 种基金the“Special Project for City-Academy Scientific and Technological Innovation Cooperation”of Changchun(21SH14)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2019230)。
文摘Chiral materials with the same atomic compositions exhibit different chemical,physical,and biological properties because of their distinct spatial structures.Herein,a chiral strategy was proposed to develop poly(lactic acid)(PLA)nanoparticle as an efficient nanoadjuvant to activate adaptive anticancer immunity.Two chiral nanovaccines were prepared by directly mixing amino-terminated PLA(PLLA-NH2 or PDLA-NH2)with the model protein antigen ovalbumin(OVA).After being injected into mice subcutaneously,both nanovaccines efficiently migrated to the lymph nodes to initiate the sequential anticancer immune responses.Compared with the PLLA nanovaccine(PLLA-OVA),the PDLA one(PDLA-OVA)contributed to more robust dendritic cell(DC)maturation,antigen presentation,and T lymphocyte activation.In addition to the activation of cellular immunity,PDLA-OVA also triggered a more vigorous activation of humoral immunity,which induced the production of more anti-OVA immunoglobulin G(IgG)than PLLA-OVA.When used as prophylactic or therapeutic nanovaccine toward murine melanoma models,PDLA-OVA triggered more potent adaptive anticancer immune responses that more effectively inhibited the cancer genesis and progression,indicating the significant potential of immunologically effective PDLA nanoadjuvant in cancer immunotherapy.
基金G.Z.acknowledges funding support from NIH(R01CA266981,R01AI168684,R35GM143014,R21NS114455)DoD CDMRP Breast Cancer Breakthrough Award Level II(BC210931/P1)+3 种基金NIH-NCATS KL2 scholarship(KL2TR002648)via VCU C.Kenneth and Dianne Wright Center for Clinical and Translational Research(UL1TR002649)American Cancer Society Research Scholar Grant(RSG-22-055-01-IBCD)METAvivor Early Career Investigator Award,among others.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.T.S.and F.C.acknowledge the National Natural Science Foundation of China(52103199,82102203)Guangdong Basic and Applied Basic Research Foundation(2020A1515110811).
文摘Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in combination with immune checkpoint blockade(ICB).Current cancer ICB benefits only a small subset of patients,largely due to a lack of pre-existing target cells and checkpoint targets for ICB,tumor antigenic heterogeneity,and tumor immunosuppression.Therapeutic vaccines hold the potential to enhance ICB therapeutic efficacy by expanding antitumor cell repertoires,upregulating immune checkpoint levels and hence sensitizing ICB,and reducing tumor immunosuppression.Chemically defined peptide vaccines are attractive,but their current therapeutic efficacy has been limited due to 1)poor vaccine delivery to immunomodulatory lymph nodes(LNs)and antigen(Ag)-presenting cells(APCs),2)poor immunostimulant adjuvant efficacy with restricted target cell subsets in humans,3)limited adjuvant/Ag codelivery to enhance Ag immunogenicity,and 4)limited ability to overcome tumor antigenic heterogeneity.Here,we developed nanovaccines(NVs)using pH-responsive polymeric micellular nanoparticles(NPs)for the codelivery of bi-adjuvant[Toll-like receptor(TLR)7/8 agonist R848 and TLR9 agonist CpG]and peptide neoantigens(neoAgs)to draining LNs for efficient Ag presentation in a broad range of APC subsets.These NVs potentiated the immunogenicity of peptide Ags and elicits robust antitumor T cell responses with memory,and remodeled the tumor immune milium with reduced tumor immunosuppression.As a result,NVs significantly enhanced ICB therapeutic efficacy for murine colorectal tumors and orthotopic glioblastoma multiforme(GBM).These results suggest marked potential of bi-adjuvant/neoAg-codelivering NVs for combination cancer immunotherapy.
