It remains a major challenge in phototherapeutics to achieve a high quantum yield of singlet oxygen generation and efficient photothermal conversion using a single near-infrared laser for immuno-phototherapy.To bridge...It remains a major challenge in phototherapeutics to achieve a high quantum yield of singlet oxygen generation and efficient photothermal conversion using a single near-infrared laser for immuno-phototherapy.To bridge this gap,we utilized an acceptor-donor-acceptor(A-DA)structured molecule,3,9-bis(2-methylene-((3-(1,1-dicyanomethylene)-6/7-methyl)-indanone))-5,5,11,11-tetrakis(4-hexylphenyl)-dithieno[2,3-d:2′,3′-d′]-s-indaceno[1,2-b:5,6-b′]-dithiophene(m-ITIC),and formulated it into nanoparticles(NPs)by assembling with distearoylphosphatidylethanolamine-polyethylene glycol-amino(DSPE-PEG-NH_(2)).At 688 and 768 nm,these NPs present significant near-infrared absorption and fluorescence.They simultaneously generate heat,O_(2)^(-•),and 1O_(2),with the^(1)O_(2)generation quantum yield of 56.8%and photothermal conversion efficiency(PCE)of 27.4%,enabling them excellent near-infrared(NIR)fluorescence imaging guided synergic photodynamic therapy(PDT)and photothermal therapy(PTT)capabilities.Importantly,this nanoplatform induces PANoptosis,a coordinated cell death program integrating pyroptosis,apoptosis,and necroptosis,in tumor cells,thereby amplifying immunogenic cell death(ICD)and enhancing antitumor immune responses.The combined effects lead to robust dendritic cell activation,macrophage polarization toward the M1 phenotype,elevated CD8^(+)T cell infiltration,and suppression of immunosuppressive Treg cells,resulting in significant tumor growth inhibition and prevention of lung metastasis in vivo.Furthermore,the therapeutic efficacy was validated in patient-derived tumor organoids,demonstrating translational potential.This study presents a novel strategy for NIR light-guided cancer phototherapy,wherein a single laser-activated nanoplatform simultaneously mediates efficient photothermal and photodynamic effects and induces PANoptosis driven ICD for synergistic cancer immunotherapy.展开更多
Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell ...Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell death ligand 1(PD-L1),which hijacked the antitumor immunity.In this study,we developed a reactive oxygen species(ROS)-responsive dihydroartemisinin(DHA)prodrug to facilitate the delivery of DOX via hydrophobic and electrostatic interactions.Upon internalization by tumor cells,the nanoparticles(NPs)preferentially accumulated in endoplasmic reticulum(ER),exacerbating ER stress and amplifying ICD to enhance tumor immunogenicity.Simultaneously,the oxidative intracellular environment trigged the degradation of NPs,releasing DHA,which downregulated PD-L1 by disrupting signal transducer and activator of transcription 3(STAT3)phosphorylation and inactivating the nuclear factor kappa-B(NF-κB)pathway.Consequently,the effective PD-L1 blockade and robust ICD response,synergistically inhibited breast cancer progression,significantly enhancing the chemo-immunotherapy efficacy of doxorubicin.展开更多
Colorectal cancer(CRC)remains a major global health challenge,with high recurrence and mortality despite advances in surgery,chemotherapy,and immunotherapy.The study by He et al identifies a novel mechanism by which p...Colorectal cancer(CRC)remains a major global health challenge,with high recurrence and mortality despite advances in surgery,chemotherapy,and immunotherapy.The study by He et al identifies a novel mechanism by which peroxiredoxin 1(Prdx1)inhibits CRC progression through induction of pyroptosis,a pro-inflammatory form of programmed cell death.Traditionally viewed as an intracellular antioxidant that protects tumors from oxidative stress,Prdx1 assu-mes a paradoxical immunogenic role when released extracellularly as a damageassociated molecular pattern.Using patient samples,recombinant protein assays,and murine xenograft models,the authors demonstrate that Prdx1 activates the NOD-,LRR-and pyrin domain-containing protein 3 inflammasome/caspase-1/gasdermin D pathway,triggering membrane pore formation,tumor cell lysis,and release of interleukin-1β/interleukin-18.This cascade not only halts tumor proliferation,invasion,and migration but may also enhance anti-tumor immune surveillance.The study’s strengths include rigorous mechanistic validation,clinical cohort data,inhibitor-based causal proof,and in vivo confirmation.However,questions remain regarding the upstream receptor for Prdx1,heterogeneity across CRC subtypes,and the balance between therapeutic benefit and inflammatory toxicity.By establishing Prdx1-induced pyroptosis as a driver of tumor suppression,this work advances a promising paradigm in CRC therapy,linking cell death to immune activation and pointing toward future biomarker-driven,pyroptosis-based interventions.展开更多
The field of nanomedicine has been revolutionized by the concept of immunogenic cell death(ICD)-enhanced cancer therapy,which holds immense promise for the efficient treatment of cancer.However,precise delivery of ICD...The field of nanomedicine has been revolutionized by the concept of immunogenic cell death(ICD)-enhanced cancer therapy,which holds immense promise for the efficient treatment of cancer.However,precise delivery of ICD inducer is severely hindered by complex biological barriers.How to design and build intelligent nanoplatform for adaptive and dynamic cancer therapy remains a big challenge.Herein,this article presents the design and preparation of CD44-targeting and ZIF-8 gated gold nanocage(Au@ZH) for programmed delivery of the 1,2-diaminocyclohexane-Pt(Ⅱ)(DACHPt) as ICD inducer.After actively targeting the CD44 on the surface of 4T1 tumor cell,this Pt-Au@ZH can be effectively endocytosed by the 4T1 cell and release the DACHPt in tumor acidic environment,resulting in ICD effect and superior antitumor efficacy both in vitro and in vivo in the presence of mild 808 nm laser irradiation.By integration of internal and external stimuli intelligently,this programmed nanoplatform is poised to become a cornerstone in the pursuit of effective and targeted cancer therapy in the foreseeable future.展开更多
Therapeutic antibodies are valued for their high specificity and selectivity in immu-notherapy.However,the potential toxicity they may elicit underscores the necessity of assessing their preclinical efficacy and safet...Therapeutic antibodies are valued for their high specificity and selectivity in immu-notherapy.However,the potential toxicity they may elicit underscores the necessity of assessing their preclinical efficacy and safety using suitable animal models.In this context,we review the various categories and applications of humanized mice,which have been engrafted with human cells or tissues to mimic the human immune system.These models are extensively utilized in the nonclinical assessment and development of various antibody drugs,acting as a conduit to clinical research.However,several challenges remain,including the limited lifespan of humanized mice,inadequate en-graftment of human cells,and the rudimentary nature of the immune environment in these models.The development of humanized immune system models in mice pre-sents both opportunities and challenges,potentially leading to new insights into the evolution and application of antibody therapeutics.展开更多
To treat cancer and inhibit its metastasis to the greatest extent,we proposed to develop an Au(III)agent to induce immunogenic cell death(ICD)and establish long-term immunity.To this end,we optimized a series of Au(II...To treat cancer and inhibit its metastasis to the greatest extent,we proposed to develop an Au(III)agent to induce immunogenic cell death(ICD)and establish long-term immunity.To this end,we optimized a series of Au(III)2-benzoylpyridine thiosemicarbazone complexes to obtain an Au(III)agent(5b)with excellent cytotoxicity to cancer.The results show that 5b effectively inhibits tumor growth and its metastasis in vivo.Interestingly,we revealed a new mechanism of 5b inhibiting tumor growth and metastasis:5b releases ICD-related damage-associated molecular patterns(DAMPs),such as calreticulin(CRT),ATP and high mobility group box 1(HMGB1)by inducing endoplasmic reticulum stress(ERS)and mitochondrial dysfunction,which then stimulated an antitumor CD8^(+)T cell response and Foxp^(3+)T cell depletion,thus establishing long-action antitumor immunity.展开更多
Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death(ICD),making it a promising strategy for clinical application....Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death(ICD),making it a promising strategy for clinical application.Alantolactone(A)was found to augment the anticancer efficacy of paclitaxel(P)at a molar ratio of 1:0.5(P:A)through induction of more potent ICD via modulation of STAT3 signaling pathways.Nano drug delivery systems can synergistically combine natural drugs with conventional chemotherapeutic agents,thereby enhancing multi-drug chemoimmunotherapy.To improve tumor targeting ability and bioavailability of hydrophobic drugs,an amphiphilic prodrug conjugate(HA-PTX)was chemically modified with paclitaxel(PTX)and hyaluronic acid(HA)as a backbone.Based on this concept,CD44-targeted nanodrugs(A@HAP NPs)were developed for co-delivery of A and P in colorectal cancer treatment,aiming to achieve synergistic toxicity-based chemo-immunotherapy.The uniform size and high drug loading capacity of A@HAP NPs facilitated their accumulation within tumors through enhanced permeability and retention effect as well as HA-mediated targeting,providing a solid foundation for subsequent synergistic therapy and immunoregulation.In vitro and in vivo studies demonstrated that A@HAP NPs exhibited potent cytotoxicity against tumor cells while also remodeling the immune-suppressive tumor microenvironment by promoting antigen presentation and inducing dendritic cell maturation,thus offering a novel approach for colorectal cancer chemoimmunotherapy.展开更多
Antibody humanization is critical to reduce immunogenicity and enhance efficacy in the preclinical phase of the development of therapeutic antibodies originated from animal models.Computational suggestions have long b...Antibody humanization is critical to reduce immunogenicity and enhance efficacy in the preclinical phase of the development of therapeutic antibodies originated from animal models.Computational suggestions have long been desired,but available tools focused on immunogenicity calculation of whole antibody sequences and sequence segments,missing the individual residue sites.This study introduces Site-specific Immunogenicity for Therapeutic Antibody(SITA),a novel computational framework that predicts B-cell immunogenicity score for not only the overall antibody,but also individual residues,based on a comprehensive set of amino acid descriptors characterizing physicochemical and spatial features for antibody structures.A transfer-learning-inspired framework was purposely adopted to overcome the scarcity of Antibody-Antibody structural complexes.On an independent testing dataset derived from 13 Antibody-Antibody structural complexes,SITA successfully predicted the epitope sites for Antibody-Antibody structures with a receiver operating characteristic(ROC)-area unver the ROC curve(AUC)of 0.85 and a precision-recall(PR)-AUC of 0.305 at the residue level.Furthermore,the SITA score can significantly distinguish immunogenicity levels of whole human antibodies,therapeutic antibodies and non-human-derived antibodies.More importantly,analysis of an additional 25 thera-peutic antibodies revealed that over 70%of them were detected with decreased immunogenicity after modification compared to their parent variants.Among these,nearly 66%antibodies successfully iden-tified actual modification sites from the top five sites with the highest SITA scores,suggesting the ability of SITA scores for guide the humanization of antibody.Overall,these findings highlight the potential of SITA in optimizing immunogenicity assessments during the process of therapeutic antibody design.展开更多
BACKGROUND Radiotherapy(RT)is a cornerstone of cancer treatment.Compared with conven-tional high-dose radiation,low-dose radiation(LDR)causes less damage to normal tissues while potentially modulating immune responses...BACKGROUND Radiotherapy(RT)is a cornerstone of cancer treatment.Compared with conven-tional high-dose radiation,low-dose radiation(LDR)causes less damage to normal tissues while potentially modulating immune responses and inhibiting tumor growth.LDR stimulates both innate and adaptive immunity,enhancing the activity of natural killer cells,dendritic cells,and T cells.However,the me-chanisms underlying the effects of LDR on the immune system remain unclear.AIM To explore the history,research hotspots,and emerging trends in immune response to LDR literature over the past two decades.METHODS Publications on immune responses to LDR were retrieved from the Web of Science Core Collection.Bibliometric tools,including CiteSpace and HistCite,were used to identify historical features,active topics,and emerging trends in this field.RESULTS Analysis of 1244 publications over the past two decades revealed a significant surge in research on immune responses to LDR,particularly in the last decade.Key journals such as INR J Radiat Biol,Cancers,and Radiat Res published pivotal studies.Citation networks identified key studies by authors like Twyman-Saint Victor C(2015)and Vanpouille-Box C(2017).Keyword analysis revealed hotspots such as ipilimumab,stereotactic body RT,and targeted therapy,possibly identifying future research directions.Temporal variations in keyword clusters and alluvial flow maps illustrate the evolution of research themes over time.CONCLUSION This bibliometric analysis provides valuable insights into the evolution of studies on responses to LDR,highlights research trends,and identifies emerging areas for further investigation.展开更多
African swine fever(ASF),caused by African swine fever virus(ASFV),is a highly contagious swine disease that has spread globally.Effective control strategies are not yet available.In this study,we prepared K205R mRNA,...African swine fever(ASF),caused by African swine fever virus(ASFV),is a highly contagious swine disease that has spread globally.Effective control strategies are not yet available.In this study,we prepared K205R mRNA,which was then formulated using Lipid Nanoparticle(LNP).The resulting K205R mRNA-LNP showed a particle size of approximately 86.27 nm and an mRNA encapsulation efficiency of 96.24%.Efficient expression of the K205R protein was confirmed in both HEK293T and PK15 cells.We further evaluated the immunogenicity of K205R mRNA-LNP in mice and pigs.All immunized animals developed significantly higher levels of IgG antibodies against K205R compared to the control group in the first week after the second immunization,with antibody titers reaching up to 105.Challenge experiments showed that K205R mRNA delayed the time of death.Our results suggested the successful implementation of the mRNA platform in the preparation and application of ASFV mRNA.展开更多
Ferroptosis in combination with immune therapy emerges as a promising approach for cancer therapy.Herein,dual-responsive metal-polyphenol coordinated nanomedicines were developed for pH/glutathione(GSH)-responsive syn...Ferroptosis in combination with immune therapy emerges as a promising approach for cancer therapy.Herein,dual-responsive metal-polyphenol coordinated nanomedicines were developed for pH/glutathione(GSH)-responsive synergistic ferroptosis and immunotherapy.Our innovative strategy involves the development of a manganese-polyphenol coordinated nanostructure,leveraging the biocompatibility of bovine serum albumin(BSA)as a template to encapsulate the anticancer drug sorafenib.The tumor microenvironment(pH/GSH)prompts the disassembly of MnO_(2)and epigallocatechin gallate(EGCG),thereby releases the anticancer payload.Concurrently,MnO_(2)acts to deplete intracellular GSH,which in turn suppresses glutathione peroxidase activity,leading to an accumulation of lipid peroxides with cell ferroptosis.Additionally,the release of Mn^(2+)ions bolster the cyclic guanosine monophosphlic acid(GMP)-adenosine monophosphlic acid(AMP)synthase-stimulator of interferon gene(cGAS-STING)pathway,which,in conjunction with the immunogenic cell death(ICD)effect induced by tumor cell apoptosis,significantly promotes dendritic cell(DC)maturation and enhances the presentation of tumor antigens.This successively ignites a robust innate and adaptive immune response.Both in vitro and in vivo experiments have demonstrated that the concurrent administration of ferroptosis-inducing and immune-stimulating therapies can significantly inhibit tumor growth.展开更多
The invasion of host cells by the henipavirus is facilitated through the interaction between viral attachment(G)and fusion(F)glycoproteins with receptors on the cell surface.Langya henipavirus(LayV)was newly identifie...The invasion of host cells by the henipavirus is facilitated through the interaction between viral attachment(G)and fusion(F)glycoproteins with receptors on the cell surface.Langya henipavirus(LayV)was newly identified in China in 2022.The G proteins of LayV and Mojiang virus(MojV)exhibit high amino acid homology(86%),while they are located in a unique evolutionary clade within the Henipavirus genus.In this study,the crystal structure of the LayV G protein was resolved at a 3.37Åresolution,revealing a head domain with sixβ-propeller-like domains distinct from other henipavirus G proteins,such as those of Nipah virus(NiV)and Hendra virus(HeV).Furthermore,the prominent loop in the center cavity of the LayV G protein showed unique structural features.In the ELISA and SPR assays,the LayV G protein was unable to bind to the existing henipavirus-neutralizing antibodies or the ephrin-B2 receptor.Immunogenicity studies in mice demonstrated robust antibody responses elicited by the LayV G protein.These antibodies exhibited strong reactivity against both LayV and MojV G proteins.However,only weak cross-reactivity was observed with other henipaviruses.Moreover,eight monoclonal antibodies targeting the LayV G protein were generated,two of which exhibited broad binding activity across different henipavirus G proteins.These findings underscore the need for tailored vaccines and therapeutics for LayV and related novel henipaviruses.展开更多
Scrub typhus is an acute undifferentiated febrile infectious disease transmitted by a chigger(genus Leptotrombidium)bite carrying Orientia(O.)tsutsugamushi,affecting millions of people annually while more than one bil...Scrub typhus is an acute undifferentiated febrile infectious disease transmitted by a chigger(genus Leptotrombidium)bite carrying Orientia(O.)tsutsugamushi,affecting millions of people annually while more than one billion people are susceptible.Endemic areas are expanding to Africa,Europe,Middle East,and South America which is concerning,as despite best efforts,there is no vaccine to combat the bacteria.There are now three species of Orientia and over 20 strains of O.tsutsugamushi.The past attempts to develop a vaccine have been ineffective as they confer homologous strain-specific immunity.Various immunogenic proteins of O.tsutsugamushi have been identified that interact with the extracellular matrix(fibronectin)or vMLL5 receptor and modify the cytoskeleton of non-phagocytic host cells,which aids in host cell adhesion and invasion.These highly conserved proteins involve type specific antigen 56(TSA56),47 kDa,OmpA,and autotransporter proteins(ScaA,ScaB and ScaC).TSA56 is the most immunogenic and contains four types of hypervariable regions.Out of all autotransporter proteins,ScaA provides the homologous strains specific immunity and when coupled with TSA56 it shows better protective immunity against heterologous strains.The review provides detailed insight into the potential immunogenic proteins of Orientia which can be utilized to develop the vaccine.Furthermore,studies focused on highly antigenic proteins will provide more insight into their roles in developing therapeutics and easy-to-handle rapid diagnostic kits.展开更多
Innovative anti-cancer therapies that activate the immune system show promise in combating cancers resistant to conventional treatments.Photodynamic therapy(PDT)is one such treatment,which not only directly eliminates...Innovative anti-cancer therapies that activate the immune system show promise in combating cancers resistant to conventional treatments.Photodynamic therapy(PDT)is one such treatment,which not only directly eliminates tumor cells but also functions as an in situ tumor vaccine by enhancing tumor immunogenicity and triggering anti-tumor immune responses through immunogenic cell death(ICD).However,the effectiveness of PDT in enhancing immune responses is influenced by factors,such as photosensitizers and the tumor microenvironment,particularly hypoxia.Current clinically used PDT heavily relies on oxygen(O_(2))availability and can be limited by tumor hypoxia.Additionally,the tumor immunosuppressive microenvironment induced by hypoxia affects the anti-tumor immunity of tumor-infiltrating effector T cells.Meanwhile,the immunosuppressive myeloid-lineage cells are recruited to the hypoxic tumor tissue and exhibit higher immunosuppressive capabilities under hypoxia conditions.Consequently,numerous strategies have been developed to modulate tumor hypoxia or to create hypoxia-compatible PDT,aiming to reduce the effects of tumor hypoxia on PDT-driven immunotherapy.This review investigates these strategies,including approaches to alleviate,exploit,and disregard tumor hypoxia within the context of PDT/immunotherapy.It also emphasizes the role of advanced nanomedicine and its benefits in these strategies,while outlining current challenges and future prospects in the field.展开更多
Melanoma,a common malignant skin tumor,faces challenges with multidrug resistance and high recurrence rates.Combining photodynamic therapy(PDT)and immunotherapy offers a promising personalized treatment approach.Howev...Melanoma,a common malignant skin tumor,faces challenges with multidrug resistance and high recurrence rates.Combining photodynamic therapy(PDT)and immunotherapy offers a promising personalized treatment approach.However,poor water solubility and significant side effects of photosensitizers and immune checkpoint inhibitors(ICIs)limit their application.Enhancing delivery efficiency while reducing adverse effects is crucial.Herein,we formulate BM@HSSC nanoparticles(NPs),which consist of a reduction-responsive hyaluronic acid(HA)backbone modified with photosensitizer chlorin e6(Ce6)and loaded with the programmed cell death-ligand 1(PD-L1)inhibitor BMS-1.This system synergistically integrates PDT,immunogenic cell death(ICD),and immunotherapy for melanoma treatment.BM@HSSC NPs target and accumulate at the tumor site via the CD44 receptor.The disulfide bonds(-S-S-)in the NPs react with high glutathione(GSH)concentrations in tumor cells,rapidly releasing Ce6 and BMS-1.Under 660 nm laser irradiation,BM@HSSC NPs generate cytotoxic reactive oxygen species(ROS),inducing cell apoptosis and triggering ICD via PDT damage-associated molecular patterns(DAMPs)and tumor-associated antigens(TAAs)released from ICD promote dendritic cell(DC)maturation,enhancing antigen presentation and activating cytotoxic T lymphocytes(CTLs).Meanwhile,BMS-1 blocks the programmed cell death-1(PD-1)/PD-L1 pathway,countering the immunosuppressive tumor microenvironment(iTME)and inhibiting tumor cell immune escape.This strategy amplifies antitumor immune responses by enhancing immunogenicity and synergizing with ICIs,resulting in robust antitumor efficacy.展开更多
Chemotherapeutic drugs such as doxorubicin(DOx)and oxaliplatin can induce immunogenic cell death(ICD)in tumor cells.Current studies have demonstrated that peptide-based drugs can also induce ICD in tumor cells.Unlike ...Chemotherapeutic drugs such as doxorubicin(DOx)and oxaliplatin can induce immunogenic cell death(ICD)in tumor cells.Current studies have demonstrated that peptide-based drugs can also induce ICD in tumor cells.Unlike small molecule drugs,peptide drugs not only enhance the effectiveness of immunotherapy but also offer the advantage of low biotoxicity[1].展开更多
The therapeutic efficacy and safety of mRNA-based drugs in immunological and nonimmunological applications are critically dependent on the translated protein yield,which requires precise modulation of mRNA expression ...The therapeutic efficacy and safety of mRNA-based drugs in immunological and nonimmunological applications are critically dependent on the translated protein yield,which requires precise modulation of mRNA expression kinetics.Among the factors influencing mRNA translation,immunogenicity and stability are pivotal in determining the longevity of protein production.Current optimization strategies have integrated(1)molecular engineering(e.g.,modified nucleotides),(2)advanced delivery systems(e.g.,lipid nanoparticles),and(3)adjuvant drug synergy.This review focuses on co-delivered adjuvant drugs and introduces the concept of"mRNA translation boosters"for the first time.mRNA translation boosters are classified as small-molecule compounds and macromolecular agents that improve translational fidelity through mechanisms including blockade of pattern recognition receptors,modulation of inflammatory cascades,facilitation of endosomal escape,and protection against enzymatic degradation.As clinically validated with COVID-19 mRNA vaccines,these boosters have now demonstrated expanded utility in gene editing therapies and protein replacement applications.This review addresses the immunological challenges encountered during mRNA transfection and translation while summarizing existing mRNA translation boosters that optimize protein expression kinetics.By establishing a mechanistic framework for booster selection and employment,this work provides translational guidance for advancing nucleic acid therapeutics towards their maximum clinical potential.展开更多
The Salmonella pathogenicity islands(SPIs) play crucial roles in the progression of Salmonella infection. In this study, we constructed an improved λ Red homologous recombination system to prepare single and triple d...The Salmonella pathogenicity islands(SPIs) play crucial roles in the progression of Salmonella infection. In this study, we constructed an improved λ Red homologous recombination system to prepare single and triple deletion mutants of 3 prominent SPIs(SPI-1, 2, and 3), aiming at the impact of deletion on morphology, carbon source metabolism, adhesion and invasion capacity, in vivo colonization, and immune efficacy in chicks. Our examination revealed that the surface of the single deletion mutants(SM6ΔSPI1, ΔSPI2, and ΔSPI3) exhibited a more rugged texture and appeared to be enveloped in a layer of transparent colloid, whereas the morphology of the triple deletion mutant(SM6ΔSPI1&2&3) remained unaltered when compared to the parent strain. The carbon metabolic spectrum of the SPI mutants underwent profound alterations, with a notable and statistically significant modification observed in 30 out of 95 carbon sources, primarily carbohydrates(17 out of 30). Furthermore, the adhesion capacity of the 4 mutants to Caco-2 cells was significantly reduced when compared to that of the parent strain. Moreover,the invasion capacity of mutants SM6ΔSPI1 and SM6ΔSPI1&2&3 exhibited a substantial decrease, while it was enhanced to varying degrees for SM6ΔSPI3 and SM6ΔSPI2. Importantly, none of the 4 mutants induced any clinical symptoms in the chicks. However, they did transiently colonize the spleen and liver. Notably, the SM6ΔSPI1&2&3mutant was rapidly cleared from both the spleen and liver within 8 days post-infection and no notable pathological changes were observed in the organs. Additionally, when challenged, the mutants immunized groups displayed a significant increase in antibody levels and alterations in the CD3+CD4+ and CD3+CD8+ subpopulations, and the levels of IL-4 and IFN-γ cytokines in the SM6ΔSPI1&2&3 immunized chicken serum surpassed those of other groups.In summary, the successful construction of the 4 SPI mutants lays the groundwork for further exploration into the pathogenic(including metabolic) mechanisms of SPIs and the development of safe and effective live attenuated Salmonella vaccines or carriers.展开更多
Objective:To evaluate the effectiveness of DTwP-HB-Hib vaccination dosing intervals at eight weeks versus four weeks on the immunogenicity of the diphtheria component.Methods:This is a randomized,open-label,parallel,c...Objective:To evaluate the effectiveness of DTwP-HB-Hib vaccination dosing intervals at eight weeks versus four weeks on the immunogenicity of the diphtheria component.Methods:This is a randomized,open-label,parallel,controlled trial on healthy two-month-old infants who had not received DTwP-HB-Hib vaccinations.The infants received three doses of the vaccine either at an eight-week or four-week interval.The anti-diphtheria toxoid IgG antibody levels before and after three doses of the vaccination were measured using ELISA.Results:Eighty infants were enrolled in this study,with 64 fulfilling the study requirements and randomized into two groups.All study participants exhibited uncertain protection against diphtheria antibodies(0.01-0.99 IU/mL)at the beginning of the study with an average of(0.023±0.009)IU/mL and(0.026±0.009)IU/mL in eight weeks and four weeks groups.Following three doses of the vaccination,the antibody level rose to an average of(1.320±0.234)IU/mL in the eight-week group and(1.307±0.186)IU/mL in the four-week group,with no statistically significant difference in the antibody levels observed(P=0.814).Conclusions:DTwP-HB-Hib vaccinations can be administered at an eight-week or four-week interval,as they do not significantly affect the level of anti-diphtheria IgG antibodies.展开更多
As PEGylated liposomes have witnessed remarkable advancements in drug delivery,their immunogenicity has emerged as a notable challenge.In this study,we discovered that a simple pre-injection of folic acid(FA)effective...As PEGylated liposomes have witnessed remarkable advancements in drug delivery,their immunogenicity has emerged as a notable challenge.In this study,we discovered that a simple pre-injection of folic acid(FA)effectively mitigated the immunogenicity of PEGylated liposomes and enhanced their in vivo performance by tolerating splenic marginal zone B cells.FA specifically inhibited the internalization of PEGylated liposomes by splenic marginal zone B cells,thereby reducing splenic lymphocyte proliferation and specific IgM secretion.This modulation alleviated Ig M-mediated accelerated blood clearance and adverse accumulation of the PEGylated liposomes in the skin.These findings provide new insights into the immunomodulatory effects of FA and promising avenues to enhance the efficacy and safety of PEGylated liposomal nanomedicines.展开更多
基金supported by the Natural Science Foundation of Hunan Province(2024JJ9285)the National Natural Science Foundation of China(62375289 and 62175262)+2 种基金the Hunan Provincial Natural Science Foundation of China(2023JJ40407)the Hunan Provincial Health High-Level Talent Scientific Research Project(R2023140)the Scientific Research Project of Hunan Provincial Department of Education(22B0081)。
文摘It remains a major challenge in phototherapeutics to achieve a high quantum yield of singlet oxygen generation and efficient photothermal conversion using a single near-infrared laser for immuno-phototherapy.To bridge this gap,we utilized an acceptor-donor-acceptor(A-DA)structured molecule,3,9-bis(2-methylene-((3-(1,1-dicyanomethylene)-6/7-methyl)-indanone))-5,5,11,11-tetrakis(4-hexylphenyl)-dithieno[2,3-d:2′,3′-d′]-s-indaceno[1,2-b:5,6-b′]-dithiophene(m-ITIC),and formulated it into nanoparticles(NPs)by assembling with distearoylphosphatidylethanolamine-polyethylene glycol-amino(DSPE-PEG-NH_(2)).At 688 and 768 nm,these NPs present significant near-infrared absorption and fluorescence.They simultaneously generate heat,O_(2)^(-•),and 1O_(2),with the^(1)O_(2)generation quantum yield of 56.8%and photothermal conversion efficiency(PCE)of 27.4%,enabling them excellent near-infrared(NIR)fluorescence imaging guided synergic photodynamic therapy(PDT)and photothermal therapy(PTT)capabilities.Importantly,this nanoplatform induces PANoptosis,a coordinated cell death program integrating pyroptosis,apoptosis,and necroptosis,in tumor cells,thereby amplifying immunogenic cell death(ICD)and enhancing antitumor immune responses.The combined effects lead to robust dendritic cell activation,macrophage polarization toward the M1 phenotype,elevated CD8^(+)T cell infiltration,and suppression of immunosuppressive Treg cells,resulting in significant tumor growth inhibition and prevention of lung metastasis in vivo.Furthermore,the therapeutic efficacy was validated in patient-derived tumor organoids,demonstrating translational potential.This study presents a novel strategy for NIR light-guided cancer phototherapy,wherein a single laser-activated nanoplatform simultaneously mediates efficient photothermal and photodynamic effects and induces PANoptosis driven ICD for synergistic cancer immunotherapy.
基金The National Natural Science Foundation of China(Nos.82473864,82400095)the Natural Science Foundation of Jiangsu Province(No.BK20231009)+1 种基金the National Center of Technology Innovation for Biopharmaceuticals(No.NCTIB2022HS01015)"Double First-Class"Initiative Program in China Pharmaceutical University and the National Innovation and Entrepreneurship Training Programfor Undergraduate(Nos.202310316007Z,2023103161133,2023103161333)are acknowledged for providing financial support for this work.
文摘Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell death ligand 1(PD-L1),which hijacked the antitumor immunity.In this study,we developed a reactive oxygen species(ROS)-responsive dihydroartemisinin(DHA)prodrug to facilitate the delivery of DOX via hydrophobic and electrostatic interactions.Upon internalization by tumor cells,the nanoparticles(NPs)preferentially accumulated in endoplasmic reticulum(ER),exacerbating ER stress and amplifying ICD to enhance tumor immunogenicity.Simultaneously,the oxidative intracellular environment trigged the degradation of NPs,releasing DHA,which downregulated PD-L1 by disrupting signal transducer and activator of transcription 3(STAT3)phosphorylation and inactivating the nuclear factor kappa-B(NF-κB)pathway.Consequently,the effective PD-L1 blockade and robust ICD response,synergistically inhibited breast cancer progression,significantly enhancing the chemo-immunotherapy efficacy of doxorubicin.
文摘Colorectal cancer(CRC)remains a major global health challenge,with high recurrence and mortality despite advances in surgery,chemotherapy,and immunotherapy.The study by He et al identifies a novel mechanism by which peroxiredoxin 1(Prdx1)inhibits CRC progression through induction of pyroptosis,a pro-inflammatory form of programmed cell death.Traditionally viewed as an intracellular antioxidant that protects tumors from oxidative stress,Prdx1 assu-mes a paradoxical immunogenic role when released extracellularly as a damageassociated molecular pattern.Using patient samples,recombinant protein assays,and murine xenograft models,the authors demonstrate that Prdx1 activates the NOD-,LRR-and pyrin domain-containing protein 3 inflammasome/caspase-1/gasdermin D pathway,triggering membrane pore formation,tumor cell lysis,and release of interleukin-1β/interleukin-18.This cascade not only halts tumor proliferation,invasion,and migration but may also enhance anti-tumor immune surveillance.The study’s strengths include rigorous mechanistic validation,clinical cohort data,inhibitor-based causal proof,and in vivo confirmation.However,questions remain regarding the upstream receptor for Prdx1,heterogeneity across CRC subtypes,and the balance between therapeutic benefit and inflammatory toxicity.By establishing Prdx1-induced pyroptosis as a driver of tumor suppression,this work advances a promising paradigm in CRC therapy,linking cell death to immune activation and pointing toward future biomarker-driven,pyroptosis-based interventions.
基金financially supported by the Natural Science Foundation of Jiangsu Province (No.BK20200709)the Natural Science Foundation of China (Nos.62288102,32201127 and 82270113)+2 种基金the Natural Science Foundation of Guangdong Province (No.2023A1515011386)the Natural Science Foundation of the Jiangsu Higher Education Institutes (No.20KJB430031)the startup fund from Nanjing Tech University,and Disciplinary Fund of School of Pharmaceutical Sciences (2024)。
文摘The field of nanomedicine has been revolutionized by the concept of immunogenic cell death(ICD)-enhanced cancer therapy,which holds immense promise for the efficient treatment of cancer.However,precise delivery of ICD inducer is severely hindered by complex biological barriers.How to design and build intelligent nanoplatform for adaptive and dynamic cancer therapy remains a big challenge.Herein,this article presents the design and preparation of CD44-targeting and ZIF-8 gated gold nanocage(Au@ZH) for programmed delivery of the 1,2-diaminocyclohexane-Pt(Ⅱ)(DACHPt) as ICD inducer.After actively targeting the CD44 on the surface of 4T1 tumor cell,this Pt-Au@ZH can be effectively endocytosed by the 4T1 cell and release the DACHPt in tumor acidic environment,resulting in ICD effect and superior antitumor efficacy both in vitro and in vivo in the presence of mild 808 nm laser irradiation.By integration of internal and external stimuli intelligently,this programmed nanoplatform is poised to become a cornerstone in the pursuit of effective and targeted cancer therapy in the foreseeable future.
基金supported by the Independent Research and Development Projects Foundation of Shanghai InnoStar Bio-Techology Co.,Ltd.(H23ZZYF01 and H24ZZYF01).
文摘Therapeutic antibodies are valued for their high specificity and selectivity in immu-notherapy.However,the potential toxicity they may elicit underscores the necessity of assessing their preclinical efficacy and safety using suitable animal models.In this context,we review the various categories and applications of humanized mice,which have been engrafted with human cells or tissues to mimic the human immune system.These models are extensively utilized in the nonclinical assessment and development of various antibody drugs,acting as a conduit to clinical research.However,several challenges remain,including the limited lifespan of humanized mice,inadequate en-graftment of human cells,and the rudimentary nature of the immune environment in these models.The development of humanized immune system models in mice pre-sents both opportunities and challenges,potentially leading to new insights into the evolution and application of antibody therapeutics.
基金supported by the Natural Science Foundation of Guangxi(No.2022GXNSFGA035003)the National Natural Science Foundation of China(No.22077021).
文摘To treat cancer and inhibit its metastasis to the greatest extent,we proposed to develop an Au(III)agent to induce immunogenic cell death(ICD)and establish long-term immunity.To this end,we optimized a series of Au(III)2-benzoylpyridine thiosemicarbazone complexes to obtain an Au(III)agent(5b)with excellent cytotoxicity to cancer.The results show that 5b effectively inhibits tumor growth and its metastasis in vivo.Interestingly,we revealed a new mechanism of 5b inhibiting tumor growth and metastasis:5b releases ICD-related damage-associated molecular patterns(DAMPs),such as calreticulin(CRT),ATP and high mobility group box 1(HMGB1)by inducing endoplasmic reticulum stress(ERS)and mitochondrial dysfunction,which then stimulated an antitumor CD8^(+)T cell response and Foxp^(3+)T cell depletion,thus establishing long-action antitumor immunity.
基金supported by Zhejiang Provincial Natural Science Foundation(LYY22H300001,LGF22H150016)Wenzhou Municipal Science and Technology Bureau(Y20210212)+2 种基金Application Basic Research Project of Liaoning Provincial Department of Science and Technology(2023JH2/101700072)Zhejiang Medical Doctor Association(YS2022-2-001)Health innovation talents program(Longfa Kou)from Health Commission of Zhejiang Province.
文摘Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death(ICD),making it a promising strategy for clinical application.Alantolactone(A)was found to augment the anticancer efficacy of paclitaxel(P)at a molar ratio of 1:0.5(P:A)through induction of more potent ICD via modulation of STAT3 signaling pathways.Nano drug delivery systems can synergistically combine natural drugs with conventional chemotherapeutic agents,thereby enhancing multi-drug chemoimmunotherapy.To improve tumor targeting ability and bioavailability of hydrophobic drugs,an amphiphilic prodrug conjugate(HA-PTX)was chemically modified with paclitaxel(PTX)and hyaluronic acid(HA)as a backbone.Based on this concept,CD44-targeted nanodrugs(A@HAP NPs)were developed for co-delivery of A and P in colorectal cancer treatment,aiming to achieve synergistic toxicity-based chemo-immunotherapy.The uniform size and high drug loading capacity of A@HAP NPs facilitated their accumulation within tumors through enhanced permeability and retention effect as well as HA-mediated targeting,providing a solid foundation for subsequent synergistic therapy and immunoregulation.In vitro and in vivo studies demonstrated that A@HAP NPs exhibited potent cytotoxicity against tumor cells while also remodeling the immune-suppressive tumor microenvironment by promoting antigen presentation and inducing dendritic cell maturation,thus offering a novel approach for colorectal cancer chemoimmunotherapy.
基金supported by funding from the National Key R&D Program of China(Grant Nos.:2023YFC3404000 and 2019YFA0905900)the National Natural Science Foundation of China(Grant Nos.:32370697 and 32070657)AI for the Science project of Fudan University,China(Project No.:XM06231724)。
文摘Antibody humanization is critical to reduce immunogenicity and enhance efficacy in the preclinical phase of the development of therapeutic antibodies originated from animal models.Computational suggestions have long been desired,but available tools focused on immunogenicity calculation of whole antibody sequences and sequence segments,missing the individual residue sites.This study introduces Site-specific Immunogenicity for Therapeutic Antibody(SITA),a novel computational framework that predicts B-cell immunogenicity score for not only the overall antibody,but also individual residues,based on a comprehensive set of amino acid descriptors characterizing physicochemical and spatial features for antibody structures.A transfer-learning-inspired framework was purposely adopted to overcome the scarcity of Antibody-Antibody structural complexes.On an independent testing dataset derived from 13 Antibody-Antibody structural complexes,SITA successfully predicted the epitope sites for Antibody-Antibody structures with a receiver operating characteristic(ROC)-area unver the ROC curve(AUC)of 0.85 and a precision-recall(PR)-AUC of 0.305 at the residue level.Furthermore,the SITA score can significantly distinguish immunogenicity levels of whole human antibodies,therapeutic antibodies and non-human-derived antibodies.More importantly,analysis of an additional 25 thera-peutic antibodies revealed that over 70%of them were detected with decreased immunogenicity after modification compared to their parent variants.Among these,nearly 66%antibodies successfully iden-tified actual modification sites from the top five sites with the highest SITA scores,suggesting the ability of SITA scores for guide the humanization of antibody.Overall,these findings highlight the potential of SITA in optimizing immunogenicity assessments during the process of therapeutic antibody design.
文摘BACKGROUND Radiotherapy(RT)is a cornerstone of cancer treatment.Compared with conven-tional high-dose radiation,low-dose radiation(LDR)causes less damage to normal tissues while potentially modulating immune responses and inhibiting tumor growth.LDR stimulates both innate and adaptive immunity,enhancing the activity of natural killer cells,dendritic cells,and T cells.However,the me-chanisms underlying the effects of LDR on the immune system remain unclear.AIM To explore the history,research hotspots,and emerging trends in immune response to LDR literature over the past two decades.METHODS Publications on immune responses to LDR were retrieved from the Web of Science Core Collection.Bibliometric tools,including CiteSpace and HistCite,were used to identify historical features,active topics,and emerging trends in this field.RESULTS Analysis of 1244 publications over the past two decades revealed a significant surge in research on immune responses to LDR,particularly in the last decade.Key journals such as INR J Radiat Biol,Cancers,and Radiat Res published pivotal studies.Citation networks identified key studies by authors like Twyman-Saint Victor C(2015)and Vanpouille-Box C(2017).Keyword analysis revealed hotspots such as ipilimumab,stereotactic body RT,and targeted therapy,possibly identifying future research directions.Temporal variations in keyword clusters and alluvial flow maps illustrate the evolution of research themes over time.CONCLUSION This bibliometric analysis provides valuable insights into the evolution of studies on responses to LDR,highlights research trends,and identifies emerging areas for further investigation.
基金funded by the National Key Research and Development Program of China(2022YFD1800500,2021YFD1801401,2023YFD1802600)the Central Public-interest Scientific Institution Basal Research Fund,China(Y2022PT11)the Shanghai Sailing Program,China(23YF1457400).
文摘African swine fever(ASF),caused by African swine fever virus(ASFV),is a highly contagious swine disease that has spread globally.Effective control strategies are not yet available.In this study,we prepared K205R mRNA,which was then formulated using Lipid Nanoparticle(LNP).The resulting K205R mRNA-LNP showed a particle size of approximately 86.27 nm and an mRNA encapsulation efficiency of 96.24%.Efficient expression of the K205R protein was confirmed in both HEK293T and PK15 cells.We further evaluated the immunogenicity of K205R mRNA-LNP in mice and pigs.All immunized animals developed significantly higher levels of IgG antibodies against K205R compared to the control group in the first week after the second immunization,with antibody titers reaching up to 105.Challenge experiments showed that K205R mRNA delayed the time of death.Our results suggested the successful implementation of the mRNA platform in the preparation and application of ASFV mRNA.
基金supported by the National Key R&D Program of China(No.2022YFC2304205)National Natural Science Foundation of China(Nos.51903062,52273128)the Plan on Enhancing Scientific Research in GMU(No.02-410-2405033).
文摘Ferroptosis in combination with immune therapy emerges as a promising approach for cancer therapy.Herein,dual-responsive metal-polyphenol coordinated nanomedicines were developed for pH/glutathione(GSH)-responsive synergistic ferroptosis and immunotherapy.Our innovative strategy involves the development of a manganese-polyphenol coordinated nanostructure,leveraging the biocompatibility of bovine serum albumin(BSA)as a template to encapsulate the anticancer drug sorafenib.The tumor microenvironment(pH/GSH)prompts the disassembly of MnO_(2)and epigallocatechin gallate(EGCG),thereby releases the anticancer payload.Concurrently,MnO_(2)acts to deplete intracellular GSH,which in turn suppresses glutathione peroxidase activity,leading to an accumulation of lipid peroxides with cell ferroptosis.Additionally,the release of Mn^(2+)ions bolster the cyclic guanosine monophosphlic acid(GMP)-adenosine monophosphlic acid(AMP)synthase-stimulator of interferon gene(cGAS-STING)pathway,which,in conjunction with the immunogenic cell death(ICD)effect induced by tumor cell apoptosis,significantly promotes dendritic cell(DC)maturation and enhances the presentation of tumor antigens.This successively ignites a robust innate and adaptive immune response.Both in vitro and in vivo experiments have demonstrated that the concurrent administration of ferroptosis-inducing and immune-stimulating therapies can significantly inhibit tumor growth.
基金the funding support from the National Natural Science Foundation of China(32200762).
文摘The invasion of host cells by the henipavirus is facilitated through the interaction between viral attachment(G)and fusion(F)glycoproteins with receptors on the cell surface.Langya henipavirus(LayV)was newly identified in China in 2022.The G proteins of LayV and Mojiang virus(MojV)exhibit high amino acid homology(86%),while they are located in a unique evolutionary clade within the Henipavirus genus.In this study,the crystal structure of the LayV G protein was resolved at a 3.37Åresolution,revealing a head domain with sixβ-propeller-like domains distinct from other henipavirus G proteins,such as those of Nipah virus(NiV)and Hendra virus(HeV).Furthermore,the prominent loop in the center cavity of the LayV G protein showed unique structural features.In the ELISA and SPR assays,the LayV G protein was unable to bind to the existing henipavirus-neutralizing antibodies or the ephrin-B2 receptor.Immunogenicity studies in mice demonstrated robust antibody responses elicited by the LayV G protein.These antibodies exhibited strong reactivity against both LayV and MojV G proteins.However,only weak cross-reactivity was observed with other henipaviruses.Moreover,eight monoclonal antibodies targeting the LayV G protein were generated,two of which exhibited broad binding activity across different henipavirus G proteins.These findings underscore the need for tailored vaccines and therapeutics for LayV and related novel henipaviruses.
基金funded by Department of Health Research,Government of India,New Delhi,India(grant number:YSS/2020/000116/PRCYSS).
文摘Scrub typhus is an acute undifferentiated febrile infectious disease transmitted by a chigger(genus Leptotrombidium)bite carrying Orientia(O.)tsutsugamushi,affecting millions of people annually while more than one billion people are susceptible.Endemic areas are expanding to Africa,Europe,Middle East,and South America which is concerning,as despite best efforts,there is no vaccine to combat the bacteria.There are now three species of Orientia and over 20 strains of O.tsutsugamushi.The past attempts to develop a vaccine have been ineffective as they confer homologous strain-specific immunity.Various immunogenic proteins of O.tsutsugamushi have been identified that interact with the extracellular matrix(fibronectin)or vMLL5 receptor and modify the cytoskeleton of non-phagocytic host cells,which aids in host cell adhesion and invasion.These highly conserved proteins involve type specific antigen 56(TSA56),47 kDa,OmpA,and autotransporter proteins(ScaA,ScaB and ScaC).TSA56 is the most immunogenic and contains four types of hypervariable regions.Out of all autotransporter proteins,ScaA provides the homologous strains specific immunity and when coupled with TSA56 it shows better protective immunity against heterologous strains.The review provides detailed insight into the potential immunogenic proteins of Orientia which can be utilized to develop the vaccine.Furthermore,studies focused on highly antigenic proteins will provide more insight into their roles in developing therapeutics and easy-to-handle rapid diagnostic kits.
基金supported by the Qin Chuangyuan Traditional Chinese Medicine(TCM)and Innovation Research and Development Project of Shaanxi Provincial Administration of TCM(No.2022-QCYZH-017)Natural Science Foundation of Zhejiang Province(No.LY24E030010)+5 种基金Natural Science Foundation of Shaanxi Province(Nos.2022JM183,2024JC-YBMS-272)the Shaanxi Fundamental Science Research Project for Chemistry&Biology(No.22JHQ072)Shaanxi Provincial Key R&D Program(No.2022SF-342HZ)the Fundamental Research Funds for the Central Universities(Nos.xzy012022037,xzy012023002)the Postdoctoral Science Foundation of Shaanxi Province(No.2023BSHYDZZ05)Foundation by Shaanxi Provincial Administration of TCM(No.2021-ZZ-JC032)。
文摘Innovative anti-cancer therapies that activate the immune system show promise in combating cancers resistant to conventional treatments.Photodynamic therapy(PDT)is one such treatment,which not only directly eliminates tumor cells but also functions as an in situ tumor vaccine by enhancing tumor immunogenicity and triggering anti-tumor immune responses through immunogenic cell death(ICD).However,the effectiveness of PDT in enhancing immune responses is influenced by factors,such as photosensitizers and the tumor microenvironment,particularly hypoxia.Current clinically used PDT heavily relies on oxygen(O_(2))availability and can be limited by tumor hypoxia.Additionally,the tumor immunosuppressive microenvironment induced by hypoxia affects the anti-tumor immunity of tumor-infiltrating effector T cells.Meanwhile,the immunosuppressive myeloid-lineage cells are recruited to the hypoxic tumor tissue and exhibit higher immunosuppressive capabilities under hypoxia conditions.Consequently,numerous strategies have been developed to modulate tumor hypoxia or to create hypoxia-compatible PDT,aiming to reduce the effects of tumor hypoxia on PDT-driven immunotherapy.This review investigates these strategies,including approaches to alleviate,exploit,and disregard tumor hypoxia within the context of PDT/immunotherapy.It also emphasizes the role of advanced nanomedicine and its benefits in these strategies,while outlining current challenges and future prospects in the field.
基金supported by the National Natural Sciences Foundation of China(Grant Nos.:31971308 and 81960769)Science and Technology Plan Project of Shihezi University,China(Grant No.:2023AB047)+2 种基金National S&T Major Project,China(Grant No.:2019ZX09301-147)Luzhou Science and Technology Plan,China(Grant No.:2018CDLZ-10)Sichuan Science and Technology Program,China(Grant No.:2021YFS0081).
文摘Melanoma,a common malignant skin tumor,faces challenges with multidrug resistance and high recurrence rates.Combining photodynamic therapy(PDT)and immunotherapy offers a promising personalized treatment approach.However,poor water solubility and significant side effects of photosensitizers and immune checkpoint inhibitors(ICIs)limit their application.Enhancing delivery efficiency while reducing adverse effects is crucial.Herein,we formulate BM@HSSC nanoparticles(NPs),which consist of a reduction-responsive hyaluronic acid(HA)backbone modified with photosensitizer chlorin e6(Ce6)and loaded with the programmed cell death-ligand 1(PD-L1)inhibitor BMS-1.This system synergistically integrates PDT,immunogenic cell death(ICD),and immunotherapy for melanoma treatment.BM@HSSC NPs target and accumulate at the tumor site via the CD44 receptor.The disulfide bonds(-S-S-)in the NPs react with high glutathione(GSH)concentrations in tumor cells,rapidly releasing Ce6 and BMS-1.Under 660 nm laser irradiation,BM@HSSC NPs generate cytotoxic reactive oxygen species(ROS),inducing cell apoptosis and triggering ICD via PDT damage-associated molecular patterns(DAMPs)and tumor-associated antigens(TAAs)released from ICD promote dendritic cell(DC)maturation,enhancing antigen presentation and activating cytotoxic T lymphocytes(CTLs).Meanwhile,BMS-1 blocks the programmed cell death-1(PD-1)/PD-L1 pathway,countering the immunosuppressive tumor microenvironment(iTME)and inhibiting tumor cell immune escape.This strategy amplifies antitumor immune responses by enhancing immunogenicity and synergizing with ICIs,resulting in robust antitumor efficacy.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82073975,81673563,81102762,82204715,and 82304743).
文摘Chemotherapeutic drugs such as doxorubicin(DOx)and oxaliplatin can induce immunogenic cell death(ICD)in tumor cells.Current studies have demonstrated that peptide-based drugs can also induce ICD in tumor cells.Unlike small molecule drugs,peptide drugs not only enhance the effectiveness of immunotherapy but also offer the advantage of low biotoxicity[1].
基金supported by the National Key R&D Program of China(2023YFC340200)National Natural Science Foundation of China(No.82404520,No.82273862,No.824B2106)+2 种基金the China Postdoctoral Science Foundation(2024M752834)the China National Postdoctoral Program for Innovative Talents(BX20230321)Leading Goose+“X”R&D research and development programme(2024C03088).
文摘The therapeutic efficacy and safety of mRNA-based drugs in immunological and nonimmunological applications are critically dependent on the translated protein yield,which requires precise modulation of mRNA expression kinetics.Among the factors influencing mRNA translation,immunogenicity and stability are pivotal in determining the longevity of protein production.Current optimization strategies have integrated(1)molecular engineering(e.g.,modified nucleotides),(2)advanced delivery systems(e.g.,lipid nanoparticles),and(3)adjuvant drug synergy.This review focuses on co-delivered adjuvant drugs and introduces the concept of"mRNA translation boosters"for the first time.mRNA translation boosters are classified as small-molecule compounds and macromolecular agents that improve translational fidelity through mechanisms including blockade of pattern recognition receptors,modulation of inflammatory cascades,facilitation of endosomal escape,and protection against enzymatic degradation.As clinically validated with COVID-19 mRNA vaccines,these boosters have now demonstrated expanded utility in gene editing therapies and protein replacement applications.This review addresses the immunological challenges encountered during mRNA transfection and translation while summarizing existing mRNA translation boosters that optimize protein expression kinetics.By establishing a mechanistic framework for booster selection and employment,this work provides translational guidance for advancing nucleic acid therapeutics towards their maximum clinical potential.
基金supported by the National KeyR&DProgramof China(2022YFF0710500)the National Natural Science Foundation of China(32172853 and 32373013)the Central Public-interest Scientific Institution Basal Research Fund,China(1610302022001).
文摘The Salmonella pathogenicity islands(SPIs) play crucial roles in the progression of Salmonella infection. In this study, we constructed an improved λ Red homologous recombination system to prepare single and triple deletion mutants of 3 prominent SPIs(SPI-1, 2, and 3), aiming at the impact of deletion on morphology, carbon source metabolism, adhesion and invasion capacity, in vivo colonization, and immune efficacy in chicks. Our examination revealed that the surface of the single deletion mutants(SM6ΔSPI1, ΔSPI2, and ΔSPI3) exhibited a more rugged texture and appeared to be enveloped in a layer of transparent colloid, whereas the morphology of the triple deletion mutant(SM6ΔSPI1&2&3) remained unaltered when compared to the parent strain. The carbon metabolic spectrum of the SPI mutants underwent profound alterations, with a notable and statistically significant modification observed in 30 out of 95 carbon sources, primarily carbohydrates(17 out of 30). Furthermore, the adhesion capacity of the 4 mutants to Caco-2 cells was significantly reduced when compared to that of the parent strain. Moreover,the invasion capacity of mutants SM6ΔSPI1 and SM6ΔSPI1&2&3 exhibited a substantial decrease, while it was enhanced to varying degrees for SM6ΔSPI3 and SM6ΔSPI2. Importantly, none of the 4 mutants induced any clinical symptoms in the chicks. However, they did transiently colonize the spleen and liver. Notably, the SM6ΔSPI1&2&3mutant was rapidly cleared from both the spleen and liver within 8 days post-infection and no notable pathological changes were observed in the organs. Additionally, when challenged, the mutants immunized groups displayed a significant increase in antibody levels and alterations in the CD3+CD4+ and CD3+CD8+ subpopulations, and the levels of IL-4 and IFN-γ cytokines in the SM6ΔSPI1&2&3 immunized chicken serum surpassed those of other groups.In summary, the successful construction of the 4 SPI mutants lays the groundwork for further exploration into the pathogenic(including metabolic) mechanisms of SPIs and the development of safe and effective live attenuated Salmonella vaccines or carriers.
文摘Objective:To evaluate the effectiveness of DTwP-HB-Hib vaccination dosing intervals at eight weeks versus four weeks on the immunogenicity of the diphtheria component.Methods:This is a randomized,open-label,parallel,controlled trial on healthy two-month-old infants who had not received DTwP-HB-Hib vaccinations.The infants received three doses of the vaccine either at an eight-week or four-week interval.The anti-diphtheria toxoid IgG antibody levels before and after three doses of the vaccination were measured using ELISA.Results:Eighty infants were enrolled in this study,with 64 fulfilling the study requirements and randomized into two groups.All study participants exhibited uncertain protection against diphtheria antibodies(0.01-0.99 IU/mL)at the beginning of the study with an average of(0.023±0.009)IU/mL and(0.026±0.009)IU/mL in eight weeks and four weeks groups.Following three doses of the vaccination,the antibody level rose to an average of(1.320±0.234)IU/mL in the eight-week group and(1.307±0.186)IU/mL in the four-week group,with no statistically significant difference in the antibody levels observed(P=0.814).Conclusions:DTwP-HB-Hib vaccinations can be administered at an eight-week or four-week interval,as they do not significantly affect the level of anti-diphtheria IgG antibodies.
基金supported by the National Natural Science Foundation of China(Nos.82373817 and 82003659)Shanghai Natural Science Foundation(No.23ZR1477500)Pudong Health Bureau of Shanghai(No.YC-2023-0401)。
文摘As PEGylated liposomes have witnessed remarkable advancements in drug delivery,their immunogenicity has emerged as a notable challenge.In this study,we discovered that a simple pre-injection of folic acid(FA)effectively mitigated the immunogenicity of PEGylated liposomes and enhanced their in vivo performance by tolerating splenic marginal zone B cells.FA specifically inhibited the internalization of PEGylated liposomes by splenic marginal zone B cells,thereby reducing splenic lymphocyte proliferation and specific IgM secretion.This modulation alleviated Ig M-mediated accelerated blood clearance and adverse accumulation of the PEGylated liposomes in the skin.These findings provide new insights into the immunomodulatory effects of FA and promising avenues to enhance the efficacy and safety of PEGylated liposomal nanomedicines.
