A series of biodegradable nanoparticle-based drug delivery systems have been designed utilizing poly(β-amino ester)-guanidine-phenylboronic acid(PBAE-G)polymers.In this study,a novel Lentinan-Functionalized PBAE-G-na...A series of biodegradable nanoparticle-based drug delivery systems have been designed utilizing poly(β-amino ester)-guanidine-phenylboronic acid(PBAE-G)polymers.In this study,a novel Lentinan-Functionalized PBAE-G-nanodiamond system was developed to carry ovalbumin(LNT-PBAE-G-ND@OVA).The impact of this drug delivery system on the activation and maturation of macrophages was then assessed.Furthermore,LNT-PBAE-G-ND@OVA induced potent antibody response and showed no obvious toxicity in vitro and in vivo.Moreover,treatment with LNT-PBAE-G-ND@OVA was sufficient to alter the expression of genes associated with the cGAS-STING pathway,and the LNT-PBAE-G-ND@OVA induced upregulation of costimulatory molecules.LNT-PBAE-G-ND@OVA treatment was sufficient to induce macrophage activation through a complex mechanism in which cyclic guanosine monophosphate-adenosine monophosphate(cGAMP)synthase(cGAS)-stimulator of interferon genes(STING)signaling plays an integral role.展开更多
Burkholderia pseudomallei is a causative agent of melioidosis that can infect humans and animals in endemic countries,specifically in Southeast Asia and tropical Australia.A fundamental component for the pathogenesis ...Burkholderia pseudomallei is a causative agent of melioidosis that can infect humans and animals in endemic countries,specifically in Southeast Asia and tropical Australia.A fundamental component for the pathogenesis of Burkholderia pseudomallei is the capability of the bacterium to enter,survive,replicate,and cause disease in a host cell by inducing the host cell fusion.Cell fusion results in multinucleated-giant cell formation,thus enabling the dissemination of Burkholderia pseudomallei intracellularly.cGAS reacts to Burkholderia pseudomallei infection by activating the cGAS-STING pathway and subsequently limiting host's aberrant cell division and cellular replication by inducing autophagic cell death.In this review,we discuss the host-pathogen interactions between the typeⅥsecretion system 5(T6SS-5)of Burkholderia pseudomallei and human cGAS pathway in melioidosis infections.Since T6SS-5 is a main virulent factor in Burkholderia pseudomallei and the c GAS pathway is vital for host immune response,elucidating their functions is important for better understanding the pathogenesis of Burkholderia pseudomallei.展开更多
Chemotherapeutic drugs,such as cisplatin and phenanthriplatin(PhenPt),as STING agonists to induce DNA damage and activate the cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)signaling pathway provide...Chemotherapeutic drugs,such as cisplatin and phenanthriplatin(PhenPt),as STING agonists to induce DNA damage and activate the cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)signaling pathway provides a potential strategy for clinical chemo-immunotherapy.However,treatment with Pt-based drugs leads to irreversible ectopia of phosphatidylserine(PS),a major component of the intracellular membrane,to the surface of the cancer cells by enzymes(Xkr8).Exposed PS can bind to immune cell receptors and inhibit the presentation of tumor antigens,leading to immunosuppression and attenuation of chemotherapy.Herein,we report a novel approach to enhance chemo-immunotherapy by constructing siRNA targeted Xkr8(siXkr8)-mediated tetrahedral framework nucleic acid nanogel structure concurrently loaded with PhenPt(siXkr8-FNG/PhenPt)for co-delivery of siRNA and Pt-based drugs.The results showed that siXkr8-FNG/PhenPt can not only be used as an efficient delivery carrier to deliver siXkr8,block the expression of Xkr8,reduce the exposure of PS on the cancer cells surface,but also act as an immune stimulant to activate cGAS-STING pathway,effectively improve the immunosuppressive microenvironment,produce antitumor immune response,and inhibit tumor growth and metastasis.Overall,this new delivery system is important for improving the effect of Pt-based drug chemotherapy,inducing immune enhancement and nucleic acid drug delivery.展开更多
Objective:To investigate the potential of Salvia miltiorrhiza water extract(SMWE)as a modulator of the c GAS-STING signaling pathway,which is implicated in the pathogenesis of immune and inflammatory disorders,and to ...Objective:To investigate the potential of Salvia miltiorrhiza water extract(SMWE)as a modulator of the c GAS-STING signaling pathway,which is implicated in the pathogenesis of immune and inflammatory disorders,and to elucidate its underlying mechanism of action through in vitro and in vivo experiments.Methods:The c GAS-STING signaling pathway was activated in bone marrow-derived macrophages(BMDMs),Tohoku hospital pediatrics-1(THP-1)cells,and peripheral blood mononuclear cells(PBMCs).The effect of SMWE on the expression of phosphorylated interferon regulatory factor 3(IRF3)and phosphorylated STING after aberrant activation of the c GAS-STING pathway was detected by immunoblotting.Subsequently,real-time quantitative PCR was performed to detect changes in the m RNA levels of interferon type I(IFN),interferon-stimulated genes and inflammatory factors.The effect of SMWE on STING oligomerisation and the interaction between STING,Tank Binding Kinase 1(TBK1)and IRF3 was investigated by immunoblotting.A model of acute liver injury(ALI)caused by lipopolysaccharide/Dgalactosamine(LPS/D-Ga IN)was used to test the effects of SMWE on inflammation mediated by the c GAS-STING signaling cascade.Results:SMWE significantly inhibited the phosphorylation of STING and IRF3,thereby suppressing the activation of the c GAS-STING signaling pathway.It also stopped the c GAS-STING pathway from working by stopping the production of type I interferons and interferon-stimulated genes,like interferonstimulated gene 15(ISG15)and C-X-C motif chemokine ligand 10(CXCL10).SMWE also reduced the production of pro-inflammatory cytokines,such as interleukin-6(IL-6)and tumour necrosis factor-a(TNF-a).SMWE also significantly improved ALI resulting from LPS/D-Ga IN by diminishing the hyperactivation of the c GAS-STING signalling pathway.Mechanistic analysis revealed that SMWE disrupted the interaction between STING and TBK1.Conclusion:SMWE is a potent modulator of aberrant activation of the c GAS-STING pathway and is able to prevent and treat LPS/D-Ga IN-induced ALI by inhibiting activation of the c GAS-STING pathway.展开更多
Gene therapy,harnessing the power of CRISPR-Cas9 and/or DNAzyme systems,stands as a pivotal approach in cancer therapy,enabling the meticulous manipulation of genes pivotal to tumorigenesis and immunity.However,the pu...Gene therapy,harnessing the power of CRISPR-Cas9 and/or DNAzyme systems,stands as a pivotal approach in cancer therapy,enabling the meticulous manipulation of genes pivotal to tumorigenesis and immunity.However,the pursuit of precise gene therapy encounters formidable hurdles.Herein,a near-infrared upconversion theranostic nanomachine is devised and tailors for CRISPR-Cas9/DNAzyme systems mediate precise gene therapy.An ingenious logic DNAzyme system consists of Chain 1(C_(1))/Chain 2(C_(2))and endogenous lncRNA is designed.We employ manganese modified upconversion nanoparticles for carrying ultraviolet-responsive C_(1)-PC linker-C_(2)(C_(2)P)chain and Cas9 ribonucleoprotein(RNP),with outermost coats with hyaluronic acid.Upon reaching tumor microenvironment(TME),the released Mn^(2+)ions orchestrate a trifecta:facilitating endosomal escape,activating cGAS-STING signaling,and enabling T1-magnetic resonance imaging.Under near-infrared irradiation,Cas9 RNP/C_(2)P complex dissociates,releasing Cas9 RNP into the nucleus to perform gene editing of Ptpn2,while C_(1)/C_(2) chains self-assemble with endogenous lncRNA to form a functional DNAzyme system,targeting PD-L1 mRNA for gene silencing.This strategy remodels the TME by activating cGAS-STING signaling and dual immune checkpoints blockade,thus realizing tumor elimination.Our theranostic nanomachine armed with the CRISPR-Cas9/DNAzyme logic systems,represents a resourceful and promising strategy for advancing cancer systemic immunotherapy and precise gene therapy.展开更多
文摘A series of biodegradable nanoparticle-based drug delivery systems have been designed utilizing poly(β-amino ester)-guanidine-phenylboronic acid(PBAE-G)polymers.In this study,a novel Lentinan-Functionalized PBAE-G-nanodiamond system was developed to carry ovalbumin(LNT-PBAE-G-ND@OVA).The impact of this drug delivery system on the activation and maturation of macrophages was then assessed.Furthermore,LNT-PBAE-G-ND@OVA induced potent antibody response and showed no obvious toxicity in vitro and in vivo.Moreover,treatment with LNT-PBAE-G-ND@OVA was sufficient to alter the expression of genes associated with the cGAS-STING pathway,and the LNT-PBAE-G-ND@OVA induced upregulation of costimulatory molecules.LNT-PBAE-G-ND@OVA treatment was sufficient to induce macrophage activation through a complex mechanism in which cyclic guanosine monophosphate-adenosine monophosphate(cGAMP)synthase(cGAS)-stimulator of interferon genes(STING)signaling plays an integral role.
基金supported by the Ministry of Higher Education Malaysia for Fundamental Research Grant Scheme with Project Code:FRGS/1/2019/SKK11/USM/02/5。
文摘Burkholderia pseudomallei is a causative agent of melioidosis that can infect humans and animals in endemic countries,specifically in Southeast Asia and tropical Australia.A fundamental component for the pathogenesis of Burkholderia pseudomallei is the capability of the bacterium to enter,survive,replicate,and cause disease in a host cell by inducing the host cell fusion.Cell fusion results in multinucleated-giant cell formation,thus enabling the dissemination of Burkholderia pseudomallei intracellularly.cGAS reacts to Burkholderia pseudomallei infection by activating the cGAS-STING pathway and subsequently limiting host's aberrant cell division and cellular replication by inducing autophagic cell death.In this review,we discuss the host-pathogen interactions between the typeⅥsecretion system 5(T6SS-5)of Burkholderia pseudomallei and human cGAS pathway in melioidosis infections.Since T6SS-5 is a main virulent factor in Burkholderia pseudomallei and the c GAS pathway is vital for host immune response,elucidating their functions is important for better understanding the pathogenesis of Burkholderia pseudomallei.
基金supported by the Natural Science Foundation of Shandong province(ZR2023QH204 and ZR2024ME024,China).
文摘Chemotherapeutic drugs,such as cisplatin and phenanthriplatin(PhenPt),as STING agonists to induce DNA damage and activate the cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)signaling pathway provides a potential strategy for clinical chemo-immunotherapy.However,treatment with Pt-based drugs leads to irreversible ectopia of phosphatidylserine(PS),a major component of the intracellular membrane,to the surface of the cancer cells by enzymes(Xkr8).Exposed PS can bind to immune cell receptors and inhibit the presentation of tumor antigens,leading to immunosuppression and attenuation of chemotherapy.Herein,we report a novel approach to enhance chemo-immunotherapy by constructing siRNA targeted Xkr8(siXkr8)-mediated tetrahedral framework nucleic acid nanogel structure concurrently loaded with PhenPt(siXkr8-FNG/PhenPt)for co-delivery of siRNA and Pt-based drugs.The results showed that siXkr8-FNG/PhenPt can not only be used as an efficient delivery carrier to deliver siXkr8,block the expression of Xkr8,reduce the exposure of PS on the cancer cells surface,but also act as an immune stimulant to activate cGAS-STING pathway,effectively improve the immunosuppressive microenvironment,produce antitumor immune response,and inhibit tumor growth and metastasis.Overall,this new delivery system is important for improving the effect of Pt-based drug chemotherapy,inducing immune enhancement and nucleic acid drug delivery.
基金funded by Project supported by the Natural Science Foundation of Beijing,China(No.7232321)the National Natural Science Foundation of China under the Joint Fund Key Project(No.U23A20519)。
文摘Objective:To investigate the potential of Salvia miltiorrhiza water extract(SMWE)as a modulator of the c GAS-STING signaling pathway,which is implicated in the pathogenesis of immune and inflammatory disorders,and to elucidate its underlying mechanism of action through in vitro and in vivo experiments.Methods:The c GAS-STING signaling pathway was activated in bone marrow-derived macrophages(BMDMs),Tohoku hospital pediatrics-1(THP-1)cells,and peripheral blood mononuclear cells(PBMCs).The effect of SMWE on the expression of phosphorylated interferon regulatory factor 3(IRF3)and phosphorylated STING after aberrant activation of the c GAS-STING pathway was detected by immunoblotting.Subsequently,real-time quantitative PCR was performed to detect changes in the m RNA levels of interferon type I(IFN),interferon-stimulated genes and inflammatory factors.The effect of SMWE on STING oligomerisation and the interaction between STING,Tank Binding Kinase 1(TBK1)and IRF3 was investigated by immunoblotting.A model of acute liver injury(ALI)caused by lipopolysaccharide/Dgalactosamine(LPS/D-Ga IN)was used to test the effects of SMWE on inflammation mediated by the c GAS-STING signaling cascade.Results:SMWE significantly inhibited the phosphorylation of STING and IRF3,thereby suppressing the activation of the c GAS-STING signaling pathway.It also stopped the c GAS-STING pathway from working by stopping the production of type I interferons and interferon-stimulated genes,like interferonstimulated gene 15(ISG15)and C-X-C motif chemokine ligand 10(CXCL10).SMWE also reduced the production of pro-inflammatory cytokines,such as interleukin-6(IL-6)and tumour necrosis factor-a(TNF-a).SMWE also significantly improved ALI resulting from LPS/D-Ga IN by diminishing the hyperactivation of the c GAS-STING signalling pathway.Mechanistic analysis revealed that SMWE disrupted the interaction between STING and TBK1.Conclusion:SMWE is a potent modulator of aberrant activation of the c GAS-STING pathway and is able to prevent and treat LPS/D-Ga IN-induced ALI by inhibiting activation of the c GAS-STING pathway.
基金supported by the National Natural Science Foundation of China(82302365 and 32471475)Supporting project of Nanjing University of Chinese Medicine to NSFC(XPT82302365,China)+4 种基金Yangtze River Delta Joint Sci-tech Innovation and Research Projects(2023CSJZN0600,China)the Innovation Projects of State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture(NZYSKL240201,China)Jiangsu Key Discipline Construction Fund of the 14th Five-Year Plan(Biology)Natural Science Foundation of Hubei Province(No.2024AFB517,China)Natural Science Foundation of the Higher Education Institutions of Jiangsu Province(23KJB310015,China).
文摘Gene therapy,harnessing the power of CRISPR-Cas9 and/or DNAzyme systems,stands as a pivotal approach in cancer therapy,enabling the meticulous manipulation of genes pivotal to tumorigenesis and immunity.However,the pursuit of precise gene therapy encounters formidable hurdles.Herein,a near-infrared upconversion theranostic nanomachine is devised and tailors for CRISPR-Cas9/DNAzyme systems mediate precise gene therapy.An ingenious logic DNAzyme system consists of Chain 1(C_(1))/Chain 2(C_(2))and endogenous lncRNA is designed.We employ manganese modified upconversion nanoparticles for carrying ultraviolet-responsive C_(1)-PC linker-C_(2)(C_(2)P)chain and Cas9 ribonucleoprotein(RNP),with outermost coats with hyaluronic acid.Upon reaching tumor microenvironment(TME),the released Mn^(2+)ions orchestrate a trifecta:facilitating endosomal escape,activating cGAS-STING signaling,and enabling T1-magnetic resonance imaging.Under near-infrared irradiation,Cas9 RNP/C_(2)P complex dissociates,releasing Cas9 RNP into the nucleus to perform gene editing of Ptpn2,while C_(1)/C_(2) chains self-assemble with endogenous lncRNA to form a functional DNAzyme system,targeting PD-L1 mRNA for gene silencing.This strategy remodels the TME by activating cGAS-STING signaling and dual immune checkpoints blockade,thus realizing tumor elimination.Our theranostic nanomachine armed with the CRISPR-Cas9/DNAzyme logic systems,represents a resourceful and promising strategy for advancing cancer systemic immunotherapy and precise gene therapy.
