The inherent low immunogenicity and immunosuppressive metabolism of solid tumors significantly attenuate the immunotherapeutic effect and restrict the immune response.In this work,an endoplasmic reticulum(ER)targeting...The inherent low immunogenicity and immunosuppressive metabolism of solid tumors significantly attenuate the immunotherapeutic effect and restrict the immune response.In this work,an endoplasmic reticulum(ER)targeting photodynamic oxidizer(designated as PhotoOx)is fabricated to boost the antitumor immunity by integrating photodynamic therapy(PDT)induced immunogenic cell death(ICD)with indoleamine 2,3-dioxygenase 1(IDO1)inhibition.Among which,an ER targeting photosensitizer-peptide conjugate called PhotoPe is rationally designed for optimal functionality and amphiphilicity,which could self-assemble into nano-micelles co-delivering chlorin e6 and NLG919.PhotoOx exhibits a good stability to enable ER targeting drug delivery,which could induce ER rupture to intensify PDT induced ICD and release damage associated molecular patterns(DAMPs).Furthermore,PhotoOx could effectively initiate immunological cascades,leading to the suppression of regulatory T cells(Tregs)and activation of CD8^(+)T cells when combines with IDO inhibition.Furthermore,the multi-synergistic effects of PhotoOx activate a robust systemic anti-tumor immune response,resulting in the eradication of lung and liver metastases.Such a medication strategy might inspire the rational design of biomedicine for precise drug delivery,which also provides a sophisticated mechanism for addressing the challenges of solid tumor treatment.展开更多
The quality and safety of agricultural products are closely related to human health.They also play an important role in enhancing the competitiveness of China’s agricultural products market,shaping the brand value of...The quality and safety of agricultural products are closely related to human health.They also play an important role in enhancing the competitiveness of China’s agricultural products market,shaping the brand value of agricultural products,and promoting the high-quality development of agriculture.At present,there are still a series of problems in the quality and safety of agricultural products.Relevant departments of the state should strengthen guidance and supervision,improve the quality and safety awareness and management level of agricultural product producers,and encourage producers to participate in the product certification and process certification of agricultural products.In addition,it is necessary to take effective control measures in accordance with the certification requirements,to evaluate their effectiveness,so as to improve the quality and safety of agricultural products and promote the high-quality development of China’s agriculture.展开更多
The anti-oxidative characteristic and immunosuppressive microenvironment contribute to a high resistance of tumor to many treatments.In this work,a glutathione(GSH)-responsive metal-coordinated oxidative stress amplif...The anti-oxidative characteristic and immunosuppressive microenvironment contribute to a high resistance of tumor to many treatments.In this work,a glutathione(GSH)-responsive metal-coordinated oxidative stress amplifier(designated as Cu PA)is fabricated to suppress tumor growth through elevating the cellular level of reactive oxygen species(ROS)and eliminating M2 macrophages.Among which,cooper ion(Cu^(2+))is capable of coordinating with thioredoxin(Trx)inhibitor of PX-12 and signal transducer and activator of transcription 6(STAT6)inhibitor of AS1517499 with the assistance of distearoyl phosphoethanolamine-PEG2000(DSPE-PEG2000),which can extensively increase the stability to enhance drug delivery in vitro and in vivo.Furthermore,CuPA can upregulate intracellular ROS to cause tumor cell death through restraining Trx and degrading GSH.Also,Cu PA-mediated STAT6 inhibition results in the elimination of M2 macrophage to reverse the immunosuppressive tumor microenvironment.Finally,the elevated oxidative stress and increased immune activation amplify the synergistic antitumor effect without causing obvious side effect.This work provides a new sight for synergistic tumor suppression through chemo-immunotherapy in consideration of the complex resistant tumor microenvironment.展开更多
The life-threatening colorectal cancer exhibits multilevel immunosuppressive characteristics,including low immunogenicity,abnormal cellular metabolism,and acidic immunosuppressive microenvironment.In this work,multi-s...The life-threatening colorectal cancer exhibits multilevel immunosuppressive characteristics,including low immunogenicity,abnormal cellular metabolism,and acidic immunosuppressive microenvironment.In this work,multi-synergistic chemotherapeutic drug assemblies are fabricated to activate colorectal cancer immunotherapy by modulating the multilevel immunosuppressive characteristics.Without any drug excipients,the glycolysis inhibitor of lonidamine(LON),indoleamine 2,3-dioxygenase 1(IDO-1)inhibitor of NLG919(NLG),and the photosensitizer of chlorine e6 could self-assemble into drug assemblies(LNC)with uniform nano-size distribution and increased drug stability.Moreover,LNC could also promote cellular uptake and enhance drug penetration to enable efficient drug co-delivery.Especially,the photodynamic therapy(PDT)of LNC could disrupt tumor cells to release tumor-associated antigens,thus efficiently suppressing primary tumor growth and improving tumor immunogenicity.Meanwhile,LNC could also reduce the activity of IDO-1 and attenuate the glycolysis metabolism,thereby reversing the multilevel immunosuppressive characteristics to promote T cell activation.Benefiting from the multi-synergistic effects,LNC efficiently eradicates the primary tumor growth and also activates systemic antitumor immunity for metastatic tumor inhibition.Such a simple formulation but a multi-synergistic strategy may accelerate the development of translational nanomedicine for colorectal cancer immunotherapy by using small molecular drug combinations.展开更多
基金supported by the National Natural Science Foundation of China(No.32371394)the National Key R&D Program of China(No.2021YFD1800600)+3 种基金the Special Projects in Key Areas of Colleges and Universities in Guangdong Province(No.2022ZDZX2046)the Open Project of State Key Laboratory of Respiratory Disease(No.SKLRD-OP-202502)the Postdoctoral Fellowship Program of CPSF(No.GZC20230619)Postdoctoral startup funding of Guangzhou Medical University(No.Q0301–130)。
文摘The inherent low immunogenicity and immunosuppressive metabolism of solid tumors significantly attenuate the immunotherapeutic effect and restrict the immune response.In this work,an endoplasmic reticulum(ER)targeting photodynamic oxidizer(designated as PhotoOx)is fabricated to boost the antitumor immunity by integrating photodynamic therapy(PDT)induced immunogenic cell death(ICD)with indoleamine 2,3-dioxygenase 1(IDO1)inhibition.Among which,an ER targeting photosensitizer-peptide conjugate called PhotoPe is rationally designed for optimal functionality and amphiphilicity,which could self-assemble into nano-micelles co-delivering chlorin e6 and NLG919.PhotoOx exhibits a good stability to enable ER targeting drug delivery,which could induce ER rupture to intensify PDT induced ICD and release damage associated molecular patterns(DAMPs).Furthermore,PhotoOx could effectively initiate immunological cascades,leading to the suppression of regulatory T cells(Tregs)and activation of CD8^(+)T cells when combines with IDO inhibition.Furthermore,the multi-synergistic effects of PhotoOx activate a robust systemic anti-tumor immune response,resulting in the eradication of lung and liver metastases.Such a medication strategy might inspire the rational design of biomedicine for precise drug delivery,which also provides a sophisticated mechanism for addressing the challenges of solid tumor treatment.
文摘The quality and safety of agricultural products are closely related to human health.They also play an important role in enhancing the competitiveness of China’s agricultural products market,shaping the brand value of agricultural products,and promoting the high-quality development of agriculture.At present,there are still a series of problems in the quality and safety of agricultural products.Relevant departments of the state should strengthen guidance and supervision,improve the quality and safety awareness and management level of agricultural product producers,and encourage producers to participate in the product certification and process certification of agricultural products.In addition,it is necessary to take effective control measures in accordance with the certification requirements,to evaluate their effectiveness,so as to improve the quality and safety of agricultural products and promote the high-quality development of China’s agriculture.
基金financial support of National Key R&D Program of China(No.2021YFD1800600)the National Natural Science Foundation of China(No.32371394)+1 种基金the Guangdong Basic and Applied Basic Research Foundation(No.2021B1515020043)the Special Projects in Key Areas of Colleges and Universities in Guangdong Province(No.2022ZDZX2046)。
文摘The anti-oxidative characteristic and immunosuppressive microenvironment contribute to a high resistance of tumor to many treatments.In this work,a glutathione(GSH)-responsive metal-coordinated oxidative stress amplifier(designated as Cu PA)is fabricated to suppress tumor growth through elevating the cellular level of reactive oxygen species(ROS)and eliminating M2 macrophages.Among which,cooper ion(Cu^(2+))is capable of coordinating with thioredoxin(Trx)inhibitor of PX-12 and signal transducer and activator of transcription 6(STAT6)inhibitor of AS1517499 with the assistance of distearoyl phosphoethanolamine-PEG2000(DSPE-PEG2000),which can extensively increase the stability to enhance drug delivery in vitro and in vivo.Furthermore,CuPA can upregulate intracellular ROS to cause tumor cell death through restraining Trx and degrading GSH.Also,Cu PA-mediated STAT6 inhibition results in the elimination of M2 macrophage to reverse the immunosuppressive tumor microenvironment.Finally,the elevated oxidative stress and increased immune activation amplify the synergistic antitumor effect without causing obvious side effect.This work provides a new sight for synergistic tumor suppression through chemo-immunotherapy in consideration of the complex resistant tumor microenvironment.
基金Basic and Applied Basic Research Foundation of Guangdong Province,Grant/Award Numbers:2021B1515020043,2023A1515012628National Natural Science Foundation of China,Grant/Award Numbers:32371394,82302355+1 种基金Science and Technology Program of Guangzhou,Grant/Award Numbers:2024A04J3324,2024A03J0078National Key Research and Development Program of China,Grant/Award Numbers:2021YFD1800600,2022YFE0209700。
文摘The life-threatening colorectal cancer exhibits multilevel immunosuppressive characteristics,including low immunogenicity,abnormal cellular metabolism,and acidic immunosuppressive microenvironment.In this work,multi-synergistic chemotherapeutic drug assemblies are fabricated to activate colorectal cancer immunotherapy by modulating the multilevel immunosuppressive characteristics.Without any drug excipients,the glycolysis inhibitor of lonidamine(LON),indoleamine 2,3-dioxygenase 1(IDO-1)inhibitor of NLG919(NLG),and the photosensitizer of chlorine e6 could self-assemble into drug assemblies(LNC)with uniform nano-size distribution and increased drug stability.Moreover,LNC could also promote cellular uptake and enhance drug penetration to enable efficient drug co-delivery.Especially,the photodynamic therapy(PDT)of LNC could disrupt tumor cells to release tumor-associated antigens,thus efficiently suppressing primary tumor growth and improving tumor immunogenicity.Meanwhile,LNC could also reduce the activity of IDO-1 and attenuate the glycolysis metabolism,thereby reversing the multilevel immunosuppressive characteristics to promote T cell activation.Benefiting from the multi-synergistic effects,LNC efficiently eradicates the primary tumor growth and also activates systemic antitumor immunity for metastatic tumor inhibition.Such a simple formulation but a multi-synergistic strategy may accelerate the development of translational nanomedicine for colorectal cancer immunotherapy by using small molecular drug combinations.
