Prostate cancer is an epithelial malignancy with a high incidence among elderly men.Photochemistry-based dye photodrugs(known as photosensitizers)offer a promising clinical approach for treating tumors.These agents wo...Prostate cancer is an epithelial malignancy with a high incidence among elderly men.Photochemistry-based dye photodrugs(known as photosensitizers)offer a promising clinical approach for treating tumors.These agents work by inducing immunogenic cell death(ICD),which activates antitumor immune response.This approach is favored owing to its minimal invasiveness,low toxicity,and high efficiency.However,the immunosuppressive microenvironment of characteristics of“cold”tumors significantly restricts the clinical efficacy of photodrugs.Developing an advanced nanocarrier system to deliver photodrugs and immune agonists for efficient drug delivery to tumor lesion sites and to reshape the immunosuppressive microenvironment is crucial in clinical practice.Therefore,in this study,we designed an integrin-targeted,activatable nano photodrug co-assembly with an immune agonist(RPST@IMQ)for enhancing photoimmunotherapy in prostate cancer via the reprogramming of tumor-associated macrophages.The active-targeted nanosystem enhanced the dosage of photodrug at the lesion site through systemic administration.High doses of glutathione at the tumor site cleaved the disulfide bonds of RPST@IMQ,releasing the photodrug and the immune agonist imiquimod(IMQ).Under photoirradiation,the photodrug generated significant doses of singlet oxygen to eliminate tumor cells,thereby inducing ICD to activate antitumor immune responses.Simultaneously,the released IMQ reprograms immunosuppressive M2-type tumor-associated macrophages(TAMs)in the tumor microenvironment into M1-type TAMs with tumor-killing capabilities,thereby converting“cold”tumors into“hot”tumors.This conversion enhances the therapeutic efficacy against primary and distant tumors in vivo.This study offers new insights into the development of innovative,smart,activatable nano photodrugs to enhance anticancer therapeutic outcomes.展开更多
Various obstacles[poor tissue penetration,hypoxic tumor microenvironment,and reactive oxygen species(ROS)production quenching due to aggregation]obstruct imaging-guided high-efficiency phototherapy targeting tumors.He...Various obstacles[poor tissue penetration,hypoxic tumor microenvironment,and reactive oxygen species(ROS)production quenching due to aggregation]obstruct imaging-guided high-efficiency phototherapy targeting tumors.Herein,nanophthalocyanine(ZnPcN4-TF)is elaborately designed based on a synthetic phthalocyanine derivative(ZnPcN4)and nonimmunogenic transferrin(TF)through multiple noncovalent interactions for photoacoustic(PA)imaging-guided phototherapy.By conjugating electron-rich amino groups effectively suppressed fluorescence and ROS generation due to the strong photoinduced electron transfer effect,ZnPcN4 became an ideal photothermal and PA imaging agent.ZnPcN4-TF not only effectively targeted tumor sites and accumulated there,but also,surprisingly,facilitated the enhancement of ROS production via a type I process in an aggregate compared to ZnPcN4 itself,potentially due to accelerated electron transfer.Simultaneously,ZnPcN4-TF had a substantially more powerful photothermal effect than ZnPcN4 itself.Thus,this design effectively overcomes the obstacles to photodynamic therapy(aggregation-related ROS generation quenching in a hypoxic environment).Furthermore,PA imaging solves the tissue penetration challenge in optical imaging.This study provides a broader base for designing novel photosensitizers to improve phototherapy under hypoxia.展开更多
Diverse connective tissues exhibit hierarchical anisotropic structures that intricately regulate homeostasis and tissue functions for dynamic immune response modulation.In this study,remotely manipulable hierarchical ...Diverse connective tissues exhibit hierarchical anisotropic structures that intricately regulate homeostasis and tissue functions for dynamic immune response modulation.In this study,remotely manipulable hierarchical nanostructures are tailored to exhibit multi-scale ligand anisotropy.Hierarchical nanostructure construction involves coupling liganded nanoscale isotropic/anisotropic Au(comparable to few integrin molecules-scale)to the surface of microscale isotropic/anisotropic magnetic Fe3O4(comparable to integrin cluster-scale)and then elastically tethering them to a substrate.Systematic independent tailoring of nanoscale or microscale ligand isotropy versus anisotropy in four different hierarchical nanostructures with constant liganded surface area demonstrates similar levels of integrin molecule bridging and macrophage adhesion on the nanoscale ligand isotropy versus anisotropy.Conversely,the levels of integrin cluster bridging across hierarchical nanostructures and macrophage adhesion are significantly promoted by microscale ligand anisotropy compared with microscale ligand isotropy.Furthermore,microscale ligand anisotropy dominantly activates the host macrophage adhesion and pro-regenerative M2 polarization in vivo over the nanoscale ligand anisotropy,which can be cyclically reversed by substrate-proximate versus substrate-distant magnetic manipulation.This unprecedented scale-specific regulation of cells can be diversified by unlimited tuning of the scale,anisotropy,dimension,shape,and magnetism of hierarchical structures to decipher scale-specific dynamic cell-material interactions to advance immunoengineering strategies.展开更多
In contrast to traditional treatment methods,such as surgery,chemotherapy,and radiotherapy,photodynamic therapy(PDT)is a unique non-invasive modality with accurate temporal and spatial control,minimal side effects,and...In contrast to traditional treatment methods,such as surgery,chemotherapy,and radiotherapy,photodynamic therapy(PDT)is a unique non-invasive modality with accurate temporal and spatial control,minimal side effects,and negligible drug resistance,demonstrating substantial promise in the realm of cancer treatment[1,2].展开更多
In light of the burgeoning successes of cancer immunotherapy,glioblastoma(GBM)remains refractory due to an immunosuppressive microenvironment originating from its molecular heterogeneity.Thus,identifying promising the...In light of the burgeoning successes of cancer immunotherapy,glioblastoma(GBM)remains refractory due to an immunosuppressive microenvironment originating from its molecular heterogeneity.Thus,identifying promising therapeutic targets for treating GBM and discovering methodologies to effectively regulate them is still a tremendous challenge.Here we describe photodynamic protein tyrosine phosphatase 1B(PTP1B)proteolysis mediated by a proteolysis-targeting chimera(PROTAC)nanoassembly.The PTP1B-targeting PROTAC is conjugated with a photosensitizer via a cathepsin B(Cat B)-cleavable peptide,which spontaneously forms nanoassemblies due to intermolecularπ-πstack-ing interactions.In GBM models,PROTAC nanoassemblies significantly accumulate in the tumor region across the disrupted blood-brain barrier(BBB),triggering a burst release of the photosensitizer and active PROTAC by Cat B-mediated enzymatic cleavage.Upon laser irradiation,photodynamic therapy(PDT)synergizes with PROTAC-mediated PTP1B proteolysis to induce potent immunogenic cell death(ICD)in tumor cells.Subsequently,persistent PTP1B degradation by nanoassemblies in Cat B-overexpressed intratumoral T cells downregulates exhaustion markers,reinvigorating their function-ality.These sequential processes of photodynamic PTP1B proteolysis ultimately augment T cellmediated antitumor immunity as well as protective immunity,completely eradicating the primary GBM and preventing its recurrence.Overall,our findings underscore the therapeutic potential of combining PDT with PROTAC activity for GBM immunotherapy.展开更多
基金funded by the National Key Research and Development Program of China 2023YFB3810300the National Natural Science Foundation of China 22090011,22378050,22378051+2 种基金the Science and Technology Plan Project of Liaoning Province 2023JH2/101700296the Fundamental Research Funds for the Central Universities DUT24ZD117,DUT24LAB105the National Research Foundation of Korea 2022R1A2C3005420,RS-2023-00217701.
文摘Prostate cancer is an epithelial malignancy with a high incidence among elderly men.Photochemistry-based dye photodrugs(known as photosensitizers)offer a promising clinical approach for treating tumors.These agents work by inducing immunogenic cell death(ICD),which activates antitumor immune response.This approach is favored owing to its minimal invasiveness,low toxicity,and high efficiency.However,the immunosuppressive microenvironment of characteristics of“cold”tumors significantly restricts the clinical efficacy of photodrugs.Developing an advanced nanocarrier system to deliver photodrugs and immune agonists for efficient drug delivery to tumor lesion sites and to reshape the immunosuppressive microenvironment is crucial in clinical practice.Therefore,in this study,we designed an integrin-targeted,activatable nano photodrug co-assembly with an immune agonist(RPST@IMQ)for enhancing photoimmunotherapy in prostate cancer via the reprogramming of tumor-associated macrophages.The active-targeted nanosystem enhanced the dosage of photodrug at the lesion site through systemic administration.High doses of glutathione at the tumor site cleaved the disulfide bonds of RPST@IMQ,releasing the photodrug and the immune agonist imiquimod(IMQ).Under photoirradiation,the photodrug generated significant doses of singlet oxygen to eliminate tumor cells,thereby inducing ICD to activate antitumor immune responses.Simultaneously,the released IMQ reprograms immunosuppressive M2-type tumor-associated macrophages(TAMs)in the tumor microenvironment into M1-type TAMs with tumor-killing capabilities,thereby converting“cold”tumors into“hot”tumors.This conversion enhances the therapeutic efficacy against primary and distant tumors in vivo.This study offers new insights into the development of innovative,smart,activatable nano photodrugs to enhance anticancer therapeutic outcomes.
基金supported by the National Natural Science Foundation of China(grant nos.T2322004 and 22078066)Science Research Project of Hebei Education Department(grant no.QN2025122)+5 种基金the Hebei Natural Science Foundation(grant no.B2024208046)the Basic Science Research Program through the National Research Foundation of Korea(NRF)grant funded by the Korean government(Ministry of Science and ICT(MSIT))(grant no.2022R1A2C3005420)the Basic Science Research Program through the NRF funded by the Ministry of Education(grant no.2020R1A6A1A03047902)National R&D Program through the NRF funded by the MSIT(grant no.2023R1A2C_(3)004880)BK21 FOUR projects(POSTECH)the NRF grant funded by the Korean government(MSIT)(grant no.2022R1A3B1077354)。
文摘Various obstacles[poor tissue penetration,hypoxic tumor microenvironment,and reactive oxygen species(ROS)production quenching due to aggregation]obstruct imaging-guided high-efficiency phototherapy targeting tumors.Herein,nanophthalocyanine(ZnPcN4-TF)is elaborately designed based on a synthetic phthalocyanine derivative(ZnPcN4)and nonimmunogenic transferrin(TF)through multiple noncovalent interactions for photoacoustic(PA)imaging-guided phototherapy.By conjugating electron-rich amino groups effectively suppressed fluorescence and ROS generation due to the strong photoinduced electron transfer effect,ZnPcN4 became an ideal photothermal and PA imaging agent.ZnPcN4-TF not only effectively targeted tumor sites and accumulated there,but also,surprisingly,facilitated the enhancement of ROS production via a type I process in an aggregate compared to ZnPcN4 itself,potentially due to accelerated electron transfer.Simultaneously,ZnPcN4-TF had a substantially more powerful photothermal effect than ZnPcN4 itself.Thus,this design effectively overcomes the obstacles to photodynamic therapy(aggregation-related ROS generation quenching in a hypoxic environment).Furthermore,PA imaging solves the tissue penetration challenge in optical imaging.This study provides a broader base for designing novel photosensitizers to improve phototherapy under hypoxia.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(No.RS-2023-00208427)supported by the Korea Basic Science Institute(National research Facilities and Equipment Center)grant fun-ded by the Korea government(MSIT)(No.RS-2024-00402412)+1 种基金supported by the Nano&Material Technology Develop-ment Program through the National Research Foundation of Korea(NRF)funded by Ministry of Science and ICT(RS-2024-00407093)supported by a Korea University Grant.
文摘Diverse connective tissues exhibit hierarchical anisotropic structures that intricately regulate homeostasis and tissue functions for dynamic immune response modulation.In this study,remotely manipulable hierarchical nanostructures are tailored to exhibit multi-scale ligand anisotropy.Hierarchical nanostructure construction involves coupling liganded nanoscale isotropic/anisotropic Au(comparable to few integrin molecules-scale)to the surface of microscale isotropic/anisotropic magnetic Fe3O4(comparable to integrin cluster-scale)and then elastically tethering them to a substrate.Systematic independent tailoring of nanoscale or microscale ligand isotropy versus anisotropy in four different hierarchical nanostructures with constant liganded surface area demonstrates similar levels of integrin molecule bridging and macrophage adhesion on the nanoscale ligand isotropy versus anisotropy.Conversely,the levels of integrin cluster bridging across hierarchical nanostructures and macrophage adhesion are significantly promoted by microscale ligand anisotropy compared with microscale ligand isotropy.Furthermore,microscale ligand anisotropy dominantly activates the host macrophage adhesion and pro-regenerative M2 polarization in vivo over the nanoscale ligand anisotropy,which can be cyclically reversed by substrate-proximate versus substrate-distant magnetic manipulation.This unprecedented scale-specific regulation of cells can be diversified by unlimited tuning of the scale,anisotropy,dimension,shape,and magnetism of hierarchical structures to decipher scale-specific dynamic cell-material interactions to advance immunoengineering strategies.
基金supported by the National Natural Science Foundation of China(U23A20573 and U23A20140)Science Research Project of Hebei Education Department(QN2025122)+3 种基金Hebei Natural Science Foundation(B2024208046 and H2022423314)the S&T Program of Hebei(242Q4301Z)funded by the Ministry of Science and ICT through the National Research Foundation of Korea(RS-2023-00304224)the Bio&Medical Technology Development Program of the National Research Foundation funded by the Korean government(MSIT)(2022M3E5F3080873).
文摘In contrast to traditional treatment methods,such as surgery,chemotherapy,and radiotherapy,photodynamic therapy(PDT)is a unique non-invasive modality with accurate temporal and spatial control,minimal side effects,and negligible drug resistance,demonstrating substantial promise in the realm of cancer treatment[1,2].
基金supported by grants from the National Research Foundation(NRF)of Korea,funded by the Ministry of Science(RS-2025-02219039,RS-2021-NR061836,RS-202400343156,NRF-2022R1A2C2006861,RS-2024-00463774,RS2022-NR068161 and RS-2024-00405287)the Intramural Research Program of KIST.
文摘In light of the burgeoning successes of cancer immunotherapy,glioblastoma(GBM)remains refractory due to an immunosuppressive microenvironment originating from its molecular heterogeneity.Thus,identifying promising therapeutic targets for treating GBM and discovering methodologies to effectively regulate them is still a tremendous challenge.Here we describe photodynamic protein tyrosine phosphatase 1B(PTP1B)proteolysis mediated by a proteolysis-targeting chimera(PROTAC)nanoassembly.The PTP1B-targeting PROTAC is conjugated with a photosensitizer via a cathepsin B(Cat B)-cleavable peptide,which spontaneously forms nanoassemblies due to intermolecularπ-πstack-ing interactions.In GBM models,PROTAC nanoassemblies significantly accumulate in the tumor region across the disrupted blood-brain barrier(BBB),triggering a burst release of the photosensitizer and active PROTAC by Cat B-mediated enzymatic cleavage.Upon laser irradiation,photodynamic therapy(PDT)synergizes with PROTAC-mediated PTP1B proteolysis to induce potent immunogenic cell death(ICD)in tumor cells.Subsequently,persistent PTP1B degradation by nanoassemblies in Cat B-overexpressed intratumoral T cells downregulates exhaustion markers,reinvigorating their function-ality.These sequential processes of photodynamic PTP1B proteolysis ultimately augment T cellmediated antitumor immunity as well as protective immunity,completely eradicating the primary GBM and preventing its recurrence.Overall,our findings underscore the therapeutic potential of combining PDT with PROTAC activity for GBM immunotherapy.
