Traditional treatments against advanced non-small cell lung cancer(NSCLC)with high morbidity and mortality continue to be dissatisfactory.Given this situation,there is an urgent requirement for alternative modalities ...Traditional treatments against advanced non-small cell lung cancer(NSCLC)with high morbidity and mortality continue to be dissatisfactory.Given this situation,there is an urgent requirement for alternative modalities that provide lower invasiveness,superior clinical effectiveness,and minimal adverse effects.The combination of photodynamic therapy(PDT)and immunotherapy gradually become a promising approach for high-grade malignant NSCLC.Nevertheless,owing to the absence of precise drug delivery techniques as well as the hypoxic and immunosuppressive characteristics of the tumor microenvironment(TME),the efficacy of this combination therapy approach is less than ideal.In this study,we construct a novel nanoplatform that indocyanine green(ICG),a photosensitizer,loads into hollow manganese dioxide(MnO2)nanospheres(NPs)(ICG@MnO2),and then encapsulated in PD-L1 monoclonal antibodies(anti-PD-L1)reprogrammed exosomes(named ICG@MnO2@Exo-anti-PD-L1),to effectively modulate the TME to oppose NSCLC by the synergy of PDT and immunotherapy modalities.The ICG@MnO2@Exo-anti-PD-L1 NPs are precisely delivered to the tumor sites by targeting specially PD-L1 highly expressed cancer cells to controllably release anti-PD-L1 in the acidic TME,thereby activating T cell response.Subsequently,upon endocytic uptake by cancer cells,MnO2 catalyzes the conversion of H2O2 to O2,thereby alleviating tumor hypoxia.Meanwhile,ICG further utilizes O2 to produce singlet oxygen(1O2)to kill tumor cells under 808 nm near-infrared(NIR)irradiation.Furthermore,a high level of intratumoral H2O2 reduces MnO2 to Mn2+,which remodels the immune microenvironment by polarizing macrophages from M2 to M1,further driving T cells.Taken together,the current study suggests that the ICG@MnO2@Exo-anti-PDL1 NPs could act as a novel drug delivery platform for achieving multimodal therapy in treating NSCLC.展开更多
The deep carbon cycle,which plays a critical role in mantle evolution and Earth habitability,is closely linked to the recycling of carbonate-bearing rocks through subduction.Marine carbonates are subducted to differen...The deep carbon cycle,which plays a critical role in mantle evolution and Earth habitability,is closely linked to the recycling of carbonate-bearing rocks through subduction.Marine carbonates are subducted to different depths during the closure of oceanic basins,thus carry important signatures of the disappeared oceanic basins.Petrological and geochemical features of the Hannuoba carbonatites in the northern North China Craton indicate that they were formed by melting of limestone subducted to mantle depths.Here,we show that detrital zircons carried by these carbonatites have a broad spectrum of U-Pb ages from Precambrian to Phanerozoic.Precambrian age peaks are at~2.5 Ga,2.1–2.3 Ga,1.8–2.0 Ga,~1.65 Ga,1.3–1.4 Ga,~1.1 Ga,0.91–0.94 Ga,0.74–0.81 Ga,and 0.62–0.63 Ga,respectively.The recorded age peaks are different from those in the northern North China Craton and thus preclude an origin of crustal contamination.Nevertheless,the Precambrian age spectra are compatible with those of the Xingmeng Orogen in the southeastern Central Asian Orogenic Belt.Furthermore,the significantly positiveεHf(t)values of 7.7–13.5 for the 300–373 Ma zircons are similar to those in the Xingmeng Orogen but different from those in the northern North China Craton.All these features suggest that the limestone precursor for the Hannuoba carbonatites was originated from the Paleo-Asian Ocean,and its deposition time was not earlier than 300 Ma.This indicates that the PaleoAsian Ocean still existed in the late Carboniferous to early Permian.The widespread distribution of metamorphic carbonates in the Central Asian Orogenic Belt indicates that there may have been widespread sedimentary carbonates in the Paleo-Asian Ocean.A large amount of sedimentary carbonates was probably carried into mantle during subduction of the Paleo-Asian oceanic slab,which significantly modified the chemical and physical properties of the lithospheric mantle.展开更多
基金supported by National Natural Science Foundation of China(Grant No.82203310 and No.81972023)Natural Science Foundation of Chongqing City(Grant No.CSTC2021jcyj-msxm0172 and CSTC2022nscq-msx0054)+2 种基金Science and Technology Research Program of Chongqing Municipal Education Commission(Grant No.KJQN202300478)Creative Research Group of CQ University(Grant No.CXQT21017)Program for Youth Innovation in Future Medicine from Chongqing Medical University.
文摘Traditional treatments against advanced non-small cell lung cancer(NSCLC)with high morbidity and mortality continue to be dissatisfactory.Given this situation,there is an urgent requirement for alternative modalities that provide lower invasiveness,superior clinical effectiveness,and minimal adverse effects.The combination of photodynamic therapy(PDT)and immunotherapy gradually become a promising approach for high-grade malignant NSCLC.Nevertheless,owing to the absence of precise drug delivery techniques as well as the hypoxic and immunosuppressive characteristics of the tumor microenvironment(TME),the efficacy of this combination therapy approach is less than ideal.In this study,we construct a novel nanoplatform that indocyanine green(ICG),a photosensitizer,loads into hollow manganese dioxide(MnO2)nanospheres(NPs)(ICG@MnO2),and then encapsulated in PD-L1 monoclonal antibodies(anti-PD-L1)reprogrammed exosomes(named ICG@MnO2@Exo-anti-PD-L1),to effectively modulate the TME to oppose NSCLC by the synergy of PDT and immunotherapy modalities.The ICG@MnO2@Exo-anti-PD-L1 NPs are precisely delivered to the tumor sites by targeting specially PD-L1 highly expressed cancer cells to controllably release anti-PD-L1 in the acidic TME,thereby activating T cell response.Subsequently,upon endocytic uptake by cancer cells,MnO2 catalyzes the conversion of H2O2 to O2,thereby alleviating tumor hypoxia.Meanwhile,ICG further utilizes O2 to produce singlet oxygen(1O2)to kill tumor cells under 808 nm near-infrared(NIR)irradiation.Furthermore,a high level of intratumoral H2O2 reduces MnO2 to Mn2+,which remodels the immune microenvironment by polarizing macrophages from M2 to M1,further driving T cells.Taken together,the current study suggests that the ICG@MnO2@Exo-anti-PDL1 NPs could act as a novel drug delivery platform for achieving multimodal therapy in treating NSCLC.
基金supported by the Key R&D Program of China(Grant No.2019YFA0708400)the National Natural Science Foundation of China(Grant No.41530211)the Special Fund of the State Key Laboratory of Geological Processes and Mineral Resources(Grant No.MSFGPMR01)。
文摘The deep carbon cycle,which plays a critical role in mantle evolution and Earth habitability,is closely linked to the recycling of carbonate-bearing rocks through subduction.Marine carbonates are subducted to different depths during the closure of oceanic basins,thus carry important signatures of the disappeared oceanic basins.Petrological and geochemical features of the Hannuoba carbonatites in the northern North China Craton indicate that they were formed by melting of limestone subducted to mantle depths.Here,we show that detrital zircons carried by these carbonatites have a broad spectrum of U-Pb ages from Precambrian to Phanerozoic.Precambrian age peaks are at~2.5 Ga,2.1–2.3 Ga,1.8–2.0 Ga,~1.65 Ga,1.3–1.4 Ga,~1.1 Ga,0.91–0.94 Ga,0.74–0.81 Ga,and 0.62–0.63 Ga,respectively.The recorded age peaks are different from those in the northern North China Craton and thus preclude an origin of crustal contamination.Nevertheless,the Precambrian age spectra are compatible with those of the Xingmeng Orogen in the southeastern Central Asian Orogenic Belt.Furthermore,the significantly positiveεHf(t)values of 7.7–13.5 for the 300–373 Ma zircons are similar to those in the Xingmeng Orogen but different from those in the northern North China Craton.All these features suggest that the limestone precursor for the Hannuoba carbonatites was originated from the Paleo-Asian Ocean,and its deposition time was not earlier than 300 Ma.This indicates that the PaleoAsian Ocean still existed in the late Carboniferous to early Permian.The widespread distribution of metamorphic carbonates in the Central Asian Orogenic Belt indicates that there may have been widespread sedimentary carbonates in the Paleo-Asian Ocean.A large amount of sedimentary carbonates was probably carried into mantle during subduction of the Paleo-Asian oceanic slab,which significantly modified the chemical and physical properties of the lithospheric mantle.
