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Logic-gated tumor-microenvironment nanoamplifier enables targeted delivery of CRISPR/Cas9 for multimodal cancer therapy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 795-807页

作者： Yongchun Pan Xiaowei luan Fei Zeng Xuyuan Wang Shurong Qin Qianglan Lu Guanzhong He Yanfeng Gao Xiaolian Sun Xin Han Bangshun He Yujun Song Department of Laboratory Medicine Nanjing First HospitalNanjing Medical UniversityNanjing 210006China College of Engineering and Applied Sciences State Key Laboratory of Analytical Chemistry for Life ScienceNanjing UniversityNanjing 210023China State Key Laboratory of Natural Medicines Key Laboratory of Drug Quality Control and PharmacovigilanceDepartment of Pharmaceutical AnalysisChina Pharmaceutical UniversityNanjing 211198China School of Medicine&Holistic Integrative Medicine Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources IndustrializationNanjing University of Chinese MedicineNanjing 210023China

Recent innovations in nanomaterials inspire abundant novel tumor-targeting CRISPR-based gene therapies.However,the therapeutic efficiency of traditional targeted nanotherapeutic strategies is limited by that the biomarkers vary in a spatiotemporal-dependent manner with tumor progression.Here,we propose a self-amplifying logic-gated gene editing strategy for gene/H_(2)O_(2)-mediated/starvation multimodal cancer therapy.In this approach,a hypoxia-degradable covalent-organic framework(COF) is synthesized to coat a-ZIF-8 in which glucose oxidase(GOx) and CRISPR system are packaged.To intensify intracellular redox dyshomeostasis,DNAzymes which can cleave catalase mRNA are loaded as well.When the nano system gets into the tumor,the weakly acidic and hypoxic microenvironment degrades the ZIF-8@COF to activate GOx,which amplifies intracellular H^(+)and hypoxia,accelerating the nanocarrier degradation to guarantee available CRISPR plasmid and GOx release in target cells.These tandem reactions deplete glucose and oxygen,leading to logic-gated-triggered gene editing as well as synergistic gene/H_(2)O_(2)-mediated/starvation therapy.Overall,this approach highlights the biocomputing-based CRISPR delivery and underscores the great potential of precise cancer therapy.

关键词： CRISPRdelivery Enzymeencapsulation Logic gate Hybridmaterial Hypoxia Gene editing Precise nanomedicine Multimodal therapy

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Layered niobium carbide enabling excellent kinetics and cycling stability of Li-Mg-B-H hydrogen storage material Layered niobium carbide enabling excellent kinetics

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Rare Metals 2024年第3期43卷 1153-1166页

作者： Li-Wen lu Hui luo Guang-Xu Li Yun Li Xin-Hua Wang Cun-Ke Huang Zhi-qianglan Wen-Zheng Zhou Jin Guo Mohammad Ismail Hai-Zhen Liu Guangxi Novel Battery Materials Research Center of Engineering Technology Guangxi Colleges and Universities Key Laboratory of Blue Energy and Systems IntegrationSchool of Physical Science and TechnologyGuangxi UniversityNanning530004China State Key Laboratory of Featured Metal Materials and Life-Cycle Safety for Composite Structures Nanning530004China School of Mechanical and Electrical Engineering Quzhou College of TechnologyQuzhou324000China Department of Materials Science and Engineering Zhejiang UniversityHangzhou310027China Faculty of Ocean Engineering Technology and Informatics Universiti Malaysia Terengganu21030Kuala NerusTerengganuMalaysia Key Laboratory of Advanced Energy Materials Chemistry(Ministry of Education) Nankai UniversityTianjin300071China

The Li-Mg-B-H composite(2LiBH_(4)+MgH_(2))has a high capacity of 11.4 wt%as a hydrogen storage material.However,the slow kinetics and poor cycling stability severely restrict its practical applications.In this work,a layered Nb_(2)C MXene was first synthesized and then introduced to tailor the kinetics and cycling stability of the Li-Mg-B-H composite.The milled 2LiH+MgB_(2)composites were initially hydrogenated to obtain the 2LiBH_(4)+MgH_(2)composites.The 2LiBH_(4)+MgH_(2)+5wt%Nb_(2)C can release 9.0 wt%H_(2)in 30 min at 400℃,while it is only 2.7 wt%for the undoped 2LiBH_(4)+MgH_(2).The dehydrogenation activation energies of MgH_(2)and LiBH_(4)are 123 and 154 kJ·mol^(-1)respectively for the 5 wt%Nb_(2)C-doped composite,lower than the undoped composite(164 and 165 kJ·mol^(-1)).The 2LiBH_(4)+MgH_(2)+5 wt%Nb_(2)C possesses excellent cycling stability,with the reversible capacity only slightly reduced from 9.4 wt%for the 1st cycle to 9.3 wt%for the 20th cycle.Nb_(2)C keeps stable in the composite and acts as an efficient catalyst for the Li-Mg-B-H composite.It is believed that both the layered structure and the active Nb element contribu te to the enhanced hydrogen storage performances of the Li-Mg-B-H composite.This work confirms that the Nb_(2)C MXene with layered stru cture has a significant enhancing impact on the Li-Mg-B-H hydrogen storage materials,which is different from the bulk NbC.

关键词： Hydrogen storage Lithium borohydride Magnesium hydride Nb_(2)C MXene

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Immune-adjuvant loaded Bi2Se3 nanocage for photothermal-improved PD-L1 checkpoint blockade immune-tumor metastasis therapy

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Nano Research 2019年第8期12卷 1770-1780页

作者： Yilin Song Yidan Wang Siyu Wang Yu Cheng Qianglan Lu Lifang Yang Fengping Tan Nan Li Tianjin Key Laboratory of Drug Delivery & High-Efficiency School of Pharmaceutical Science and TechnologyTianjin UniversityTianjin 300072China

Checkpoint blockade based immune therapy has shown to be effective but benefit only the minority of patients whose tumors have been pre-infiltrated by T cells. To overcome this obstacles, a PEG-modified Bi2Se3 nanocage (NC) loaded with imiquimod (R848), which could efficiently destroy the tumors thus producing enough tumor-associated antigens (TAA) and with the existence of R848, a toll-like-receptor-7 agonist, could generate strong anti-cancer immune responses is reported in this study. Moreover, immunogenic Bi2Se3 NC-PEG/R848 mediated photothermal therapy (PTT) sensitizes tumors to checkpoint inhibition mediated by a PD-L1 antibody, not only ablating cancer cells upon NIR laser but also causing strong anti-cancer immunity to suppress distant tumor growth post PTT. Both in vitro and in vivo experiments demonstrate that the Bi2Se3 NC-PEG/R848 could effectively activate a PTT-induced immune response as well as silence immune resistance based on PD-L1 checkpoint blockade to ablate the primary tumor and further inhibit the tumor metastasis. Bi2Se3 NC reported here exhibits high photothermal conversion efficiency and stability, as well as competent drug loading capacity with large hollow structures and high surface area. Our study not only provides a facial way to synthesize Bi2Se3 NC, but also offers an alternative strategy for tumor metastasis.

关键词： Bi2Se3 nanocage R848 checkpoint blockade photothermal-immune therapy anti-tumor metastasis

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Rod-shape inorganic biomimetic mutual-reinforcing MnO2-Au nanozymes for catalysis-enhanced hypoxic tumor therapy

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Nano Research 2020年第8期13卷 2246-2258页

作者： Lifang Yang Chuchu Ren Min Xu Yilin Song Qianglan Lu Yule Wang Yan Zhu Xinxing Wang Nan Li Tianjin Key Laboratory of Drug Delivery&High-Efficiency School of Pharmaceutical Science and TechnologyTianjin UniversityTianjin300072China Tianjin State Key Laboratory of Modern Chinese Medicine Tianjin University of Traditional Chinese MedicineBeihua South RoadJingHai DistrictTianjin301617China Research and Development Center of TCM Tianjin International Joint Academy of Biotechnology and Medicine220 Dongting RoadTEDATianjin300457China Tianjin Institute of Environmental and Operational Medicine 1 Dali RoadHeping DistrictTianjin300050China

Biomimetic nanozymes possessing natural enzyme-mimetic activities have been extensively applied in nanocatalytic tumor therapy.However,engineering hybrid biomimetic nanozymes to achieve superior nanozyme activity remained to be an intractable challenge in hypoxic tumors.Herein,a rod-like biomimetic hybrid inorganic MnO2-Au nanozymes are developed,where MnO2 and ultrasmall Au nanoparticles(NPs)are successively deposited on the mesoporous silica nanorod to cooperatively improve the O2 content and thermal sensitivity of hypoxic solid tumors guided by multi-modal imaging.Under the catalyzing of MnO2,the intratumoral H2O2 is decomposed to greatly accelerate O2 generation,which could boost the curative effect of radiation therapy(RT)and further enhance the Au-catalyzed glucose oxidation.Mutually,the Au NPs can steadily and efficiently catalyze the oxidation of glucose in harsh tumor microenvironment,thus sensitizing tumor cells to thermal ablation for mild photothermal therapy and further promoting the catalytic efficiency of MnO2 with the self-supplied H2O2/H+.As a result,this mutual-reinforcing cycle can endow the nanoplatform with accelerated O2 generation,thus alleviating hypoxic environment and further boosting RT effect.Furthermore,acute glucose consuming can induce downregulation expression of heat shock protein(HSP),achieving starvation-promoted mild photothermal therapy.This synthesized hybrid nanozymes proves to be a versatile theranostic agent for nanocatalytic cancer therapy.

关键词： nanozyme self-supplied mutual-reinforcing hypoxia catalysis-enhanced therapy

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NIR-II driven plasmon-enhanced cascade reaction for tumor microenvironment-regulated catalytic therapy based on bio-breakable Au-Ag nanozyme

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Nano Research 2020年第8期13卷 2118-2129页

作者： Min Xu Qianglan Lu Yiling Song Lifang Yang Chuchu Ren Wen Li Ping Liu Yule Wang Yan Zhu Nan Li Tianjin Key Laboratory of Drug Delivery&High-Efficiency School of Pharmaceutical Science and TechnologyTianjin UniversityTianjin300072China Tianjin State Key Laboratory of Modern Chinese Medicine Tianjin University of Traditional Chinese MedicineTianjin301617China Research and Development Center of TCM Tianjin International Joint Academy of Biotechnology and MedicineTianjin300457China

Emerging nanozymes with natural enzyme-mimicking catalytic activities have inspired extensive research interests due to their high stability,low cost,and simple preparation,especially in the field of catalytic tumor therapy.Here,bio-breakable nanozymes based on glucose-oxidase(GOx)-loaded biomimetic Au–Ag hollow nanotriangles(Au–Ag–GOx HTNs)are designed,and they trigger an near-infrared(NIR)-II-driven plasmon-enhanced cascade catalytic reaction through regulating tumor microenvironment(TME)for highly efficient tumor therapy.Firstly,GOx can effectively trigger the generation of gluconic acid(H+)and hydrogen peroxide(H2O2),thus depleting nutrients in the tumor cells as well as modifying TME to provide conditions for subsequent peroxidase(POD)-like activity.Secondly,NIR-II induced surface plasmon resonance can induce hot electrons to enhance the catalytic activity of Au–Ag–GOx HTNs,eventually boosting the generation of hydroxyl radicals(•OH).Interestingly,the generated H2O2 and H+can simultaneously induce the degradation of Ag nanoprisms to break the intact triangle nanostructure,thus promoting the excretion of Au–Ag–GOx HTNs to avoid the potential risks of drug metabolism.Overall,the NIR-II driven plasmon-enhanced catalytic mechanism of this bio-breakable nanozyme provides a promising approach for the development of nanozymes in tumor therapy.

关键词： near-infrared(NIR)-II driven plasmon-enhanced catalysis Au-Ag hollow nan otria ngles bio-breakable cascade reaction

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结直肠肿瘤DNA甲基化标志的筛选及诊断价值

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中华胃肠外科杂志 2015年第11期18卷 1149-1153页

作者：马炯杨青兰邓超金黑鹰龚伟王水明陈豪范怡梅江苏省江阴市中医院外科 214400 南京中医药大学第三附属医院全国肛肠医疗中心全国肛肠医疗中心江苏省中西医结合结直肠癌诊疗中心南京中医药大学第一临床医学院南京大学医学遗传教研室

目的筛选有潜在诊断价值的甲基化基因，探讨其在国人结直肠肿瘤中的甲基化特征，以期寻找有较高诊断价值的DNA甲基化筛查标志。方法收集2013年6—8月期间于南京中医药大学第三附属医院接受手术治疗的10例结直肠癌患者的肿瘤及其距离肿瘤... 详细信息

目的筛选有潜在诊断价值的甲基化基因，探讨其在国人结直肠肿瘤中的甲基化特征，以期寻找有较高诊断价值的DNA甲基化筛查标志。方法收集2013年6—8月期间于南京中医药大学第三附属医院接受手术治疗的10例结直肠癌患者的肿瘤及其距离肿瘤10cm以上组织标本及接受内镜下切除的10例结直肠腺瘤患者的组织标本。分别采用BSP法和qMSP法检测上述标本中SNCA、MAL、INA、SPG20、FBN1、CNRIP1、TFP12和0sMR8个基因的甲基化特征，筛选出有潜在筛查价值的基因，并绘制接受者工作特征（ROC）曲线。结果BSP法检测的8个基因中，SNCA、SPG20和FBN1基因在癌和腺瘤组织中100％检测到甲基化，而在癌旁组织中均未检测到甲基化：其余5个基因在癌、癌旁和腺瘤中均有不同程度表达。qMSP法检测的10对癌与癌旁组织中的SNCA甲基化阳性例数分别为5例和1例，SPG20分别为8例和1例，FBN1分别7例和0例，差异均有统计学意义（分别P=0．070、P=0．003和P=0．007）。SNCA、SPG20和FBN1基因甲基化诊断结直肠癌的ROC曲线下面积（AUC）分别为0．890、0．730和0．880。结论SNCA、SPG20和FBN1对于结直肠肿瘤为具有潜在筛查价值的基因。

关键词：结直肠肿瘤基因甲基化肿瘤筛查

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