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Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity

Acta Pharmaceutica Sinica B 2024年第1期14卷 350-364页

作者： Yongshun Zhang Lan Yang Yangsen Ou Rui Hu guangsheng du Shuang Luo Fuhua Wu Hairui Wang Zhiqiang Xie Yu Zhang Chunting He Cheng Ma Tao Gong Ling Zhang Zhirong Zhang Xun Sun Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China Med-X Center for Materials College of Polymer Science and EngineeringSichuan UniversityChengdu 610065China

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10(PTEN)gene in cancer cells may be associated with immunosuppressive tumor microenvironment(TME)and poor response to immune checkpoint blockade(ICB)therapy.Therefore,efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy.Here,we screened an adeno-associated virus(AAV)capsid for efficient PTEN gene delivery into B16F10 tumor cells.We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death(ICD)and increasing immune cell infiltration.Moreover,we developed an anti-PD-1 loaded phospholipid-based phase separation gel(PPSG),which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo.In order to effectively inhibit the recurrence of melanoma,we further applied a triple therapy based on AAV6-PTEN,PPSG^(@anti-PD-1)and CpG,and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory,which completely rejected tumor recurrence.We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

关键词： Triple therapy Adeno-associated virus PTEN PPSG@anti-PD-1 CpG Immunogenic cell death Antitumor immune response Immune memory

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Recent progress in application of nanovaccines for enhancing mucosal immune responses

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药学学报:英文版 2023年第6期13卷 2334-2345页

作者： guangsheng du Ming Qin Xun Sun Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

Mucosal vaccines that stimulate both mucosal and systemic immune responses are desirable,as they could prevent the invading pathogens at their initial infection sites in a convenient and userfriendly way. Nanovaccines are receiving increasing attention for mucosal vaccination due to their merits in overcoming mucosal immune barriers and in enhancing immunogenicity of the encapsulated antigens.Herein, we summarized several nanovaccine strategies that have been reported for enhancing mucosal immune responses, including designing nanovaccines that have superior mucoadhesion and mucus penetration capacity, designing nanovaccines with better targeting efficiency to M cells or antigen-presenting cells, and co-delivering adjuvants by using nanovaccines. The reported applications of mucosal nanovaccines were also briefly discussed, including prevention of infectious diseases, and treatment of tumors and autoimmune diseases. Future research progresses in mucosal nanovaccines may promote the clinical translation and application of mucosal vaccines.

关键词： Mucosal vaccines Nanovaccines Cell targeting Adjuvants Infectious diseases Mucus adhesion and penetration Mucosal immune system M cells

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An antigen self-assembled and dendritic cell-targeted nanovaccine for enhanced immunity against cancer

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Acta Pharmaceutica Sinica B 2023年第8期13卷 3518-3534页

作者： Yunting Zhang Min Jiangy guangsheng du Xiaofang Zhong Chunting He Ming Qin Yingying Hou Rong Liu Xun Sun Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

The rise of nanotechnology has opened new horizons for cancer immunotherapy.However,most nano vaccines fabricated with nanomaterials suffer from carrier-related concerns,including low drug loading capacity,unpredictable metabolism,and potential systemic toxicity,which bring obstacles for their clinical translation.Herein,we developed an antigen self-assembled nanovaccine,which was resulted from a simple acryloyl modification of the antigen to induce self-assembly.Furthermore,a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid(Zol)were integrated or absorbed onto the nanoparticles(denoted as MEAO-Z)to intensify the immune response.The synthesized nano vaccine with a diameter of around 70 nm showed successful lymph node transportation,high dendritic cell internalization,promoted costimulatory molecule expression,and preferable antigen cross-presentation.In virtue of the above superiorities,MEAO-Z induced remarkably higher titers of serum antibody,stronger cytotoxic T lymphocyte immune responses and IFN-γsecretion than free antigen and adjuvants.In vivo,MEAO-Z significantly suppressed EG7-OVA tumor groth and prolonged the survival time of tumor-bearing mice.These results indicated the translation promise of our self-assembled nano vaccine for immune potentiation and cancer immunotherapy.

关键词： Subunit antigen Self-assembled nanovaccine Dendritic cell Mannose receptor Zoledronic acid Antigen cross-presentation Cellular immunity Cancer immunotherapy

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Nanoparticles with rough surface improve the therapeutic effect of photothermal immunotherapy against melanoma

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2934-2949页

作者： Jiao Xue Yining Zhu Shuting Bai Chunting He guangsheng du Yuandong Zhang Yao Zhong Wenfei Chen Hairui Wang Xun Sun Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

Photothermal therapy has been intensively investigated for treating cancer in recent years.However,the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence.To address this challenge,immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites.Here,we engineered silica-based core-shell nanoparticles(JQ-1@PSNs-R),in which silica cores were coated with the photothermal agent polydopamine,and a bromodomain-containing protein 4(BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photo thermal and immune therapy for tumor elimination.Importantly,to improve the therapeutic effect,we increased the surface roughness of the nanoparticles by hydrofluoric acid(HF) etching during the fabrication process,and found that the internalization of JQ-1@PSNs-R was significantly improved,leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1.In the animal studies,the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy,successfully activated tumor-specific immune responses against residual tumor cells,and further prevented tumor metastasis and recurrence.Our results indicated that JQ-1@PSNs-R could serve as an innovative and effective strategy for combined cancer therapy.

关键词： Photothermal therapy Immunotherapy Rough surface Polydopamine-coated silica nanoparticles JQ-1 Melanoma

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ThyroidNet:A Deep Learning Network for Localization and Classification of Thyroid Nodules

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Computer Modeling in Engineering & Sciences 2024年第4期139卷 361-382页

作者： Lu Chen Huaqiang Chen Zhikai Pan Sheng Xu guangsheng Lai Shuwen Chen Shuihua Wang Xiaodong Gu Yudong Zhang Ultrasonic Department Zhongda Hospital Affiliated to Southeast UniversityNanjing210009China School of Physics and Information Engineering Jiangsu Second Normal UniversityNanjing211200China School of Computing and Mathematical Sciences University of LeicesterLeicesterLE17RHUK Department of Information Systems Faculty of Computing and Information TechnologyKing Abdulaziz UniversityJeddah21589Saudi Arabia State Key Laboratory of MillimeterWaves Southeast UniversityNanjing210096China Jiangsu Province Engineering Research Center of Basic Education Big Data Application Jiangsu Second Normal UniversityNanjing211200China School of Software Engineering Quanzhou Normal UniversityQuanzhou362000China Department of Biological Sciences Xi’an Jiaotong-Liverpool UniversitySuzhou215123China

Aim:This study aims to establish an artificial intelligence model,ThyroidNet,to diagnose thyroid nodules using deep learning techniques accurately.Methods:A novel method,ThyroidNet,is introduced and evaluated based on deep learning for the localization and classification of thyroid nodules.First,we propose the multitask TransUnet,which combines the TransUnet encoder and decoder with multitask learning.Second,we propose the dualLoss function,tailored to the thyroid nodule localization and classification tasks.It balances the learning of the localization and classification tasks to help improve the model’s generalization ability.Third,we introduce strategies for augmenting the data.Finally,we submit a novel deep learning model,ThyroidNet,to accurately detect thyroid nodules.Results:ThyroidNet was evaluated on private datasets and was comparable to other existing methods,including U-Net and TransUnet.Experimental results show that ThyroidNet outperformed these methods in localizing and classifying thyroid nodules.It achieved improved accuracy of 3.9%and 1.5%,respectively.Conclusion:ThyroidNet significantly improves the clinical diagnosis of thyroid nodules and supports medical image analysis tasks.Future research directions include optimization of the model structure,expansion of the dataset size,reduction of computational complexity and memory requirements,and exploration of additional applications of ThyroidNet in medical image analysis.

关键词： ThyroidNet deep learning TransUnet multitask learning medical image analysis

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Single-cell mass spectrometry studies of drug metabolism heterogeneity and primary resistance to gefitinib in non-small cell lung cancer cells

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Chinese Chemical Letters 2024年第2期35卷 436-440页

作者： Guizhen Zhu Yaoyao Zhao Wenmei Zhang Yuanyuan Wu Yuanxing Liu guangsheng Guo Xiayan Wang Zhihong Liu Center of Excellence for Environmental Safety and Biological Effects Beijing Key Laboratory for Green Catalysis and SeparationDepartment of ChemistryBeijing University of TechnologyBeijing 100124China Minzu University of China Beijing 100081China Key Laboratory for the Synthesis and Application of Organic Functional Molecules College of Health Science and EngineeringHubei UniversityWuhan 430062China

Patients with epidermal growth factor receptor(EGFR)wild-type non-small cell lung cancer(NSCLC)often show primary resistance to gefitinib therapy.It is thus necessary to study the metabolism of gefitinib in NSCLC cells to comprehensively reveal the reasons for the primary resistance of tumors.Herein,we develop a platform for studying drug metabolism heterogeneity based on single-cell mass spectrometry(sDMH-scMS)by integrating living-cell electrolaunching ionization MS(ILCEI-MS)and high-performance liquid chromatography-MS(HPLC-MS)analysis,and the primary resistance of NSCLC cells to gefitinib was studied using this platform.The ILCEI-MS analysis showed that approximately 11.9%of NSCLC single cells contained the gefitinib metabolite M11;HPLC-MS detection diluted the intensity of M11 in subpopulations and concealed the heterogeneity of drug metabolism in tumor single cells.The intensity of gefitinib in EGFR wild-type A549 cells was markedly lower than in mutant PC9 cells,and the intensity of gefitinib metabolites was significantly higher than in PC9 cells,suggesting that the primary resistance of NSCLC cells is related to gefitinib metabolism.Moreover,the combination of gefitinib and the drug-metabolizing enzyme inhibitorα-naphthoflavone was shown to overcome the primary resistance of the NSCLC cells.Overall,the results of this study are expected to be applicable for clinical drug resistance diagnosis and treatment at the single-cell level.

关键词： Single-cell mass spectrometry Drug metabolism Non-small cell lung cancer Gefitinib Primary resistance

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A perspective on the key factors of safety for rechargeable magnesium batteries

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Journal of Energy Chemistry 2024年第7期94卷 656-676页

作者： Shuangshuang Tan Jie Xu Rongrui Deng Qiannan Zhao Chaohe Xu guangsheng Huang Jingfeng Wang Fusheng Pan National Engineering Research Center for Magnesium Alloys Chongqing UniversityChongqing 400044China National Innovation Center for Industry-Education Integration of Energy Storage Technology College of Materials Science and EngineeringChongqing UniversityChongqing 400044China Chongqing Institute of New Energy Storage Materials and Equipment Chongqing 401135China

Rechargeable Mg batteries(RMBs)have become one of the best subsitutes for lithium-ion batteries due to the high volumetric capacity,abundant resources,and uniform plating behavior of Mg metal anode.However,the safety hazard induced by the formation of high-modulue Mg dendrites under a high current density(10 mA cm^(-1))was still revealed in recent years.It has forced researchers to re-examine the safety of RMBs.In this review,the intrinsic safety factors of key components in RMBs,such as uneven plating,pitting and flammability of Mg anode,heat release and crystalline water decomposition of cathode,strong corrosion,low oxidition stability and flammability of electrolytes,and soforth,are systematacially summarized.Their origins,formation mechanisms,and possible safety hazards are deeply discussed.To develop high-performance Mg anode,current strategies including designing artificial SEl,three-dimensional substrates,and Mg alloys are summarized.For practical electrolytes,the configurations of boron-centered anions and simple Mg salts and the functionalized solvent with high boiling point and low flammability are suggested to comprehensively design.In addition,the future study should more focus on the investigation on the thermal runaway and decomposition of cathode materials and separa-tors.This review aims to provide fundamental insights into the relationship between electrochemistry and safety,further promoting the sustainable development of RMBs.

关键词： Rechargeable Mg batteries Battery safety Mg dendrites Electrolyte decomposition Intrinsic safety issues

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High MXene loading, nacre-inspired MXene/ANF electromagnetic interference shielding composite films with ultralong strain-tofailure and excellent Joule heating performance

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Nano Research 2024年第3期17卷 2061-2069页

作者： Jiaen Wang Tianliang Song Wei Ming Moxi Yele Longfu Chen Hao Zhang Xiaojuan Zhang Benliang Liang guangsheng Wang School of Physical Science and Engineering Beijing Jiaotong UniversityBeijing 100044China College of Chemistry and Materials Engineering Beijing Technology and Business UniversityBeijing 100048China Key Laboratory of Bio-Inspired Smart Interfacial Science and Technology of Ministry of Education School of ChemistryBeihang UniversityBeijing 100191China

The high power density and intelligence of next-generation flexible electronic devices bring many challenges to fabricate flexible composite films with electromagnetic interference(EMI)shielding effectiveness(SE)property and excellent toughness via a simple method.Herein,inspired by the layered structure and biopolymer matrix networks in natural nacre,nacre-like layered Ti_(3)C2TX(MXene)/aramid nanofiber(ANF)films were fabricated through sol-gel,vacuum-assisted filtration,and hot-pressing.Three-dimensional(3D)interconnected aramid nanofibers networks between adjacent layered MXene result in an ultralong strain-to-failure of the film.Even though the functional filler MXene contents are as high as 60 wt.%and 70 wt.%,the strain-to-failure of the films could reach astonishing values of 18.34%±1.86%and 14.43%±1.26%,respectively.And the tensile strength could maintain about 85 MPa.Excitingly,with such a high filler,the film can also withstand double folding and vigorous rubbing without damage,which could better adapt to a harsh application environment.The result means that this work provides a convenient way to prepare other high functional filler composite films with excellent mechanical performance.The EMI SE values could reach 45 and 52.15 dB at 60 wt.%and 70 wt.%MXene in 8.2–12.4 GHz.Meanwhile,the films have prominent Joule heating properties,high sensitivity(<15 s),small voltage operation(0.5 V),and high operation constancy(1300 s).Therefore,nacre-inspired MXene/ANF composite films in this work have ability to apply in many areas including communication technology,military,and aerospace.

关键词： bioinspired aramid nanofiber networks ultralong strain-to-failure toughening mechanism electromagnetic interference shielding

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dual-Defect Engineering Strategy Enables High-durability Rechargeable Magnesium-Metal Batteries

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Nano-Micro Letters 2024年第9期16卷 449-461页

作者： Fuyu Chen Bai‑Qing Zhao Kaifeng Huang Xiu‑Fen Ma Hong‑Yi Li Xie Zhang Jiang Diao Jili Yue guangsheng Huang Jingfeng Wang Fusheng Pan National Innovation Center for Lndustry‑Education Integration of Energy Storage Technology School of Materials Science and EngineeringChongqing UniversityChongqing 400044People’s Republic of China National Magnesium Alloy Material Engineering Technology Research Center Chongqing UniversityChongqing 400044People’s Republic of China Materials and Energy Division Beijing Computational Science Research CenterBeijing 100193People’s Republic of China School of Materials Science and Engineering Northwestern Polytechnical UniversityXi’an 710072People’s Republic of China National Key Laboratory of Advanced Casting Technologies Chongqing UniversityChongqing 400044People’s Republic of China

Rechargeable magnesium-metal batteries(RMMBs)are promising next-generation secondary batteries;however,their development is inhibited by the low capacity and short cycle lifespan of cathodes.Although various strategies have been devised to enhance the Mg^(2+)migration kinetics and structural stability of cathodes,they fail to improve electronic conductivity,rendering the cathodes incompatible with magnesium-metal anodes.Herein,we propose a dual-defect engineering strategy,namely,the incorporation of Mg^(2+)pre-intercalation defect(P-Mgd)and oxygen defect(Od),to simultaneously improve the Mg^(2+)migration kinetics,structural stability,and electronic conductivity of the cathodes of RMMBs.Using lamellar V_(2)O_(5)·nH_(2)O as a demo cathode material,we prepare a cathode comprising Mg0.07V_(2)O_(5)·1.4H_(2)O nanobelts composited with reduced graphene oxide(MVOH/rGO)with P-Mgd and Od.The Od enlarges interlayer spacing,accelerates Mg^(2+)migration kinetics,and prevents structural collapse,while the P-Mgd stabilizes the lamellar structure and increases electronic conductivity.Consequently,the MVOH/rGO cathode exhibits a high capacity of 197 mAh g^(−1),and the developed Mg foil//MVOH/rGO full cell demonstrates an incredible lifespan of 850 cycles at 0.1 A g^(−1),capable of powering a light-emitting diode.The proposed dual-defect engineering strategy provides new insights into developing high-durability,high-capacity cathodes,advancing the practical application of RMMBs,and other new secondary batteries.

关键词： Rechargeable magnesium-metal batteries dual-defect engineering Vanadium-based cathode High durability Lamellar structure

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Single-shot AAV-vectored vaccine against SARS-CoV-2 with fast and long-lasting immunity

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Acta Pharmaceutica Sinica B 2023年第5期13卷 2219-2233页

作者： Fuhua Wu Shuang Luo Yongshun Zhang Yangsen Ou Hairui Wang Zhaofei Guo Chunting He Shuting Bai Penghui He Min Jiang Xiaoyan Chen guangsheng du Xun Sun Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

due to the insufficient long-term protection and significant efficacy reduction to new variants of current COVID-19 vaccines,the epidemic prevention and control are still challenging.Here,we employ a capsid and antigen structure engineering(CASE)strategy to manufacture an adenoassociated viral serotype 6-based vaccine(S663V-RBD),which expresses trimeric receptor binding domain(RBD)of spike protein fused with a biological adjuvant RS09.Impressively,the engineered S663V-RBD could rapidly induce a satisfactory RBD-specific IgG titer within 2 weeks and maintain the titer for more than 4 months.Compared to the licensed BBIBP-CorV(Sinopharm,China),a single-dose S663V-RBD induced more endurable and robust immune responses in mice and elicited superior neutralizing antibodies against three typical SARS-CoV-2 pseudoviruses including wild type,C.37(Lambda)and B.1.617.2(Delta).More interestingly,the intramuscular injection of S663V-RBD could overcome pre-existing immunity against the capsid.Given its effectiveness,the CASE-based S663VRBD may provide a new solution for the current and next pandemic.

关键词： AAV vectors Capsid engineering Vaccine Antigen structure design SARS-CoV-2

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