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Dendritic nanomedicine enhances chemoimmunotherapy by disturbing metabolism of cancer-associated fibroblasts for deep penetration and activating function of immune cells

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3680-3696页

作者： Yunkun Li Xiaoding Shen Haitao Ding Yuxin Zhang Dayi Pan Liping Su Yahui Wu Zaixiang Fang Jie Zhoua Qiyong Gong Kui Luo Department of Radiology Huaxi MR Research Center(HMRRC)Frontiers Science Center for Disease-Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Functional and Molecular Imaging Key laboratory of Sichuan Province and Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengdu 610041China Department of Radiology West China Xiamen Hospital of Sichuan UniversityXiamen 361021China

Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune ***,we constructed a PEGylated dendritic epirubicin(Epi)prodrug(Epi-P4D)to regulate the metabolism of cancer-associated fibroblasts(CAFs),thus enhancing Epi penetration into both multicellular tumor spheroids(MTSs)and tumor tissues in mouse colon cancer(CT26),mouse breast cancer(4T1)and human breast cancer(MDA-MB-231)*** cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin,α-SMA,and collagen ***,thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell(DC)maturation and subsequent immune activation,including elevating the CD4^(+)T cell population,reducing CD4^(+)and CD8^(+)T cell hyperactivation and exhaustion,and amplifying the natural killer(NK)cell proportion and effectively activating *** a result,this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.

关键词： Dendritic prodrug Enhanced penetration Metabolic intervention Cancer-associated fibroblasts Immunogenic cell death Chemotherapy Immunotherapy Immune microenvironment reconstitution

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Current perspectives on mesenchymal stem cells as a potential therapeutic strategy for non-alcoholic fatty liver disease

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World Journal of Stem Cells 2024年第7期16卷 760-772页

作者： Yan Jiang Narazah Mohd Yusoff Jiang Du Emmanuel Jairaj Moses Jun-Tang Lin School of Nursing Xinxiang Medical UniversityXinxiang 453000Henan ProvinceChina Department of Biomedical Sciences Advanced Medical and Dental InstituteUniversiti Sains MalaysiaKepala Batas 13200Pulau PinangMalaysia Advanced Medical and Dental Institute Universiti Sains MalaysiaKepala Batas 13200Pulau PinangMalaysia Henan Joint International Research laboratory of Stem Cell Medicine School of Medical EngineeringXinxiang Medical UniversityXinxiang 453003Henan ProvinceChina Stem Cells and biotherapy Engineering Research Center of Henan National Joint Engineering Laboratory of Stem Cells and BiotherapySchool of Life Science and TechnologyXinxiang Medical UniversityXinxiang 453003Henan ProvinceChina Henan Joint International Research laboratory of Stem Cell Medicine School of Medical EngineeringXinxiang Medical UniversityXinxiang 453000Henan ProvinceChina

Non-alcoholic fatty liver disease(NAFLD)has emerged as a significant health challenge,characterized by its widespread prevalence,intricate natural progression and multifaceted *** NAFLD initially presents as benign fat accumulation,it may progress to steatosis,non-alcoholic steatohepatitis,cirrhosis,and hepatocellular *** stem cells(MSCs)are recognized for their intrinsic self-renewal,superior biocompatibility,and minimal immunogenicity,positioning them as a therapeutic innovation for liver ***,this review aims to elucidate the potential roles of MSCs in alleviating the progression of NAFLD by alteration of underlying molecular pathways,including glycolipid metabolism,inflammation,oxidative stress,endoplasmic reticulum stress,and *** insights are expected to provide further understanding of the potential of MSCs in NAFLD therapeutics,and support the development of MSC-based therapy in the treatment of NAFLD.

关键词： Non-alcoholic induced fatty liver disease Mesenchymal stem cells Lipid accumulation Inflammation Oxidative stress Endoplasmic reticulum stress Fibrosis

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A novel deep generative model for mRNA vaccine development: Designing 5′ UTRs with N1-methyl-pseudouridine modification

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1814-1826页

作者： Xiaoshan Tang Miaozhe Huo Yuting Chen Hai Huang Shugang Qin Jiaqi Luo Zeyi Qin Xin Jiang Yongmei Liu Xing Duan Ruohan Wang Lingxi Chen Hao Li Na Fan Zhongshan He Xi He Bairong Shen Shuai Cheng Li Xiangrong Song Institute of Systems Genetics Department of Critical Care MedicineFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610000China Department of Computer Science City University of Hong KongHong Kong 99907China Department of Biology Brandeis UniversityBostonMA 02453USA

Efficient translation mediated by the 5'untranslated region(5'UTR)is essential for the robust efficacy of mRNA ***,the N1-methyl-pseudouridine(m1)modification of mRNA can impact the translation efficiency of the 5'*** discovered that the optimal 5'UTR for m1y-modified mRNA(m1y-5'UTR)differs significantly from its unmodified counterpart,high-lighting the need for a specialized tool for designing mly-5'UTRs rather than directly utilizing high-expression endogenous gene 5'*** response,we developed a novel machine learning-based tool,Smart5UTR,which employs a deep generative model to identify superior m1y-5'UTRs in *** tailored loss function and network architecture enable Smart5UTR to overcome limitations inherent in existing *** a result,Smart5UTR can successfully design superior 5'UTRs,greatly benefiting mRNA vaccine ***,Smart5UTR-designed superior 5'UTRs significantly enhanced antibody titers induced by COVID-19 mRNA vaccines against the Delta and Omicron variants of SARS-CoV-2,surpassing the performance of vaccines using high-expression endogenous gene 5'UTRs.

关键词： mRNA vaccine Machine learning 5'UTR mRNA design Sequence design N1-Methyl-pseudouridine COVID-19 SARS-CoV-2

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pH-Responsive polymer boosts cytosolic siRNA release for retinal neovascularization therapy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 781-794页

作者： Shuai Guo Chunhui Li Changrong Wang Xiaowen Cao Xinyue Liu Xing-Jie Liang Yuanyu Huang Yuhua Weng School of Medical Technology Advanced Research Institute of Multidisciplinary ScienceSchool of Life ScienceKey Laboratory of Molecular Medicine and BiotherapyKey Laboratory of Medical Molecule Science and Pharmaceutics EngineeringBeijing Institute of TechnologyBeijing 100081China School of Pharmacy Shandong New Drug Loading&Release Technology and Preparation Engineering LaboratoryBinzhou Medical UniversityYantai 264003China School of Ophthalmology and Optometry School of Biomedical EngineeringThe Eye HospitalWenzhou Medical UniversityWenzhou 325027China Chinese Academy of Sciences(CAS) Key Laboratory for Biomedical Effects of Nanomaterials and NanosafetyCAS Center for Excellence in NanoscienceNational Center for Nanoscience and Technology of ChinaBeijing 100190China

Small interfering RNA(siRNA)has a promising future in the treatment of ocular diseases due to its high efficiency,specificity,and low toxicity in inhibiting the expression of target genes and ***,due to the unique anatomical structure of the eye and various barriers,delivering nucleic acids to the retina remains a significant *** this study,we rationally design PACD,an A-B-C type non-viral vector copolymer composed of a hydrophilic PEG block(A),a siRNA binding block(B)and a pH-responsive block(C).PACDs can self-assemble into nanosized polymeric micelles that compact siRNAs into polyplexes through simple *** evaluating its pH-responsive activity,gene silencing efficiency in retinal cells,intraocular distribution,and anti-angiogenesis therapy in a mouse model of hypoxia-induced angiogenesis,we demonstrate the efficiency and safety of PACD in delivering siRNA in the *** are surprised to discover that,the PACD/siRNA polyplexes exhibit remarkable intracellular endosomal escape efficiency,excellent gene silencing,and inhibit retinal *** study provides design guidance for developing efficient nonviral ocular nucleic acid delivery systems.

关键词： SiRNA Oculardeliverysystem Block polymer Endosomalescape Retinal neovascularization Blood-retinal barrier VEGFA Safety

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Pan-cancer immunogenic death analysis identifies key roles of CXCR3 and CCL18 in hepatocellular carcinoma

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Genes & Diseases 2024年第2期11卷 568-570页

作者： Jia Guo Xin Sun Guowei Pan Ce Li Xin He Xiaofang Che Zan Teng Xiujuan Qu Yunpeng Liu Bowen Yang Department of Medical Oncology Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning ProvinceLiaoning Provincial Clinical Research Center for CancerClinical Cancer Research Center of ShenyangThe First Hospital of China Medical UniversityShenyangLiaoning 110001China Research Center for Universal Health School of Public HealthChina Medical UniversityShenyangLiaoning 110122China

Immunogenic death is a form of programmed cell death that is common in the development and progression of ***,its impact on tumor progression differs depending on the location of the ***,it also plays an important role in antitumor immunity because the process of immunogenic death can release substances that activate immunity.1 Therefore,in this study,the key mechanism of mediating immunogenic death in hepatocellular carcinoma(HCC)was found from the excavation of the immunogenic death characteristics of pan-cancer and the in-depth investigation of its effects on different tumor types(Fig.1A).

关键词： death CXCR3 immunity

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Development of small molecule drugs targeting immune checkpoints

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Cancer Biology & Medicine 2024年第5期21卷 382-399页

作者： Luoyi Chen Xinchen Zhao Xiaowei Liu Yujie Ouyang Chuan Xu Ying Shi Department of Oncology Sichuan Academy of Medical SciencesSichuan Provincial People’s HospitalSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengdu 610054China Institute for Breast Health Medicine State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Acupuncture and Massage College Chengdu University of Traditional Chinese MedicineChengdu 611137China

Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune *** of small molecule drugs or biological materials,especially antibody-based ICIs,are actively being studied and antibodies are currently widely ***,such as anti-tumor efficacy,poor membrane permeability,and unneglected tolerance issues of antibody-based ICIs,remain evident but are thought to be overcome by small molecule *** structural studies have broadened the scope of candidate immune checkpoint molecules,as well as innovative chemical *** way of comparison,small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic *** ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions,including immune regulation,anti-angiogenesis,and cell cycle *** this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins,which will lay the foundation for further exploration.

关键词： Immune checkpoints small molecule drugs programmed death protein 1 CD47 signal-regulatory proteinα

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Large-scale loss-of-function perturbations reveal a comprehensive epigenetic regulatory network in breast cancer

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Cancer Biology & Medicine 2024年第1期21卷 83-103页

作者： Yumei Wang Haiyan Wang Wei Shao Yuhui Chen Yu Gui Chao Hu Xiaohong Yi Lijun Huang Shasha Li Dong Wang School of Basic Medical Sciences State Key Laboratory of Southwestern Chinese Medicine ResourcesChengdu University of Traditional Chinese MedicineChengdu 611137China Department of Pathology School of MedicineQinghai UniversityXining 810001China Omics Biosciences Inc Beijing 100871China laboratory of Integrative Medicine Clinical Research Center for BreastState Key Laboratory of BiotherapyWest China HospitalSichuan University and Collaborative Innovation CenterChengdu 610041China State Key laboratory of Southwestern Chinese Medicine Resources School of PharmacyChengdu University of Traditional Chinese MedicineChengdu 611137China Department of Endocrinology and Metabolism Guangdong Provincial Key Laboratory of Diabetology&Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity ResearchMedical Center for Comprehensive Weight ControlThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510630China

Objective:Epigenetic abnormalities have a critical role in breast cancer by regulating gene expression;however,the intricate interrelationships and key roles of approximately 400 epigenetic regulators in breast cancer remain *** is important to decipher the comprehensive epigenetic regulatory network in breast cancer cells to identify master epigenetic regulators and potential therapeutic ***:We employed high-throughput sequencing-based high-throughput screening(HTS^(2))to effectively detect changes in the expression of 2,986 genes following the knockdown of 400 epigenetic ***,bioinformatics analysis tools were used for the resulting gene expression signatures to investigate the epigenetic regulations in breast ***:Utilizing these gene expression signatures,we classified the epigenetic regulators into five distinct clusters,each characterized by specific *** discovered functional similarities between BAZ2B and SETMAR,as well as CLOCK and ***,we observed that CLOCK functions in a manner opposite to that of HDAC8 in downstream gene ***,we constructed an epigenetic regulatory network based on the gene expression signatures,which revealed 8 distinct modules and identified 10 master epigenetic regulators in breast ***:Our work deciphered the extensive regulation among hundreds of epigenetic *** identification of 10 master epigenetic regulators offers promising therapeutic targets for breast cancer treatment.

关键词： Epigenetic regulators breast cancer regulatory network HTS^(2)

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Aptamers targeting SARS-CoV-2 nucleocapsid protein exhibit potential ant1ip1 an-coronavirus activity

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1186-1198页

作者： Minghui Yang Chunhui Li Guoguo Ye Chenguang Shen Huiping Shi Liping Zhong Yuxin Tian Mengyuan Zhao Pengfei Wu Abid Hussain Tian Zhang Haiyin Yang Jun Yang Yuhua Weng Xinyue Liu Zhimin Wang Lu Gan Qianyu Zhang Yingxia Liu Ge Yang Yuanyu Huang Yongxiang Zhao School of Life Science Advanced Research Institute of Multidisciplinary ScienceKey Laboratory of Molecular Medicine and BiotherapyBeijing Institute of TechnologyBeijing 100081China National Clinical Research Center for infectious disease Shenzhen Third People’s HospitalSecond Hospital Affiliated to Southern University of Science and TechnologyShenzhen 518112China Guangdong Provincial Key laboratory of Tropical Disease Research School of Public HealthSouthern Medical UniversityGuangzhou 510515China State Key laboratory of Targeting Oncology National Center for International Research of Biotargeting TheranosticsGuangxi Key Laboratory of Biotargeting TheranosticsCollaborative Innovation Center for Targeting Tumor Diagnosis and TherapyGuangxi Medical UniversityNanning 530021China CAMS Key laboratory of Antiviral Drug Research Beijing Key Laboratory of Antimicrobial AgentsInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China

Emerging and recurrent infectious diseases caused by human coronaviruses(HCoVs)continue to pose a significant threat to global public health *** light of this ongoing threat,the development of a broad-spectrum drug to combat HCoVs is an urgently ***,we report a series of anti-pan-coronavirus ssDNA aptamers screened using Systematic Evolution of Ligands by Exponential Enrichment(SELEX).These aptamers have nanomolar affinity with the nucleocapsid protein(NP)of Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and also show excellent binding efficiency to the N proteins of both SARS,MERS,HCoV-OC43 and-NL63 with affinity KD values of 1.31 to 135.36 *** aptamer-based therapeutics exhibited potent antiviral activity against both the authentic SARS-CoV-2 prototype strain and the Omicron variant(BA.5)with EC50 values at 2.00 nM and 41.08 nM,*** protein docking analysis also evidenced that these aptamers exhibit strong affinities for N proteins of pan-coronavirus and other HCoVs(−229E and-HKU1).In conclusion,we have identified six aptamers with a high pan-coronavirus antiviral activity,which could potentially serve as an effective strategy for preventing infections by unknown coronaviruses and addressing the ongoing global health threat.

关键词： acute threat conclusion

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Insights and implications of sexual dimorphism in osteoporosis

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Bone Research 2024年第1期12卷 20-49页

作者： Yuan-Yuan Zhang Na Xie Xiao-Dong Sun Edouard C.Nice Yih-Cherng Liou Canhua Huang Huili Zhu Zhisen Shen Key laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China West China School of Basic Medical Sciences&Forensic Medicine Sichuan UniversityChengdu 610041China Department of Biochemistry and Molecular Biology Monash UniversityClaytonVIC 3800Australia Department of Biological Sciences Faculty of ScienceNational University of SingaporeSingapore 117543Republic of Singapore Department of biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China Hospitaland West China School of Basic Medical Sciences&Forensic MedicineSichuan UniversityChengdu 610041China Key laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education Department of Reproductive MedicineWest China Second University Hospital of Sichuan UniversityChengduChina Department of Otorhinolaryngology and Head and Neck Surgery The Affiliated Lihuili HospitalNingbo University315040 NingboZhejiangChina

Osteoporosis,a metabolic bone disease characterized by low bone mineral density and deterioration of bone microarchitecture,has led to a high risk of fatal osteoporotic fractures *** evidence has revealed that sexual dimorphism is a notable feature of osteoporosis,with sex-specific differences in epidemiology and ***,females are more susceptible than males to osteoporosis,while males are more prone to disability or death from the *** date,sex chromosome abnormalities and steroid hormones have been proven to contribute greatly to sexual dimorphism in osteoporosis by regulating the functions of bone *** the sex-specific differences in osteoporosis and its related complications is essential for improving treatment strategies tailored to women and *** literature review focuses on the mechanisms underlying sexual dimorphism in osteoporosis,mainly in a population of aging patients,chronic glucocorticoid administration,and ***,we highlight the implications of sexual dimorphism for developing therapeutics and preventive strategies and screening approaches tailored to women and ***,the challenges in translating bench research to bedside treatments and future directions to overcome these obstacles will be discussed.

关键词： osteoporosis epidemiology overcome

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Branched glycopolymer prodrug-derived nanoassembly combined with a STING agonist activates an immuno-supportive status to boost anti-PD-L1 antibody therapy

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2194-2209页

作者： Zhilin Li Qianfeng Zhang Zhiqian Li Long Ren Dayi Pan Qiyong Gong Zhongwei Gu Hao Cai Kui Luo Department of Radiology Huaxi MR Research Center(HMRRC)Clinical Research Center for BreastDepartment of Breast SurgeryDepartment of Thoracic Surgery and Institute of Thoracic OncologyFrontiers Science Center for Disease-Related Molecular NetworkState Key Laboratory of BiotherapyWest China Hospital Sichuan UniversityChengdu 610041China Functional and Molecular Imaging Key laboratory of Sichuan Province and Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengdu 610041China Department of Radiology West China Xiamen Hospital of Sichuan UniversityXiamen 361021China Key laboratory of Medicinal Chemistry for Natural Resource Ministry of EducationYunnan Key Laboratory of Research and Development for Natural ProductsSchool of PharmacyYunnan UniversityKunming 650500China

Despite the great potential of anti-PD-L1 antibodies for immunotherapy,their low response rate due to an immunosuppressive tumor microenvironment has hampered their *** address this issue,we constructed a cell membrane-coated nanosystem(mB4S)to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor *** this system,Epirubicin(EPI)as an immunogenic cell death(ICD)inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes(STING)agonist was encapsulated into *** internalization of mB4S,EPI was acidic-responsively released to induce ICD,which was characterized by an increased level of calreticulin(CRT)exposure and enhanced ATP ***,diABZI effectively activated the STING *** with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells(DCs)and CD8+T cells,promoting cytokines secretion,up-regulating M1-like tumor-associated macrophages(TAMs)and down-regulating immunosuppressive myeloid-derived suppressor cells(MDSCs).Therefore,this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+T cells infiltration,creating an immuno-supportive microenvironment,thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.

关键词： Glycopolymer Polymer prodrug Immunogenic cell death Nanoassembly Epirubicin STING pathway Immuno-supportive microenvironment Immunotherapy

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