50 results on '"Cong-Fei Xu"'
Search Results
2. Engineering nano‐clustered multivalent agonists to cross‐link TNF receptors for cancer therapy
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Yue Zhang, Gui Zhao, Yi‐Fang Chen, Shi‐Kun Zhou, Yue Wang, Yi‐Qun Sun, Song Shen, Cong‐Fei Xu, and Jun Wang
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antibody ,cancer therapy ,drug delivery ,nanoparticle ,TNFR ,Chemistry ,QD1-999 ,Biology (General) ,QH301-705.5 - Abstract
Abstract Tumor necrosis factor receptors (TNFRs) are promising targets for cancer therapy. However, activating their downstream signaling requires cross‐linking of TNFRs. Herein, to devise strong agonists of TNFRs, ligands targeting TNFRs, such as OX40L and tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), were fused with a multivalent protein scaffold (MV) to prepare multivalent agonists for cross‐linking TNFRs. The nano‐clustered multivalent‐OX40L (MV‐OX40L) and MV‐TRAIL could promote T cell activation and directly induce tumor cell apoptosis. Moreover, to develop a universal nano‐adaptor for the rapid preparation of multivalent agonists of different TNFRs, the Fc receptor that could immobilize antibodies was fused with MV to prepare MV‐FcR, which could multimerize commercial agonist antibodies targeting TNFRs, such as anti‐OX40 antibody (αOX40). Simply incubating αOX40 with MV‐FcR could prepare MV‐αOX40 to enhance its antitumor efficacy. In addition, MV‐FcR could multimerize with other therapeutic antibodies, such as anti‐PD‐L1 antibody, to enhance their valency. This study provides a promising strategy for engineering multivalent antitumor protein drugs.
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- 2023
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3. Immunomodulating nano-adaptors potentiate antibody-based cancer immunotherapy
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Cheng-Tao Jiang, Kai-Ge Chen, An Liu, Hua Huang, Ya-Nan Fan, Dong-Kun Zhao, Qian-Ni Ye, Hou-Bing Zhang, Cong-Fei Xu, Song Shen, Meng-Hua Xiong, Jin-Zhi Du, Xian-Zhu Yang, and Jun Wang
- Subjects
Science - Abstract
Current strategies to boost anti-tumor immune response include the use of immune checkpoint inhibitors and bispecific T cell-engaging antibodies. Here the authors describe a versatile antibody immobilization nanoplatform that can be used to deliver different combinations of immunotherapeutics, showing therapeutic superiority in pre-clinical models.
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- 2021
- Full Text
- View/download PDF
4. Delivery systems for siRNA drug development in cancer therapy
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Cong-fei Xu and Jun Wang
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RNA interference ,Cancer therapy ,Delivery systems ,siRNA ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Since the discovery of the Nobel prize-winning mechanism of RNA interference (RNAi) ten years ago, it has become a promising drug target for the treatment of multiple diseases, including cancer. There have already been some successful applications of siRNA drugs in the treatment of age-related macular degeneration and respiratory syncytial virus infection. However, significant barriers still exist on the road to clinical applications of siRNA drugs, including poor cellular uptake, instability under physiological conditions, off-target effects and possible immunogenicity. The successful application of siRNA for cancer therapy requires the development of clinically suitable, safe and effective drug delivery systems. Herein, we review the design criteria for siRNA delivery systems and potential siRNA drug delivery systems for cancer therapy, including chemical modifications, lipid-based nanovectors, polymer-mediated delivery systems, conjugate delivery systems, and others.
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- 2015
- Full Text
- View/download PDF
5. Progress in nanoparticle-based regulation of immune cells
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Ya-Nan Fan, Gui Zhao, Yue Zhang, Qian-Ni Ye, Yi-Qun Sun, Song Shen, Yang Liu, Cong-Fei Xu, and Jun Wang
- Abstract
Immune cells are indispensable defenders of the human body, clearing exogenous pathogens and toxicities or endogenous malignant and aging cells. Immune cell dysfunction can cause an inability to recognize, react, and remove these hazards, resulting in cancers, inflammatory diseases, autoimmune diseases, and infections. Immune cells regulation has shown great promise in treating disease, and immune agonists are usually used to treat cancers and infections caused by immune suppression. In contrast, immunosuppressants are used to treat inflammatory and autoimmune diseases. However, the key to maintaining health is to restore balance to the immune system, as excessive activation or inhibition of immune cells is a common complication of immunotherapy. Nanoparticles are efficient drug delivery systems widely used to deliver small molecule inhibitors, nucleic acid, and proteins. Using nanoparticles for the targeted delivery of drugs to immune cells provides opportunities to regulate immune cell function. In this review, we summarize the current progress of nanoparticle-based strategies for regulating immune function and discuss the prospects of future nanoparticle design to improve immunotherapy.
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- 2023
6. In Situ Programming of Nanovaccines for Lymph Node-Targeted Delivery and Cancer Immunotherapy
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Liangjie Jin, Dongmei Yang, Yonghong Song, Dongdong Li, Weijia Xu, Yueqiang Zhu, Cong-Fei Xu, Yang Lu, and Xianzhu Yang
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General Engineering ,General Physics and Astronomy ,General Materials Science - Published
- 2022
7. Optimized Cationic Lipid-assisted Nanoparticle for Delivering CpG Oligodeoxynucleotides to Treat Hepatitis B Virus Infection
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Yi-Fang Chen, Yan Wang, Yue Wang, Ying-Li Luo, Zi-Dong Lu, Xiao-Jiao Du, Cong-Fei Xu, and Jun Wang
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Pharmacology ,Organic Chemistry ,Pharmaceutical Science ,Molecular Medicine ,Pharmacology (medical) ,Biotechnology - Abstract
Hepatitis B virus (HBV) infection is such a global health problem that hundreds of millions of people are HBV carriers. Current anti-viral agents can inhibit HBV replication, but can hardly eradicate HBV. Cytosine-phosphate-guanosine (CpG) oligodeoxynucleotides (ODNs) are an adjuvant that can activate plasmacytoid dendritic cells (pDCs) and conventional dendritic cells (cDCs) to induce therapeutic immunity for HBV eradication. However, efficient delivery of CpG ODNs into pDCs and cDCs remains a challenge. In this study, we constructed a series of cationic lipid-assisted nanoparticles (CLANs) using different cationic lipids to screen an optimal nanoparticle for delivering CpG ODNs into pDCs and cDCs.We constructed different CLANWe found that CLAN fabricated with 1,2-Dioleoyl-3-trimethylammonium propane (DOTAP) showed the highest efficiency for delivering CpG ODNs into pDCs and cDCs, resulting in strong therapeutic immunity in HBV-carrier mice. By using CLANWe screened an optimized CLAN fabricated with DOTAP for efficient delivery of CpG ODNs to pDCs and cDCs, which can act as a therapeutic vaccine adjuvant for treating HBV infection.
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- 2022
8. Rigid Shell Decorated Nanodevice with Fe/H 2 O 2 Supply and Glutathione Depletion Capabilities for Potentiated Ferroptosis and Synergized Immunotherapy
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Xu Dai, Yueqiang Zhu, Miao Su, Junbin Chen, Song Shen, Cong‐Fei Xu, and Xianzhu Yang
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Biomaterials ,Electrochemistry ,Condensed Matter Physics ,Electronic, Optical and Magnetic Materials - Published
- 2023
9. An Intracellular pH-Actuated Polymer for Robust Cytosolic Protein Delivery
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Wei Xu, Wei-Min Miao, Jin-Zhi Du, Yue Zhang, Jia-Xian Li, Jun Wang, Cong-Fei Xu, Feng-Qin Luo, and Qi-Song Tong
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chemistry.chemical_classification ,Chemistry ,Intracellular pH ,media_common.quotation_subject ,Cell ,General Chemistry ,Plasma protein binding ,Polymer ,Cytosol ,medicine.anatomical_structure ,Biophysics ,medicine ,Internalization ,media_common - Abstract
Robust cytosolic protein delivery requires both efficient protein binding with delivery vehicles and effective protein release after cell internalization. Although a variety of stimuli-responsive c...
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- 2021
10. Engineering tumor-specific gene nanomedicine to recruit and activate T cells for enhanced immunotherapy
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Yue Wang, Shi-Kun Zhou, Yan Wang, Zi-Dong Lu, Yue Zhang, Cong-Fei Xu, and Jun Wang
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
PD-1/PD-L1 blockade therapy that eliminates intratumoral inhibition signals of T cells is successful, but poor therapeutic benefits are often observed. Increasing T-cell infiltration and the quantity of PD-1/PD-L1 inhibitors in tumor tissue can improve efficacy but remains challenging. Herein, we devised tumor-specific gene nanomedicines to mobilize tumor cells themselves to robustly secrete CXCL9 (a chemokine of T cells) and anti-PD-L1 scFv (αPD-L1, a blocking agent of PD-L1) for enhanced immunotherapy. Our tyrosinase promoter-driven gene nanomedicine, NPTyr-C9AP, can specifically coexpress CXCL9 and αPD-L1 in melanoma cells, thereby forming a sharp gradient of CXCL9 between tumor and peripheral tissues for T-cell recruitment and a high intratumoral concentration of αPD-L1 for enhancing T-cell activation. As a result, NPTyr-C9AP treatment showed strong antimelanoma effects. Furthermore, specific coexpression of CXCL9 and αPD-L1 in various tumor cells was achieved by replacing the tyrosinase promoter of NPTyr-C9AP with a survivin promoter, which increased the infiltration and activation of T cells as well as therapeutic efficacy in multiple tumors. This study provides a novel strategy to maximize the immunotherapeutic outcome regardless of the heterogeneous tumor microenvironment.
- Published
- 2022
11. HSP70-Promoter-Driven CRISPR/Cas9 System Activated by Reactive Oxygen Species for Multifaceted Anticancer Immune Response and Potentiated Immunotherapy
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Liang Zhao, Dongdong Li, Yuxi Zhang, Qiaoyi Huang, Zhenghai Zhang, Chaoran Chen, Cong-Fei Xu, Xiao Chu, Yu Zhang, and Xianzhu Yang
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Dendrimers ,General Engineering ,Immunity ,General Physics and Astronomy ,B7-H1 Antigen ,CRISPR-Associated Protein 9 ,Cell Line, Tumor ,Tumor Microenvironment ,Immunologic Factors ,General Materials Science ,Immunotherapy ,CRISPR-Cas Systems ,Reactive Oxygen Species ,Immune Checkpoint Inhibitors - Abstract
To address the low response rate to immune checkpoint blockade (ICB) therapy, we propose a specific promoter-driven CRISPR/Cas9 system, F-PC/pHCP, that achieves permanent genomic disruption of PD-L1 and elicits a multifaceted anticancer immune response to potentiate immunotherapy. This system consists of a chlorin e6-encapsulated fluorinated dendrimer and HSP70-promoter-driven CRISPR/Cas9. F-PC/pHCP under 660 nm laser activated the HSP70 promoter and enabled the specific expression of the Cas9 protein to disrupt the PD-L1 gene, preventing immune escape. Moreover, F-PC/pHCP also induced immunogenic cell death (ICD) of tumor cells and reprogrammed the immunosuppressive tumor microenvironment. Overall, this specific promoter-driven CRISPR/Cas9 system showed great anticancer efficacy and, more importantly, stimulated an immune memory response to inhibit distant tumor growth and lung metastasis. This CRISPR/Cas9 system represents an alternative strategy for ICB therapy as well as enhanced cancer immunotherapy.
- Published
- 2022
12. Co-delivery of Phagocytosis Checkpoint Silencer and Stimulator of Interferon Genes Agonist for Synergetic Cancer Immunotherapy
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Yi-Fang Chen, Cong-Fei Xu, Zi-Dong Lu, Song Shen, and Jun Wang
- Subjects
Male ,0301 basic medicine ,Small interfering RNA ,Materials science ,medicine.medical_treatment ,Antineoplastic Agents ,Mice, Transgenic ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Phagocytosis ,Cancer immunotherapy ,Antigen ,Antigens, Neoplasm ,Cell Line, Tumor ,medicine ,Animals ,General Materials Science ,Receptors, Immunologic ,Cells, Cultured ,Tumor microenvironment ,Membrane Proteins ,Neoplasms, Experimental ,030104 developmental biology ,030220 oncology & carcinogenesis ,Stimulator of interferon genes ,Cancer research ,Immunotherapy ,Nucleotides, Cyclic ,Signal transduction ,CD8 ,Signal Transduction - Abstract
Efficient capture and presentation of tumor antigens by antigen-presenting cells (APCs), especially dendritic cells (DCs), are crucial for activating the anti-tumor immunity. However, APCs are immunosuppressed in the tumor microenvironment, which hinders the tumor elimination. To reprogram APCs for inducing strong anti-tumor immunity, we report here a co-delivery immunotherapeutic strategy targeting the phagocytosis checkpoint (signal regulatory protein α, SIRPα) and stimulator of interferon genes (STING) of APCs to jointly enhance their ability of capturing and presenting tumor antigens. In brief, a small interfering RNA targeting SIRPα (siSIRPα) and a STING agonist (cGAMP) were co-delivered into APCs by the encapsulation into poly(ethylene glycol)-b-poly(lactide-co-glycolide)-based polymeric nanoparticles (NPsiSIRPα/cGAMP). siSIRPα-mediated SIRPα silence promoted APCs to actively capture tumor antigens by engulfing tumor cells. The cGAMP-stimulated STING signaling pathway further enhanced the functions of APCs, thereby increased the activation and expansion of CD8+ T cells. Using ovalbumin (OVA)-expressing melanoma as a model, we demonstrated that NPsiSIRPα/cGAMP stimulated the activation of OVA-specific CD8+ T cells and induced holistic anti-tumor immune responses by reversing the immunosuppressive phenotype of APCs. Collectively, this co-delivery strategy synergistically enhanced the functions of APCs and can be extended to the treatment of tumors with poor immunogenicity.
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- 2021
13. dsRNA as broad-spectrum antiviral therapeutics
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Cong-Fei Xu
- Subjects
Drug Discovery ,Molecular Medicine - Published
- 2022
14. Rational designs of in vivo CRISPR-Cas delivery systems
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Guojun Chen, Yue Zhang, Jun Wang, Gui Zhao, Zi-Dong Lu, Anna Czarna, Ying-Li Luo, Cong-Fei Xu, and Zhen Gu
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Transcription, Genetic ,Computer science ,Genetic Vectors ,Pharmaceutical Science ,02 engineering and technology ,Computational biology ,Exosomes ,Genome ,Epigenome ,03 medical and health sciences ,Drug Delivery Systems ,Genome editing ,In vivo ,CRISPR ,Clustered Regularly Interspaced Short Palindromic Repeats ,Gene Regulatory Networks ,030304 developmental biology ,Ribonucleoprotein ,Gene Editing ,0303 health sciences ,RNA ,021001 nanoscience & nanotechnology ,Lipids ,humanities ,Drug delivery ,Nucleic acid ,Nanoparticles ,CRISPR-Cas Systems ,0210 nano-technology - Abstract
The CRISPR-Cas system initiated a revolution in genome editing when it was, for the first time, demonstrated success in the mammalian cells. Today, scientists are able to readily edit genomes, regulate gene transcription, engineer posttranscriptional events, and image nucleic acids using CRISPR-Cas-based tools. However, to efficiently transport CRISPR-Cas into target tissues/cells remains challenging due to many extra- and intra-cellular barriers, therefore largely limiting the applications of CRISPR-based therapeutics in vivo. In this review, we summarize the features of plasmid-, RNA- and ribonucleoprotein (RNP)-based CRISPR-Cas therapeutics. Then, we survey the current in vivo delivery systems. We specify the requirements for efficient in vivo delivery in clinical settings, and highlight both efficiency and safety for different CRISPR-Cas tools.
- Published
- 2021
15. An All-in-One Nanomedicine Consisting of CRISPR-Cas9 and an Autoantigen Peptide for Restoring Specific Immune Tolerance
- Author
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Jing Liu, Anna Czarna, Cong-Fei Xu, Xiao-Jiao Du, Ya-Nan Fan, Yun-Jiu Gan, Song Shen, Yue Zhang, Li-Fang Liang, Gui Zhao, Zi-Dong Lu, Jun Wang, Zhe-Xiong Lian, and Ying-Li Luo
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Materials science ,Surface Properties ,Peptide ,medicine.disease_cause ,Autoantigens ,030226 pharmacology & pharmacy ,Autoimmunity ,Immune tolerance ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Mice, Inbred NOD ,Immune Tolerance ,medicine ,Animals ,Humans ,General Materials Science ,Particle Size ,Cell Engineering ,Cells, Cultured ,CD86 ,chemistry.chemical_classification ,CD40 ,biology ,Dendritic Cells ,Cell biology ,Nanomedicine ,chemistry ,030220 oncology & carcinogenesis ,Drug delivery ,biology.protein ,CRISPR-Cas Systems ,Peptides ,CD80 - Abstract
Nanotechnology has shown great promise in treating diverse diseases. However, developing nanomedicines that can cure autoimmune diseases without causing systemic immunosuppression is still quite challenging. Herein, we propose an all-in-one nanomedicine comprising an autoantigen peptide and CRISPR-Cas9 to restore specific immune tolerance by engineering dendritic cells (DCs) into a tolerogenic phenotype, which can expand autoantigen-specific regulatory T (Treg) cells. In brief, we utilized cationic lipid-assisted poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-PLGA) nanoparticles to simultaneously encapsulate an autoimmune diabetes-relevant peptide (2.5mi), a CRISPR-Cas9 plasmid (pCas9), and three guide RNAs (gRNAs) targeting costimulatory molecules (CD80, CD86, and CD40). We demonstrated that the all-in-one nanomedicine was able to effectively codeliver these components into DCs, followed by simultaneous disruption of the three costimulatory molecules and presentation of the 2.5mi peptide on the genome-edited DCs. The resulting tolerogenic DCs triggered the generation and expansion of autoantigen-specific Treg cells by presenting the 2.5mi peptide to CD4+ T cells in the absence of costimulatory signals. Using autoimmune type 1 diabetes (T1D) as a typical disease model, we demonstrated that our nanomedicine prevented autoimmunity to islet components and inhibited T1D development. Our all-in-one nanomedicine achieved codelivery of CRISPR-Cas9 and the peptide to DCs and could be easily applied to other autoimmune diseases by substitution of different autoantigen peptides.
- Published
- 2020
16. A General Strategy for Macrotheranostic Prodrug Activation: Synergy between the Acidic Tumor Microenvironment and Bioorthogonal Chemistry
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Youyong Yuan, Yalan Tu, Jun Wang, Kewei Wang, Yansong Dong, and Cong-Fei Xu
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Cell Survival ,Polymers ,Mice, Nude ,Tetrazoles ,Context (language use) ,Antineoplastic Agents ,Breast Neoplasms ,010402 general chemistry ,01 natural sciences ,Catalysis ,Theranostic Nanomedicine ,Tetrazine ,chemistry.chemical_compound ,Mice ,Cell Line, Tumor ,Tumor Microenvironment ,Animals ,Prodrugs ,Micelles ,Cell Proliferation ,chemistry.chemical_classification ,Tumor microenvironment ,Mice, Inbred BALB C ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Optical Imaging ,Mammary Neoplasms, Experimental ,General Chemistry ,General Medicine ,Hydrogen-Ion Concentration ,Prodrug ,Combinatorial chemistry ,0104 chemical sciences ,Enzyme ,Drug delivery ,Click chemistry ,Biophysics ,Nanoparticles ,Click Chemistry ,Female ,Drug Screening Assays, Antitumor ,Bioorthogonal chemistry - Abstract
Prodrugs activated by endogenous stimuli face the problem of tumor heterogeneity. Bioorthogonal prodrug activation that utilizes an exogenous click reaction has the potential to solve this problem, but most of the strategies currently used rely on the presence of endogenous receptors or overexpressed enzymes. We herein integrate the acidic, extracellular microenvironment of a tumor and a click reaction as a general strategy for prodrug activation. This was achieved by using a tumor pH-responsive polymer containing tetrazine groups, which formed unreactive micelles in the blood but disassembled in response to tumor pH. The vinyl ether group on the macrotheranostic prodrug (CyPVE) is activated by the tetrazine groups, which was confirmed by tumor-specific fluorescence activation and phototoxicity restoration. Therefore, the bioorthogonal reactions in the context of the ubiquitous acidic tumor microenvironment can provide a general strategy for bioorthogonal prodrug activation.
- Published
- 2020
17. Dually regulating the proliferation and the immune microenvironment of melanomaviananoparticle-delivered siRNA targeting onco-immunologic CD155
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Song Shen, Zi-Dong Lu, Yan Wang, Anna Czarna, Yue Wang, Ying-Li Luo, Jun Wang, Cong-Fei Xu, and Yi-Fang Chen
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Skin Neoplasms ,Biomedical Engineering ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Tumor Microenvironment ,medicine ,Animals ,Gene silencing ,General Materials Science ,CD155 ,RNA, Small Interfering ,Melanoma ,neoplasms ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,Oncogene ,biology ,Chemistry ,medicine.disease ,Immune checkpoint ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Nanoparticles ,Receptors, Virus ,Reprogramming ,Poliovirus Receptor - Abstract
Studies have shown that the simultaneous regulation of tumor cell proliferation and the suppressive tumor immune microenvironment (TIME) could achieve better therapeutic effects. However, the targets of the proliferation and the TIME are different, which greatly limits the development of cancer therapy. A recent study found CD155, a highly expressed poliovirus receptor in melanoma cells and melanoma-infiltrating macrophages, functions as both an oncogene and immune checkpoint. Thus, it is supposed that targeting CD155 could bring dual therapeutic effects. Herein, we propose silencing the CD155 of melanoma cells and melanoma-infiltrating macrophages by a nanoparticle-delivered small interference RNA (siRNA) targeting CD155 (siCD155). We encapsulated siCD155 into cationic lipid-assisted nanoparticles (CLANsiCD155) and demonstrated that the intravenous injection of CLANsiCD155 could efficiently deliver siCD155 into melanoma cells and melanoma-infiltrating macrophages. The downregulation of CD155 in melanoma cells directly inhibited their proliferation, and meanwhile, the downregulation of CD155 in melanoma-infiltrating macrophages increased the activation of NK cells and T cells. Owing to this dual effect, CLANsiCD155 significantly inhibited the growth of B16-F10 melanoma. Our study suggests that nanoparticle-delivered siCD155 may be a simple but effective strategy for inhibiting tumor proliferation and reprogramming TIME.
- Published
- 2020
18. Delivery of mRNA for regulating functions of immune cells
- Author
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Jia Shi, Meng-Wen Huang, Zi-Dong Lu, Xiao-Jiao Du, Song Shen, Cong-Fei Xu, and Jun Wang
- Subjects
COVID-19 Vaccines ,SARS-CoV-2 ,Liposomes ,Pharmaceutical Science ,COVID-19 ,Humans ,Nanoparticles ,RNA, Messenger - Abstract
Abnormal immune cell functions are commonly related to various diseases, including cancer, autoimmune diseases, and infectious diseases. Messenger RNA (mRNA)-based therapy can regulate the functions of immune cells or assign new functions to immune cells, thereby generating therapeutic immune responses to treat these diseases. However, mRNA is unstable in physiological environments and can hardly enter the cytoplasm of target cells; thus, effective mRNA delivery systems are critical for developing mRNA therapy. The two mRNA vaccines of Pfizer-BioNTech and Moderna have demonstrated that lipid nanoparticles (LNPs) can deliver mRNA into dendritic cells (DCs) to induce immunization against severe acute respiratory syndrome coronavirus 2, which opened the floodgates to the development of mRNA therapy. Apart from DCs, other immune cells are promising targets for mRNA therapy. This review summarized the barriers to mRNA delivery and advances in mRNA delivery for regulating the functions of different immune cells.
- Published
- 2021
19. Enhanced Primary Tumor Penetration Facilitates Nanoparticle Draining into Lymph Nodes after Systemic Injection for Tumor Metastasis Inhibition
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Ying-Li Luo, Jing Liu, Xiao-Jiao Du, Hongjun Li, Cong-Fei Xu, Jin-Zhi Du, and Jun Wang
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medicine.medical_treatment ,General Physics and Astronomy ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Metastasis ,Mice ,Cell Movement ,Cell Line, Tumor ,Neoplasms ,Animals ,Humans ,Medicine ,Neoplasm Invasiveness ,General Materials Science ,Cell Proliferation ,Chemotherapy ,business.industry ,General Engineering ,Intravasation ,021001 nanoscience & nanotechnology ,medicine.disease ,Primary tumor ,0104 chemical sciences ,Lymphatic system ,Lymphatic Metastasis ,Drug delivery ,Cancer research ,Systemic administration ,Heterografts ,Nanoparticles ,Lymph ,0210 nano-technology ,business - Abstract
Lymph nodes (LNs) are normally the primary site of tumor metastasis, and effective delivery of chemotherapeutics into LNs through systemic administration is critical for metastatic cancer treatment. Here, we uncovered that improved perfusion in a primary tumor facilitates nanoparticle translocation to LNs for inhibiting tumor metastasis. On the basis of our finding that an iCluster platform, which undergoes size reduction from ∼100 nm to ∼5 nm at the tumor site, markedly improved particle perfusion in the interstitium of the primary tumor, we further revealed in the current study that such tumor-specific size transition promoted particle intravasation into tumor lymphatics and migration into LNs. Quantitative analysis indicated that the drug deposition in LNs after iCluster treatment was significantly higher in the presence of a primary tumor in comparison with that after primary tumor resection. Early intervention of metastatic 4T1 tumors with iCluster chemotherapy and subsequent surgical resection of the primary tumor resulted in significantly extending animal survival, with 4 out of the 10 mice remaining completely tumor-free for 110 days. Additionally, in the more clinical relevant late metastatic model, iCluster inhibited the metastatic colonies to the lungs and extended animal survival time. This finding provides insights into the design of more effective nanomedicines for treating metastatic cancer.
- Published
- 2019
20. Facile Hydrophobization of siRNA with Anticancer Drug for Non-Cationic Nanocarrier-Mediated Systemic Delivery
- Author
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Xianzhu Yang, Meng-Hua Xiong, Zhi-Ting Cao, Jun Wang, Dongdong Li, and Cong-Fei Xu
- Subjects
Small interfering RNA ,Polymers ,Antineoplastic Agents ,Bioengineering ,02 engineering and technology ,Micelle ,Polyethylene Glycols ,Drug Delivery Systems ,Cations ,Neoplasms ,PEG ratio ,Humans ,General Materials Science ,RNA, Small Interfering ,Cytotoxicity ,Micelles ,Drug Carriers ,Chemistry ,Mechanical Engineering ,Cationic polymerization ,General Chemistry ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,Anticancer drug ,Combinatorial chemistry ,Doxorubicin ,Lactates ,Nanoparticles ,Doxorubicin Hydrochloride ,Nanocarriers ,0210 nano-technology ,Hydrophobic and Hydrophilic Interactions - Abstract
The inherent features of small interfering RNA (siRNA), including a relatively high molecular weight, negative charge, and hydrophilic nature, lead to the widespread use of cationic polymers and lipid-based nanocarriers, which might induce potential cytotoxicity, thus limiting their clinical application. Here, we report a facile strategy for changing the inherent features of siRNA molecules by achieving hydrophobization. We found that the simple mixing of siRNA and doxorubicin hydrochloride (DOX·HCl) could form a hydrophobic complex, which was readily encapsulated into noncationic PEG- b-PLA micelles for systemic delivery. In addition to delivering DOX·HCl, this strategy could be extended to deliver other hydrochloride forms of anticancer drugs with large hydrophobic domains. This facile strategy efficiently avoids the use of cationic nanocarriers, providing a new avenue for siRNA delivery.
- Published
- 2019
21. Nanoparticle-delivered siRNA targeting Bruton's tyrosine kinase for rheumatoid arthritis therapy
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Hou-Bing Zhang, An Liu, Cong-Fei Xu, Zhi-Ting Cao, Gui Zhao, Zu-Qi Zuo, Yue Zhang, and Jun Wang
- Subjects
Small interfering RNA ,Biomedical Engineering ,Arthritis ,Inflammation ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Arthritis, Rheumatoid ,Mice ,hemic and lymphatic diseases ,Agammaglobulinaemia Tyrosine Kinase ,Adalimumab ,medicine ,Animals ,Gene silencing ,Bruton's tyrosine kinase ,General Materials Science ,RNA, Small Interfering ,Protein Kinase Inhibitors ,biology ,business.industry ,021001 nanoscience & nanotechnology ,medicine.disease ,0104 chemical sciences ,Rheumatoid arthritis ,biology.protein ,Cancer research ,Nanoparticles ,medicine.symptom ,0210 nano-technology ,business ,Tyrosine kinase ,medicine.drug - Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease that can cause irreversible joint deformity. There is still no cure for RA, and current therapeutics, including methotrexate and adalimumab, cause serious off-target effects and systemic immunosuppression, which in turn increases the risk of infection. Bruton's tyrosine kinase (BTK) in macrophages and B cells has been demonstrated to be a promising therapeutic target for RA. However, high doses of BTK inhibitors are required for efficient BTK suppression, which limits their clinical use. Small interfering RNA (siRNA) is promising for the silencing of specific genes and has been used for the treatment of multiple diseases. To deliver siRNA into macrophages and B cells for BTK gene silencing, we employed cationic lipid-assisted PEG-b-PLGA nanoparticles (CLANs) to encapsulate siRNA. We demonstrated that macrophages and B cells were able to efficiently ingest the CLANs both in vitro and in vivo. Thereafter, we encapsulated siRNA targeting BTK (siBTK) into the CLANs, denoted as CLANsiBTK, and demonstrated that CLANsiBTK significantly inhibited BTK expression in macrophages and B cells. In a collagen-induced mouse arthritis model, CLANsiBTK treatment dramatically reduced joint inflammation and other RA symptoms but showed no toxicity, proving that using CLANsiBTK is a promising approach for RA therapy.
- Published
- 2019
22. The effect of surface poly(ethylene glycol) length on in vivo drug delivery behaviors of polymeric nanoparticles
- Author
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Ji-Long Wang, Jun Wang, Jinxian Yang, Ying-Li Luo, Hongjun Li, Shoaib Iqbal, Song Shen, Xiaodong Ye, Xiao-Jiao Du, Jie Cao, and Cong-Fei Xu
- Subjects
Biophysics ,Mice, Nude ,Nanoparticle ,Antineoplastic Agents ,Bioengineering ,Docetaxel ,macromolecular substances ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Polyethylene Glycols ,Biomaterials ,Lactones ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Neoplasms ,PEG ratio ,Copolymer ,Animals ,Drug Carriers ,Mice, Inbred BALB C ,Mice, Inbred ICR ,Molecular mass ,technology, industry, and agriculture ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Molecular Weight ,Chemical engineering ,chemistry ,Mechanics of Materials ,Drug delivery ,Ceramics and Composites ,Nanoparticles ,Female ,Absorption (chemistry) ,0210 nano-technology ,Ethylene glycol - Abstract
Engineering nanoparticles of reasonable surface poly(ethylene glycol) (PEG) length is important for designing efficient drug delivery systems. Eliminating the disturbance by other nanoproperties, such as size, PEG density, etc., is crucial for systemically investigating the impact of surface PEG length on the biological behavior of nanoparticles. In the present study, nanoparticles with different surface PEG length but similar other nanoproperties were prepared by using poly(ethylene glycol)-block-poly(e-caprolactone) (PEG-b -PCL) copolymers of different molecular weights and incorporating different contents of PCL 3500 homopolymer . The molecular weight of PEG block in PEG-PCL was between 3400 and 8000 Da, the sizes of nanoparticles were around 100 nm, the terminal PEG density was controlled at 0.4 PEG/nm 2 (or the frontal PEG density was controlled at 0.16 PEG/nm2 ). Using these nanoproperties well-designed nanoparticles, we demonstrated PEG length-dependent changes in the biological behaviors of nanoparticles and exhibited nonmonotonic improvements as the PEG molecular weight increased from 3400 to 8000 Da. Moreover, under the experimental conditions, we found nanoparticles with a surface PEG length of 13.8 nm (MW = 5000 Da) significantly decreased the absorption with serum protein and interaction with macrophages, which led to prolonged blood circulation time , enhanced tumor accumulation and improved antitumor efficacy. The present study will help to establish a relatively precise relationship between surface PEG length and the in vivo behavior of nanoparticles.
- Published
- 2018
23. Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases
- Author
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Cong-Fei Xu, Zhi-Yao Chen, Ying-Li Luo, Yang Liu, Zhen Gu, Jing Liu, Zhi-Ting Cao, Zi-Dong Lu, Kai-Ge Chen, Jun Wang, Hongjun Li, Xianzhu Yang, and Song Shen
- Subjects
0301 basic medicine ,Male ,Inflammasomes ,Protein Conformation ,Science ,General Physics and Astronomy ,Adipose tissue ,Inflammation ,02 engineering and technology ,Peritonitis ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Genome editing ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,CRISPR ,Animals ,Guide RNA ,Amino Acid Sequence ,lcsh:Science ,Gene Editing ,Messenger RNA ,Multidisciplinary ,integumentary system ,Cas9 ,business.industry ,Calcium-Binding Proteins ,Inflammasome ,General Chemistry ,Genetic Therapy ,021001 nanoscience & nanotechnology ,Mice, Inbred C57BL ,030104 developmental biology ,Caspase Activation and Recruitment Domain ,Cancer research ,Female ,lcsh:Q ,medicine.symptom ,CRISPR-Cas Systems ,0210 nano-technology ,business ,Apoptosis Regulatory Proteins ,medicine.drug - Abstract
The NLRP3 inflammasome is a well-studied target for the treatment of multiple inflammatory diseases, but how to promote the current therapeutics remains a large challenge. CRISPR/Cas9, as a gene editing tool, allows for direct ablation of NLRP3 at the genomic level. In this study, we screen an optimized cationic lipid-assisted nanoparticle (CLAN) to deliver Cas9 mRNA (mCas9) and guide RNA (gRNA) into macrophages. By using CLAN encapsulating mCas9 and gRNA-targeting NLRP3 (gNLRP3) (CLANmCas9/gNLRP3), we disrupt NLRP3 of macrophages, inhibiting the activation of the NLRP3 inflammasome in response to diverse stimuli. After intravenous injection, CLANmCas9/gNLRP3 mitigates acute inflammation of LPS-induced septic shock and monosodium urate crystal (MSU)-induced peritonitis. In addition, CLANmCas9/gNLRP3 treatment improves insulin sensitivity and reduces adipose inflammation of high-fat-diet (HFD)-induced type 2 diabetes (T2D). Thus, our study provides a promising strategy for treating NLRP3-dependent inflammatory diseases and provides a carrier for delivering CRISPR/Cas9 into macrophages., Activation of the NLRP3 inflammasome triggers the production of inflammatory cytokines. Here, the authors inactivate NLRP3 in macrophages using CRISPR/Cas9 encapsulated in nanoparticles, and show that administration in mice is effective in preventing septic shock and peritonitis, and in improving diabetes-associated inflammation and insulin resistance.
- Published
- 2018
24. Immunomodulating nano-adaptors potentiate antibody-based cancer immunotherapy
- Author
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Song Shen, Cheng-Tao Jiang, Hua Huang, Jin-Zhi Du, Meng-Hua Xiong, Qian-Ni Ye, Ya-Nan Fan, Dong-Kun Zhao, Jun Wang, Kai-Ge Chen, Cong-Fei Xu, Xianzhu Yang, An Liu, and Hou-Bing Zhang
- Subjects
Cytotoxicity, Immunologic ,Male ,0301 basic medicine ,medicine.drug_class ,T-Lymphocytes ,Science ,medicine.medical_treatment ,T cell ,General Physics and Astronomy ,CD8-Positive T-Lymphocytes ,Monoclonal antibody ,Article ,General Biochemistry, Genetics and Molecular Biology ,Natural killer cell ,Immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cancer immunotherapy ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Multidisciplinary ,biology ,Chemistry ,Immunity ,Antibodies, Monoclonal ,General Chemistry ,Immunotherapy ,Chimeric antigen receptor ,Cell biology ,Killer Cells, Natural ,Mice, Inbred C57BL ,Immobilized Proteins ,030104 developmental biology ,medicine.anatomical_structure ,Nanotechnology in cancer ,030220 oncology & carcinogenesis ,Drug delivery ,biology.protein ,Nanoparticles ,Female ,Antibody - Abstract
Modulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an ‘adaptor’ while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models., Current strategies to boost anti-tumor immune response include the use of immune checkpoint inhibitors and bispecific T cell-engaging antibodies. Here the authors describe a versatile antibody immobilization nanoplatform that can be used to deliver different combinations of immunotherapeutics, showing therapeutic superiority in pre-clinical models.
- Published
- 2021
25. Polyphosphoester-Based Nanocarrier for Combined Radio-Photothermal Therapy of Breast Cancer
- Author
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Chunshui Yu, Chun-Yang Sun, Cong-Fei Xu, and Beibei Zhang
- Subjects
Radiosensitizer ,Combination therapy ,business.industry ,medicine.medical_treatment ,0206 medical engineering ,Biomedical Engineering ,02 engineering and technology ,Photothermal therapy ,021001 nanoscience & nanotechnology ,020601 biomedical engineering ,Biomaterials ,Radiation therapy ,chemistry.chemical_compound ,chemistry ,Cancer research ,Curcumin ,Medicine ,Nanomedicine ,Nanocarriers ,Growth inhibition ,0210 nano-technology ,business - Abstract
Recently, clinical research on tumor therapy has gradually shifted from traditional monotherapy toward combination therapy as tumors are complex, diverse, and heterogeneous. Combination therapy may be essential for achieving the optimized treatment efficacy of tumors through distinct tumor-inhibiting mechanisms. At the same time, nanocarriers are emerging as an excellent strategy for delivering both drugs simultaneously. This work presents utilization of a polyphosphoester-based nanocarrier (NPIR/Cur) to achieve the codelivery of hydrophobic photothermal agent IR-780 and radiosensitizer curcumin (Cur). The IR-780 and curcumin coencapsulated NPIR/Cur exhibited adequate drug loading, a prolonged blood half-life, enhanced passive tumor homing, and improved curcumin bioavailability as well as combined therapeutic functions. Briefly, NPIR/Cur could not only achieve effective thermal ablation through the conversion of near-infrared light to heat, but also give rise to a significant boosted local radiation dose to trigger promoted radiation damages, thus resulting in enhanced tumor cell growth inhibition. In conclusion, the as-prepared NPIR/Cur manifested excellent performance in facilitating combined photothermal and radiation therapy, thus expanding the application range of PPE-based carriers in nanomedicine, and also prompting exploration of their potential for other effective combination therapies.
- Published
- 2021
26. Optimized nanoparticle-mediated delivery of CRISPR-Cas9 system for B cell intervention
- Author
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Min Li, Zhi-Yao Chen, Cong-Fei Xu, Ya-Nan Fan, Zhe-Xiong Lian, Jun Wang, Yucai Wang, and Ying-Li Luo
- Subjects
0301 basic medicine ,Chemistry ,Cas9 ,Cell ,Condensed Matter Physics ,Atomic and Molecular Physics, and Optics ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Genome editing ,In vivo ,medicine ,CRISPR ,General Materials Science ,Electrical and Electronic Engineering ,Nanocarriers ,Receptor ,B cell - Abstract
B cells exert multiple effector functions, and dysfunctions of B cells often lead to initiation and progression of diseases, including autoimmune and inflammatory diseases. Therefore, B cell intervention may be an effective strategy to treat diseases involving B cells. The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing system has been widely used for DNA deletion, insertion, and replacement. Nanocarriers have been developed as relatively mature systems and may be applied to deliver the CRISPR-Cas9 system to B cells in vivo. In this study, we created a library of nanoparticles (NPs) with different polyethylene glycol densities and zeta potentials and screened an optimal NP for in vivo B cell targeting. The selected NP could deliver the CRISPR-Cas9 system to B cells and induce Cas9 expression inside the cell environment. Injection of the NP encapsulated with Cas9/gB220 (NPCas9/gB220) into mice could disrupt B220 expression in B cells, suggestive of its applications to intervene the expression of the target molecule in B cells. Moreover, the treatment with NPCas9/gBAFFR could decrease the number of B cells and exert therapeutic effect in rheumatoid arthritis, as B-cell activating factor receptor (BAFFR) is vital for the survival and functions of B cells. In conclusion, we developed a carrier for the delivery of the CRISPR-Cas9 gene editing system for B cell intervention that could be used for the treatment of diseases related to B cell dysfunctions.
- Published
- 2018
27. Macrophage-Specific in Vivo Gene Editing Using Cationic Lipid-Assisted Polymeric Nanoparticles
- Author
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Jun Wang, Cong-Fei Xu, Ying-Li Luo, Xiao-Jiao Du, Zhen Gu, Xianzhu Yang, Ji-Long Wang, Hongjun Li, Jing Liu, and Zhi-Ting Cao
- Subjects
0301 basic medicine ,Polymers ,General Physics and Astronomy ,02 engineering and technology ,Diet, High-Fat ,Diabetes Mellitus, Experimental ,Mice ,03 medical and health sciences ,Plasmid ,Genome editing ,In vivo ,Cations ,Animals ,Humans ,CRISPR ,General Materials Science ,Guide RNA ,Gene ,Cells, Cultured ,Gene Editing ,Chemistry ,Cas9 ,Macrophages ,General Engineering ,Netrin-1 ,021001 nanoscience & nanotechnology ,Lipids ,In vitro ,Cell biology ,Mice, Inbred C57BL ,HEK293 Cells ,RAW 264.7 Cells ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Nanoparticles ,CRISPR-Cas Systems ,0210 nano-technology - Abstract
The CRISPR/Cas9 gene editing technology holds promise for the treatment of multiple diseases. However, the inability to perform specific gene editing in targeted tissues and cells, which may cause off-target effects, is one of the critical bottlenecks for therapeutic application of CRISPR/Cas9. Herein, macrophage-specific promoter-driven Cas9 expression plasmids (pM458 and pM330) were constructed and encapsulated in cationic lipid-assisted PEG-b-PLGA nanoparticles (CLAN). The obtained nanoparticles encapsulating the CRISPR/Cas9 plasmids were able to specifically express Cas9 in macrophages as well as their precursor monocytes both in vitro and in vivo. More importantly, after further encoding a guide RNA targeting Ntn1 (sgNtn1) into the plasmid, the resultant CLANpM330/sgNtn1 successfully disrupted the Ntn1 gene in macrophages and their precursor monocytes in vivo, which reduced expression of netrin-1 (encoded by Ntn1) and subsequently improved type 2 diabetes (T2D) symptoms. Meanwhile, the Ntn1 gene was ...
- Published
- 2018
28. Dual-functional super bispecific nano-antibodies derived from monoclonal antibodies potentiate the antitumor effect of innate immune cells
- Author
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Cheng-Tao Jiang, Dong-Kun Zhao, Qian-Ni Ye, Kai-Ge Chen, Yu-Qi Liao, An Liu, Jun Wang, Song Shen, and Cong-Fei Xu
- Subjects
medicine.drug_class ,medicine.medical_treatment ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,02 engineering and technology ,010402 general chemistry ,Monoclonal antibody ,01 natural sciences ,In vivo ,medicine ,General Materials Science ,Innate immune system ,biology ,Chemistry ,Effector ,Immunotherapy ,021001 nanoscience & nanotechnology ,Acquired immune system ,In vitro ,0104 chemical sciences ,Cell biology ,biology.protein ,Antibody ,0210 nano-technology ,Biotechnology - Abstract
Innate immune cells, including natural killer cells and macrophages, are crucial in tumor surveillance and elimination. In contrast to the relatively complicated process of antigen-specific adaptive immunity, innate immune cells exhibit spontaneous tumoricidal effects by releasing cytolytic granules to adjacent tumor cells or by directly phagocytizing adjacent tumor cells. These effects of innate immune cells highlight the importance and necessity of spatial proximity between activated effector cells and tumor cells in innate antitumor immunity. Here, we describe two dual-functional super bispecific nano-antibodies (S-BsNA) constructed by immobilizing two types of traditional monoclonal antibodies (αKLRG1 and αPDL1, or αCSF1R and αCD47) onto a universal antibody-immobilization platform. The S-BsNA simultaneously regulate the antitumor response of innate immune cells and establish a close physical connection between effector cells and tumor cells. The superiority of S-BsNA over the parental monoclonal antibodies was evaluated in multiple tumor models in vitro and in vivo. S-BsNA can efficiently augment innate antitumor immunity both in vitro and in vivo and can be an alternative modality of immunotherapy, expanding its benefits to a larger patient pool.
- Published
- 2021
29. Biomaterials‐Based Delivery of Therapeutic Antibodies for Cancer Therapy
- Author
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Qian-Ni Ye, Jun Wang, Yue Wang, Song Shen, and Cong-Fei Xu
- Subjects
biology ,business.industry ,medicine.drug_class ,medicine.medical_treatment ,Biomedical Engineering ,Cancer therapy ,Tumor penetration ,Antibodies, Monoclonal ,Pharmaceutical Science ,Biocompatible Materials ,Monoclonal antibody ,Cancer treatment ,Biomaterials ,Antineoplastic Agents, Immunological ,Cancer immunotherapy ,Neoplasms ,Cancer research ,Principal mechanism ,biology.protein ,Humans ,Medicine ,Immunotherapy ,Delivery system ,Antibody ,business - Abstract
Considerable breakthroughs in the treatment of malignant tumors using antibody drugs, especially immunomodulating monoclonal antibodies (mAbs), have been made in the past decade. Despite technological advancements in antibody design and manufacture, multiple challenges face antibody-mediated cancer therapy, such as instability in vivo, poor tumor penetration, limited response rate, and undesirable off-target cytotoxicity. In recent years, an increasing number of biomaterials-based delivery systems have been reported to enhance the antitumor efficacy of antibody drugs. This review summarizes the advances and breakthroughs in integrating biomaterials with therapeutic antibodies for enhanced cancer therapy. A brief introduction to the principal mechanism of antibody-based cancer therapy is first established, and then various antibody immobilization strategies are provided. Finally, the current state-of-the-art in biomaterials-based antibody delivery systems and their applications in cancer treatment are summarized, highlighting how the delivery systems augment the therapeutic efficacy of antibody drugs. The outlook and perspective on biomaterials-based delivery of antitumor antibodies are also discussed.
- Published
- 2021
30. Responsive Nanocarriers as an Emerging Platform for Cascaded Delivery of Nucleic Acids to Cancer
- Author
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Shoaib Iqbal, Xianzhu Yang, Cong-Fei Xu, Jun Wang, and Yang Liu
- Subjects
0301 basic medicine ,Cell ,Pharmaceutical Science ,02 engineering and technology ,Biology ,03 medical and health sciences ,In vivo ,Neoplasms ,Nucleic Acids ,Extracellular ,medicine ,Animals ,Humans ,Drug Carriers ,Tumor microenvironment ,021001 nanoscience & nanotechnology ,030104 developmental biology ,medicine.anatomical_structure ,Biochemistry ,Delayed-Action Preparations ,Drug delivery ,Nucleic acid ,Nanoparticles ,Nanocarriers ,0210 nano-technology ,Intracellular - Abstract
Cascades of systemic and intracellular obstacles, including low stability in blood, little tumor accumulation, weak tumor penetration, poor cellular uptake, inefficient endosomal escape and deficient disassembly in the cytoplasm, must be overcome in order to deliver nucleic acid drugs for cancer therapy. Nanocarriers that are sensitive to a variety of physiological stimuli, such as pH, redox status, and cell enzymes, are substantially changing the landscape of nucleic acid drug delivery by helping to overcome cascaded systemic and intracellular barriers. This review discusses nucleic acid-based therapeutics, systemic and intracellular barriers to efficient nucleic acid delivery, and nanocarriers responsive to extracellular and intracellular biological stimuli to overcome individual barriers. In particular, responsive nanocarriers for the cascaded delivery of nucleic acids in vivo are highlighted. Developing novel cascaded nanocarriers that transform their physicochemical properties in response to various stimuli in a timely and spatially controlled manner for nucleic acid drug delivery holds great potential for translating the promise of nucleic acid drugs and achieving clinically successful cancer therapy.
- Published
- 2017
31. In situ repurposing of dendritic cells with CRISPR/Cas9-based nanomedicine to induce transplant tolerance
- Author
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Zhi-Ting Cao, Hou-Bing Zhang, Zhe-Xiong Lian, Song Shen, Jun Wang, Yue Zhang, Ying-Li Luo, Cong-Fei Xu, Zhi-Bin Zhao, Gui Zhao, and Jia Shi
- Subjects
Graft Rejection ,medicine.medical_specialty ,T cell ,Biophysics ,Bioengineering ,02 engineering and technology ,Lymphocyte Activation ,Organ transplantation ,Biomaterials ,03 medical and health sciences ,In vivo ,CRISPR-Associated Protein 9 ,medicine ,Animals ,CD40 Antigens ,030304 developmental biology ,0303 health sciences ,Mice, Inbred BALB C ,CD40 ,biology ,Chemistry ,Graft Survival ,hemic and immune systems ,Dendritic cell ,Dendritic Cells ,021001 nanoscience & nanotechnology ,medicine.disease ,In vitro ,Endocytosis ,Transplant rejection ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Nanomedicine ,Mechanics of Materials ,Ceramics and Composites ,biology.protein ,Cancer research ,Transplantation Tolerance ,CRISPR-Cas Systems ,0210 nano-technology ,Reprogramming ,RNA, Guide, Kinetoplastida - Abstract
Organ transplantation is the only effective method to treat end-stage organ failure. However, it is continuously plagued by immune rejection, which is mostly caused by T cell-mediated reactions. Dendritic cells (DCs) are professional antigen-presenting cells, and blocking the costimulatory signaling molecule CD40 in DCs inhibits T cell activation and induces transplant tolerance. In this study, to relieve graft rejection, Cas9 mRNA (mCas9) and a guide RNA targeting the costimulatory molecule CD40 (gCD40) were prepared and encapsulated into poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PEG-b-PLGA)-based cationic lipid-assisted nanoparticles (CLAN), denoted CLANmCas9/gCD40. CLAN effectively delivered mCas9/gCD40 into DCs and disrupted CD40 in DCs at the genomic level both in vitro and in vivo. After intravenous injection into an acute mouse skin transplant model, CLANmCas9/gCD40-mediated CD40 disruption significantly inhibited T cell activation, which reduced graft damage and prolonged graft survival. This work provides a promising strategy for reprogramming DCs with nanoparticles carrying the CRISPR/Cas9 system to abate transplant rejection.
- Published
- 2019
32. Corrigendum to 'Co-delivery of all-trans-retinoic acid and doxorubicin for cancer therapy with synergistic inhibition of cancer stem cells' [Biomaterials 37 (2015) 405–414]
- Author
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Yang Liu, Yan Bao, Rong Sun, Xiao-Jiao Du, Yaping Li, Shi-Yong Li, Cong-Fei Xu, Zhi-Ting Cao, Yan-Hua Zhu, Song Shen, Jun Wang, and Xianzhu Yang
- Subjects
Co delivery ,business.industry ,Biophysics ,All trans ,Cancer therapy ,Retinoic acid ,Bioengineering ,Biomaterials ,chemistry.chemical_compound ,chemistry ,Mechanics of Materials ,Cancer stem cell ,Ceramics and Composites ,Cancer research ,Medicine ,Doxorubicin ,business ,medicine.drug - Published
- 2020
33. Restoring anti-tumor functions of T cells via nanoparticle-mediated immune checkpoint modulation
- Author
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Jun Wang, Yan-Hua Zhu, Song Shen, Jin-Xing Xia, Xiao-Jiao Du, Rong Sun, Shi-Yong Li, Cong-Fei Xu, and Yang Liu
- Subjects
0301 basic medicine ,Adoptive cell transfer ,T cell ,medicine.medical_treatment ,Melanoma, Experimental ,Pharmaceutical Science ,chemical and pharmacologic phenomena ,02 engineering and technology ,CD8-Positive T-Lymphocytes ,Biology ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,Polyethylene Glycols ,03 medical and health sciences ,Interleukin 21 ,Lymphocytes, Tumor-Infiltrating ,medicine ,Animals ,Humans ,Cytotoxic T cell ,CTLA-4 Antigen ,IL-2 receptor ,RNA, Small Interfering ,Antigen-presenting cell ,Cell Proliferation ,Immunotherapy ,021001 nanoscience & nanotechnology ,Natural killer T cell ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,Lactates ,Cancer research ,Nanoparticles ,Female ,0210 nano-technology ,T-Lymphocytes, Cytotoxic - Abstract
The core purpose of cancer immunotherapy is the sustained activation and expansion of the tumor specific T cells, especially tumor-infiltrating cytotoxic T lymphocytes (CTLs). Currently, one of the main foci of immunotherapy involving nano-sized carriers is on cancer vaccines and the role of professional antigen presenting cells, such as dendritic cells (DCs) and other phagocytic immune cells. Besides the idea that cancer vaccines promote T cell immune responses, targeting immune inhibitory pathways with nanoparticle delivered regulatory agents such as small interfering RNA (siRNA) to the difficultly-transfected tumor-infiltrating T cells may provide more information on the utility of nanoparticle-mediated cancer immunotherapy. In this study, we constructed nanoparticles to deliver cytotoxic T lymphocyte-associated molecule-4 (CTLA-4)-siRNA (NPsiCTLA-4) and showed the ability of this siRNA delivery system to enter T cells both in vitro and in vivo. Furthermore, T cell activation and proliferation were enhanced after NPsiCTLA-4 treatment in vitro. The ability of direct regulation of T cells of this CTLA-4 delivery system was assessed in a mouse model bearing B16 melanoma. Our results demonstrated that this nanoparticle delivery system was able to deliver CTLA-4-siRNA into both CD4(+) and CD8(+) T cell subsets at tumor sites and significantly increased the percentage of anti-tumor CD8(+) T cells, while it decreased the ratio of inhibitory T regulatory cells (Tregs) among tumor infiltrating lymphocytes (TILs), resulting in augmented activation and anti-tumor immune responses of the tumor-infiltrating T cells. These data support the use of potent nanoparticle-based cancer immunotherapy for melanoma.
- Published
- 2016
34. CD205-TLR9-IL-12 axis contributes to CpG-induced oversensitive liver injury in HBsAg transgenic mice by promoting the interaction of NKT cells with Kupffer cells
- Author
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Zhigang Tian, Jun Wang, Rongbin Zhou, Meijuan Zheng, Cong-Fei Xu, Xin Hou, and Xiaolei Hao
- Subjects
Cytotoxicity, Immunologic ,0301 basic medicine ,Cell Communication ,Lymphocyte Activation ,Fas ligand ,Mice ,Immunology and Allergy ,RNA, Small Interfering ,Antigens, Viral ,Liver injury ,Interleukin ,hemic and immune systems ,Fas receptor ,Natural killer T cell ,Interleukin-12 ,Infectious Diseases ,Oligodeoxyribonucleotides ,Interleukin 12 ,Chemical and Drug Induced Liver Injury ,medicine.symptom ,NKT cell ,Signal Transduction ,Research Article ,liver injury ,Hepatitis B virus ,Fas Ligand Protein ,Kupffer Cells ,Immunology ,Kupffer cell ,Mice, Transgenic ,Receptors, Cell Surface ,Inflammation ,Biology ,Minor Histocompatibility Antigens ,03 medical and health sciences ,Antigens, CD ,CpG ,medicine ,Animals ,Humans ,Lectins, C-Type ,fas Receptor ,medicine.disease ,Molecular biology ,Mice, Inbred C57BL ,030104 developmental biology ,Toll-Like Receptor 9 ,Hepatocytes ,Fas signaling pathway ,Natural Killer T-Cells - Abstract
Gut-derived bacterial products contribute to liver inflammation and injury during chronic hepatitis B virus infection; however, the underlying mechanisms remain obscure. In this study, hepatitis B surface antigen transgenic (HBs-Tg) mice and their wild-type (WT) control C57BL/6 mice were injected with CpG-oligodeoxynucleotides (ODNs) to mimic the translocation of gut microbial products into the systemic circulation. We found that, compared with the WT mice, the HBs-Tg mice were oversensitive to CpG-ODN-induced liver injury, which was dependent on natural killer T (NKT) cells. CpG-ODN injection enhanced the expression of Fas ligand (FasL) on NKT cells. In addition, hepatocytes from the HBs-Tg mice expressed higher levels of Fas than did those from the WT mice, which was further augmented by CpG-ODN. Interaction of Fas and FasL was involved in the cytotoxicity of NKT cells against hepatocytes in the HBs-Tg mice. Moreover, Kupffer cells in the HBs-Tg mice expressed higher levels of CD205 and produced greater amounts of interleukin (IL)-12 than did those in the WT mice. Finally, the depletion of Kupffer cells, neutralization of IL-12 or specific silencing of CD205 on Kupffer cells significantly inhibited CpG-ODN-induced liver injury and NKT activation in the HBs-Tg mice. Our data suggest that CD205-expressing Kupffer cells respond to CpG-ODNs and subsequently release IL-12 to promote NKT cell activation. Activated NKT cells induce liver damage through the Fas signaling pathway in HBs-Tg mice.
- Published
- 2016
35. Optimization of lipid-assisted nanoparticle for disturbing neutrophils-related inflammation
- Author
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Zhi-Ting Cao, Jun Wang, Cong-Fei Xu, Zi-Dong Lu, Yang Liu, and Ying-Li Luo
- Subjects
0301 basic medicine ,Male ,Neutrophils ,Polyesters ,Biophysics ,Bioengineering ,Inflammation ,White adipose tissue ,Polyethylene Glycols ,Biomaterials ,03 medical and health sciences ,Insulin resistance ,Immune system ,PEG ratio ,medicine ,Animals ,Molecular Targeted Therapy ,Particle Size ,Gene Editing ,Drug Carriers ,biology ,Base Sequence ,Chemistry ,Genetic Therapy ,medicine.disease ,Lipids ,Cell biology ,Mice, Inbred C57BL ,Drug Liberation ,030104 developmental biology ,Cellular Microenvironment ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,Mechanics of Materials ,Neutrophil elastase ,Drug delivery ,Models, Animal ,Ceramics and Composites ,biology.protein ,Nanoparticles ,medicine.symptom ,CRISPR-Cas Systems ,Insulin Resistance ,Infiltration (medical) - Abstract
Inflammation is closely related to the development of many diseases and is commonly characterized by abnormal infiltration of immune cells, especially neutrophils. The current therapeutics of inflammatory diseases give little attention to direct modulation of these diseases with respect to immune cells. Nanoparticles are applied for efficient drug delivery into the disease-related immune cells, but their performance is significantly affected by their surface properties. In this study, to optimize the properties of nanoparticles for modulating neutrophils-related inflammation, we prepared a library of poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-b-PLGA)-based cationic lipid-assisted nanoparticles (CLANs) with different surface PEG density and surface charge. Optimized CLANs for neutrophils targeting were screened in high-fat diet (HFD)-induced type 2 diabetes (T2D) mice. Then, a CRISPR-Cas9 plasmid expressing a guide RNA (gRNA) targeting neutrophil elastase (NE) was encapsulated into the optimized CLAN and denoted as CLANpCas9/gNE. After intravenous injection, CLANpCas9/gNE successfully disrupted the NE gene of neutrophils and mitigated the insulin resistance of T2D mice via reducing the inflammation in epididymal white adipose tissue (eWAT) and in the liver. This strategy provides an example of abating the inflammatory microenvironment by directly modulating immune cells with nanoparticles carrying genome editing tools.
- Published
- 2018
36. Invariant NKT cells promote alcohol-induced steatohepatitis through interleukin-1β in mice
- Author
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Zhigang Tian, Zhexiong Lian, Rui Sun, Yongyan Chen, Haiming Wei, Kele Cui, Guoxiu Yan, Cong-Fei Xu, Li Bai, Rongbin Zhou, and Jun Wang
- Subjects
Male ,Inflammasomes ,Kupffer Cells ,Interleukin-1beta ,Inflammation ,Biology ,Mice ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Animals ,RNA, Messenger ,RNA, Small Interfering ,Mice, Knockout ,Liver injury ,Hepatology ,Caspase 1 ,Kupffer cell ,Inflammasome ,Natural killer T cell ,medicine.disease ,CARD Signaling Adaptor Proteins ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Immunology ,Cancer research ,Natural Killer T-Cells ,Alcoholic fatty liver ,medicine.symptom ,Steatohepatitis ,Steatosis ,Apoptosis Regulatory Proteins ,Carrier Proteins ,Fatty Liver, Alcoholic ,medicine.drug - Abstract
Background & Aims It was reported that alcohol consumption activated the NLRP3 inflammasome in Kupffer cells, leading to mature interleukin (IL)-1β release in alcoholic liver injury; however, how IL-1β promotes liver injury remains unclear. Methods We investigated the role of IL-1β in alcoholic steatohepatitis by using a chronic plus single-binge ethanol consumption mouse model. Results Here, liver steatosis was accompanied by notably increased invariant natural killer T (iNKT) cell numbers and activation, and iNKT-deficient Jα18 −/− mice developed less alcohol-induced steatosis, with reduced liver inflammation and neutrophil infiltration. Kupffer cells and IL-1β were required for the hepatic iNKT accumulation, as either blocking IL-1β signaling with a recombinant IL-1 receptor antagonist (IL-1Ra), depleting Kupffer cells by clodronate liposomes, or specifically silencing IL-1β in Kupffer cells by nanoparticle-encapsulated siRNA, resulted in inhibited hepatic iNKT cell accumulation and activation, as well as amelioration of alcoholic fatty liver. In addition, IL-1β overexpression in hepatocytes was sufficient to compensate for Kupffer cell depletion. Increased gene and protein expression of mature IL-1β correlated with elevated expression of the NLRP3 inflammasome components NLRP3, ASC, and cleaved caspase-1 in Kupffer cells from ethanol–exposed wild-type mice. NLRP3 deficiency led to the attenuation of alcoholic steatosis, similarly as Kupffer cell depletion, almost without hepatic NKT cells. Conclusions After alcohol–exposure Kupffer cell-derived IL-1β triggered by NLRP3 activation, recruits and activates hepatic iNKT cells, subsequently promoting liver inflammation and neutrophil infiltration, and inducing alcoholic liver injury.
- Published
- 2015
37. CLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation
- Author
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Jun Cui, Yanqing Yang, Rongbin Zhou, Wei Jiang, Li Bai, Tao Gong, Tiantian Tang, Xiaqiong Wang, Jun Wang, Cong-Fei Xu, and Xueting Lang
- Subjects
0301 basic medicine ,Mitochondrial ROS ,Inflammasomes ,Science ,Immunoblotting ,General Physics and Astronomy ,Mitochondrion ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Mitochondrial Proteins ,03 medical and health sciences ,Chlorides ,Chloride Channels ,Cell Line, Tumor ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Animals ,Humans ,Secretion ,Cells, Cultured ,chemistry.chemical_classification ,Mice, Knockout ,Reactive oxygen species ,Multidisciplinary ,Innate immune system ,Ion Transport ,integumentary system ,Inflammasome ,General Chemistry ,Cell biology ,Mitochondria ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,Biochemistry ,Potassium ,RNA Interference ,Efflux ,Reactive Oxygen Species ,Intracellular ,medicine.drug ,Protein Binding - Abstract
The NLRP3 inflammasome can sense different pathogens or danger signals, and has been reported to be involved in the development of many human diseases. Potassium efflux and mitochondrial damage are both reported to mediate NLRP3 inflammasome activation, but the underlying, orchestrating signaling events are still unclear. Here we show that chloride intracellular channels (CLIC) act downstream of the potassium efflux-mitochondrial reactive oxygen species (ROS) axis to promote NLRP3 inflammasome activation. NLRP3 agonists induce potassium efflux, which causes mitochondrial damage and ROS production. Mitochondrial ROS then induces the translocation of CLICs to the plasma membrane for the induction of chloride efflux to promote NEK7–NLRP3 interaction, inflammasome assembly, caspase-1 activation, and IL-1β secretion. Thus, our results identify CLICs-dependent chloride efflux as an essential and proximal upstream event for NLRP3 activation., The NLRP3 inflammasome is key to the regulation of innate immunity against pathogens or stress, but the underlying signaling regulation is still unclear. Here the authors show that chloride intracellular channels (CLIC) interface between mitochondria stress and inflammasome activation to modulate inflammatory responses.
- Published
- 2017
38. Chromatin-remodelling factor Brg1 regulates myocardial proliferation and regeneration in zebrafish
- Author
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Fang Wang, Cong-Fei Xu, Nannan Chang, Ying Luo, Chenglu Xiao, Jing-Wei Xiong, Fuchou Tang, Yu Hou, Aibin He, Jun Wang, Lu Gao, Xiaojun Zhu, Jinrong Peng, and Keping Hu
- Subjects
0301 basic medicine ,Cardiac fibrosis ,Science ,General Physics and Astronomy ,Chromatin Remodeling Factor ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Animals, Genetically Modified ,03 medical and health sciences ,medicine ,Animals ,Regeneration ,MEF2C ,Zebrafish ,Cyclin-Dependent Kinase Inhibitor p57 ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Multidisciplinary ,Kinase ,GATA4 ,Regeneration (biology) ,Myocardium ,Heart ,General Chemistry ,DNA Methylation ,Zebrafish Proteins ,medicine.disease ,biology.organism_classification ,Cell biology ,Up-Regulation ,030104 developmental biology ,DNA methylation - Abstract
The zebrafish possesses a remarkable capacity of adult heart regeneration, but the underlying mechanisms are not well understood. Here we report that chromatin remodelling factor Brg1 is essential for adult heart regeneration. Brg1 mRNA and protein are induced during heart regeneration. Transgenic over-expression of dominant-negative Xenopus Brg1 inhibits the formation of BrdU+/Mef2C+ and Tg(gata4:EGFP) cardiomyocytes, leading to severe cardiac fibrosis and compromised myocardial regeneration. RNA-seq and RNAscope analyses reveal that inhibition of Brg1 increases the expression of cyclin-dependent kinase inhibitors such as cdkn1a and cdkn1c in the myocardium after ventricular resection; and accordingly, myocardial-specific expression of dn-xBrg1 blunts myocardial proliferation and regeneration. Mechanistically, injury-induced Brg1, via its interaction with Dnmt3ab, suppresses the expression of cdkn1c by increasing the methylation level of CpG sites at the cdkn1c promoter. Taken together, our results suggest that Brg1 promotes heart regeneration by repressing cyclin-dependent kinase inhibitors partly through Dnmt3ab-dependent DNA methylation., The adult zebrafish heart is capable of regeneration but the molecular mechanisms are poorly understood. Here the authors show that chromatin remodeling factor Brg1 represses cyclin-dependent kinase inhibitors to promote myocardial regeneration.
- Published
- 2016
39. Development of 'CLAN' Nanomedicine for Nucleic Acid Therapeutics
- Author
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Cong-Fei Xu, Jun Wang, Xianzhu Yang, Song Shen, Ying-Li Luo, and Shoaib Iqbal
- Subjects
Kupffer Cells ,Macromolecular Substances ,Computer science ,02 engineering and technology ,Computational biology ,010402 general chemistry ,01 natural sciences ,Polyethylene Glycols ,Biomaterials ,Genome editing ,Neoplasms ,Nucleic Acids ,Animals ,Humans ,General Materials Science ,Clan ,Zebrafish ,Gene Editing ,Heart ,General Chemistry ,021001 nanoscience & nanotechnology ,Lipids ,0104 chemical sciences ,Nanomedicine ,Target site ,Immune System ,Lactates ,Neoplastic Stem Cells ,Nucleic acid ,Nanoparticles ,CRISPR-Cas Systems ,0210 nano-technology ,Biotechnology - Abstract
Nucleic acid-based macromolecules have paved new avenues for the development of therapeutic interventions against a spectrum of diseases; however, their clinical translation is limited by successful delivery to the target site and cells. Therefore, numerous systems have been developed to overcome delivery challenges to nucleic acids. From the viewpoint of clinical translation, it is highly desirable to develop systems with clinically validated materials and controllability in synthesis. With this in mind, a cationic lipid assisted PEG-b-PLA nanoparticle (CLAN) is designed that is capable of protecting nucleic acids via encapsulation inside the aqueous core, and delivers them to target cells, while maintaining or improving nucleic acid function. The system is formulated from clinically validated components (PEG-b-PLA and its derivatives) and can be scaled-up for large scale manufacturing, offering potential for its future use in clinical applications. Here, the development and working mechanisms of CLANs, the ways to improve its delivery efficacy, and its application in various disease treatments are summarized. Finally, a prospective for the further development of CLAN is also discussed.
- Published
- 2019
40. Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy
- Author
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Cong-Fei Xu, Xianzhu Yang, Chun Yang Sun, Yan Hua Zhu, Jun Wang, Zhi Ting Cao, Jin-Zhi Du, Hongjun Li, Hong-Xia Wang, Xiao-Jiao Du, and Shuming Nie
- Subjects
Materials science ,media_common.quotation_subject ,Antineoplastic Agents ,Apoptosis ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Pancreatic cancer ,Cell Line, Tumor ,Neoplasms ,Spheroids, Cellular ,medicine ,Humans ,Neoplasm Metastasis ,Internalization ,media_common ,Cisplatin ,Tumor microenvironment ,Multidisciplinary ,Cancer ,Biological Sciences ,021001 nanoscience & nanotechnology ,medicine.disease ,Extravasation ,0104 chemical sciences ,Cancer cell ,Cancer research ,Nanomedicine ,Nanoparticles ,0210 nano-technology ,medicine.drug ,Biomedical engineering - Abstract
A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ∼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ∼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.
- Published
- 2016
41. Targeting glucose uptake of glioma cells by siRNA delivery with polymer nanoparticle
- Author
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Yang Liu, Jun Wang, Yan-Hua Zhu, Song Shen, and Cong-Fei Xu
- Subjects
Text mining ,Chemistry ,business.industry ,Glucose uptake ,Glioma ,Polymer nanoparticle ,Cancer research ,medicine ,Pharmaceutical Science ,business ,medicine.disease - Published
- 2016
42. Co-delivery of all-trans-retinoic acid and doxorubicin for cancer therapy with synergistic inhibition of cancer stem cells
- Author
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Song Shen, Cong-Fei Xu, Xiao-Jiao Du, Shi-Yong Li, Rong Sun, Jun Wang, and Yang Liu
- Subjects
Co delivery ,Chemistry ,business.industry ,All trans ,Cancer therapy ,Retinoic acid ,Pharmaceutical Science ,chemistry.chemical_compound ,Text mining ,Cancer stem cell ,Cancer research ,medicine ,Doxorubicin ,business ,medicine.drug - Published
- 2016
43. Nanoparticle-facilitated autophagy inhibition promotes the efficacy of chemotherapeutics against breast cancer stem cells
- Author
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Yunjiao Zhang, Cong-Fei Xu, Zhi-Ting Cao, Rong Sun, Jun Wang, Longping Wen, and Song Shen
- Subjects
0301 basic medicine ,Biophysics ,Bioengineering ,Antineoplastic Agents ,Breast Neoplasms ,Tumor initiation ,Mice, SCID ,Metastasis ,Biomaterials ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Breast cancer ,Cancer stem cell ,Cell Line, Tumor ,medicine ,Autophagy ,Animals ,Humans ,Doxorubicin ,Mice, Inbred ICR ,business.industry ,medicine.disease ,030104 developmental biology ,Treatment Outcome ,Docetaxel ,Mechanics of Materials ,030220 oncology & carcinogenesis ,Immunology ,Ceramics and Composites ,Cancer research ,Neoplastic Stem Cells ,Nanoparticles ,Drug Therapy, Combination ,Female ,Stem cell ,business ,medicine.drug - Abstract
Cancer stem cells (CSCs) have garnered increasing attention over the past decade, as they are believed to play a crucial role in tumor initiation, progression and metastasis, relapse and drug resistance. Therapeutic strategies which simultaneously exterminate both bulk tumor cells and the rare CSC subpopulation may produce striking response and result in long-term tumor remission. Accumulating evidence provides insight into the function of autophagy in maintenance, plasticity and survival of CSCs. The role of autophagy in the susceptibility of breast CSCs to chemotherapeutics was investigated in the present work, reduced 'stemness' and increased susceptibility to chemotherapy drugs (doxorubicin, DOX and docetaxel, DTXL) were observed after chloroquine (CQ)-mediated autophagy inhibition in sorted ALDH(hi) cells of breast cancer cell line MDA-MB-231. We further proved that nanoparticle-mediated autophagy inhibition promoted the efficacy of chemotherapeutics against ALDH(hi) MDA-MB-231 cells in vitro. Administration of drug delivery systems significantly prolonged the circulation half-life and augmented enrichment of two different drugs in tumor tissues and ALDH(hi) cells. More importantly, compared with single treatment, the combined delivery systems NPCQ/NPDOX and NPCQ/DOX (NPCQ/NPDTXL and NPCQ/DTXL) showed most effective and persistent tumor growth inhibitory effect by eliminating bulk tumor cells as well as CSCs (p
- Published
- 2016
44. Tumor acidity-sensitive linkage-bridged block copolymer for therapeutic siRNA delivery
- Author
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Xianzhu Yang, Cong-Fei Xu, Yang Liu, Chun-Yang Sun, Jun Wang, Yan-Hua Zhu, Song Shen, and Hou-Bing Zhang
- Subjects
Drug ,Materials science ,media_common.quotation_subject ,Biophysics ,Bioengineering ,Breast Neoplasms ,Cell Cycle Proteins ,macromolecular substances ,02 engineering and technology ,Protein Serine-Threonine Kinases ,010402 general chemistry ,01 natural sciences ,Polyethylene Glycols ,Biomaterials ,chemistry.chemical_compound ,Mice ,Polylactic Acid-Polyglycolic Acid Copolymer ,Cell Line, Tumor ,Proto-Oncogene Proteins ,PEG ratio ,Animals ,Humans ,Breast ,Lactic Acid ,RNA, Small Interfering ,Internalization ,media_common ,technology, industry, and agriculture ,Hydrogen-Ion Concentration ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,PLGA ,RNAi Therapeutics ,chemistry ,Targeted drug delivery ,Mechanics of Materials ,Delayed-Action Preparations ,Drug delivery ,Ceramics and Composites ,PEGylation ,Nanoparticles ,Female ,0210 nano-technology ,Ethylene glycol ,Polyglycolic Acid ,Biomedical engineering - Abstract
The design of ideal nanoparticle delivery systems should be capable of meeting the requirements of several stages of drug delivery, including prolonged circulation, enhanced accumulation and penetration in the tumor, facilitated cellular internalization and rapid release of the active drug in the tumor cells. However, among the current design strategies, meeting the requirements of one stage often conflicts with the other. Herein, a tumor pH-labile linkage-bridged block copolymer of poly(ethylene glycol) with poly(lacide-co-glycolide) (PEG-Dlinkm-PLGA) was used for siRNA delivery to fulfill all aforementioned requirements of these delivery stages. The obtained siRNA-encapsulating PEG-Dlinkm-PLGA nanoparticle gained efficiently prolonged circulation in the blood and preferential accumulation in tumor sites via the PEGylation. Furthermore, the PEG surface layer was detached in response to the tumor acidic microenvironment to facilitate cellular uptake, and the siRNA was rapidly released within tumor cells due to the hydrophobic PLGA layer. Hence, PEG-Dlinkm-PLGA nanoparticles met the requirements of several stages of drug delivery, and resulted in the enhanced therapeutic effect of the nanoparticular delivery systems.
- Published
- 2015
45. Tumor Acidity-Sensitive Polymeric Vector for Active Targeted siRNA Delivery
- Author
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Jun Wang, Yang Liu, Xianzhu Yang, Cong-Fei Xu, Song Shen, Hongjun Li, Jin-Xing Xia, Zhi-Ting Cao, and Chun-Yang Sun
- Subjects
Polymers ,media_common.quotation_subject ,General Chemistry ,Mononuclear phagocyte system ,Biochemistry ,Molecular biology ,Micelle ,Catalysis ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,chemistry ,In vivo ,Neoplasms ,PEG ratio ,PEGylation ,Biophysics ,Tissue Distribution ,RNA, Small Interfering ,Internalization ,Ethylene glycol ,Micelles ,Protein adsorption ,media_common - Abstract
Although surface PEGylation of siRNA vectors is effective for preventing protein adsorption and thereby helps these vectors to evade the reticuloendothelial system (RES) in vivo, it also suppresses the cellular uptake of these vectors by target cells. This dilemma could be overcome by employing stimuli-responsive shell-detachable nanovectors to achieve enhanced cellular internalization while maintaining prolonged blood circulation. Among the possible stimuli, dysregulated pH in tumor (pHe) is the most universal and practical. However, the design of pHe-sensitive system is problematic because of the subtle differences between the pHe and pH in other tissues. Here, a simple acid-sensitive bridged copolymer is developed and used for tumor-targeted systemic delivery of siRNA. After forming the micelleplex delivery system, the corresponding nanoparticles (Dm-NP) might undergo several modifications as follows: (i) a poly(ethylene glycol) (PEG) corona, which is stable in the circulatory system and protects nanovectors from RES clearance; (ii) a pHe responsive linkage breakage, which induces PEG detachment at tumor sites and thereby facilitates cell targeting; and (iii) a cell-penetration peptide, which is exposed upon the removal of PEG and further enhances cellular uptake. Thus, Dm-NP achieved both prolonged circulation and effective accumulation in tumor cells and resulted in the safe and enhanced inhibition of non-small cell lung cancer growth.
- Published
- 2015
46. Facile Generation of Tumor-pH-Labile Linkage-Bridged Block Copolymers for Chemotherapeutic Delivery
- Author
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Jin-Zhi Du, Cong-Fei Xu, Jun Wang, Zhi-Ting Cao, Yang Liu, and Chun-Yang Sun
- Subjects
Biocompatibility ,Polymers ,Nanotechnology ,Antineoplastic Agents ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Micelle ,Catalysis ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Neoplasms ,PEG ratio ,Humans ,Chemistry ,technology, industry, and agriculture ,General Medicine ,General Chemistry ,Hydrogen-Ion Concentration ,021001 nanoscience & nanotechnology ,Combinatorial chemistry ,0104 chemical sciences ,Drug delivery ,Nanomedicine ,Nanoparticles ,Nanocarriers ,0210 nano-technology ,Ethylene glycol - Abstract
Successful bench-to-bedside translation of nanomedicine relies heavily on the development of nanocarriers with superior therapeutic efficacy and high biocompatibility. However, the optimal strategy for improving one aspect often conflicts with the other. Herein, we report a tactic of designing tumor-pH-labile linkage-bridged copolymers of clinically validated poly(D,L-lactide) and poly(ethylene glycol) (PEG-Dlink(m)-PDLLA) for safe and effective drug delivery. Upon arriving at the tumor site, PEG-Dlink(m)-PDLLA nanoparticles will lose the PEG layer and increase zeta potential by responding to tumor acidity, which significantly enhances cellular uptake and improves the in vivo tumor inhibition rate to 78.1% in comparison to 47.8% of the non-responsive control. Furthermore, PEG-Dlink(m)-PDLLA nanoparticles show comparable biocompatibility with the clinically used PEG-b-PDLLA micelle. The improved therapeutic efficacy and safety demonstrate great promise for our strategy in future translational studies.
- Published
- 2015
47. Co-delivery of all-trans-retinoic acid and doxorubicin for cancer therapy with synergistic inhibition of cancer stem cells
- Author
-
Yan-Hua Zhu, Song Shen, Yaping Li, Shi-Yong Li, Xiao-Jiao Du, Zhi-Ting Cao, Cong-Fei Xu, Xianzhu Yang, Yan Bao, Jun Wang, Yang Liu, and Rong Sun
- Subjects
Combination therapy ,medicine.medical_treatment ,Static Electricity ,Biophysics ,Retinoic acid ,Bioengineering ,Breast Neoplasms ,Tretinoin ,Mice, SCID ,Pharmacology ,Biomaterials ,chemistry.chemical_compound ,Drug Delivery Systems ,Cancer stem cell ,Mice, Inbred NOD ,Cell Line, Tumor ,Neoplasms ,Proliferating Cell Nuclear Antigen ,medicine ,Animals ,Humans ,Doxorubicin ,Particle Size ,Cell Proliferation ,Chemotherapy ,business.industry ,Cell Differentiation ,Drug Synergism ,Gene Expression Regulation, Neoplastic ,chemistry ,Mechanics of Materials ,Drug delivery ,Cancer cell ,Injections, Intravenous ,Ceramics and Composites ,Neoplastic Stem Cells ,Nanoparticles ,Female ,Stem cell ,business ,medicine.drug - Abstract
Combination treatment through simultaneous delivery of two or more drugs with nanoparticles has been demonstrated to be an elegant and efficient approach for cancer therapy. Herein, we employ a combination therapy for eliminating both the bulk tumor cells and the rare cancer stem cells (CSCs) that have a high self-renewal capacity and play a critical role in cancer treatment failure. All-trans-retinoic acid (ATRA), a powerful differentiation agent of cancer stem cells and the clinically widely used chemotherapy agent doxorubicin (DOX) are simultaneously encapsulated in the same nanoparticle by a single emulsion method. It is demonstrated that ATRA and DOX simultaneous delivery-based therapy can efficiently deliver the drugs to both non-CSCs and CSCs to differentiate and kill the cancer cells. Differentiation of CSCs into non-CSCs can reduce their self-renewal capacity and increase their sensitivity to chemotherapy; with the combined therapy, a significantly improved anti-cancer effect is demonstrated. Administration of this combinational drug delivery system can markedly augment the enrichment of drugs both in tumor tissues and cancer stem cells, prodigiously enhancing the suppression of tumor growth while reduce the incidence of CSC in a synergistic manner.
- Published
- 2014
48. Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy.
- Author
-
Hong-Jun Li, Jin-Zhi Du, Xiao-Jiao Du, Cong-Fei Xu, Chun-Yang Sun, Hong-Xia Wang, Zhi-Ting Cao, Xian-Zhu Yang, Yan-Hua Zhu, Shuming Nie, and Jun Wang
- Subjects
NANOPARTICLES ,NANOMEDICAL research ,CANCER treatment ,DENDRIMERS ,CANCER cells ,THERAPEUTICS - Abstract
A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ~100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ~5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
49. Tumor Acidity-Sensitive Polymeric Vector for Active Targeted siRNA Delivery.
- Author
-
Chun-Yang Sun, Song Shen, Cong-Fei Xu, Hong-Jun Li, Yang Liu, Zhi-Ting Cao, Xian-Zhu Yang, Jin-Xing Xia, and Jun Wang
- Published
- 2015
- Full Text
- View/download PDF
50. Separation, Identification and Functional Properties of Bovine Milk Fat Globule Membrane Components: A Review of Recent Progress
- Author
-
WANG Cong, FEI Xu, WANG Xiuying, LIU Xiaojun
- Subjects
milk ,milk fat globule membrane ,separation and preparation ,composition, function ,Food processing and manufacture ,TP368-456 - Abstract
The milk fat globule membrane (MFGM) is the membrane surrounding fat globules in milk, and its content in milk is very small. However, due to its good physiological activity and application potential in food processing, the basic research and application of MFGM have attracted more and more attention. In this paper, we review recent progress in the separation, preparation, structural characterization, compositional identification and analysis, physiological activity and application characteristics of MFGM, in order to provide theoretical support for the application of MFGM in the food industries, especially in functional foods.
- Published
- 2023
- Full Text
- View/download PDF
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