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MicroRNA-122-functionalized DNA tetrahedron stimulate hepatic differentiation of human mesenchymal stem cells for acute liver failure therapy

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Bioactive Materials 2023年第10期28卷 50-60页

作者： Hongyan Wei Fenfang li Tiantian Xue Haixia Wang Enguo Ju mingqiang li Yu Tao Laboratory of Biomaterials and Translational Medicine Center for NanomedicineThe Third Affiliated HospitalSun Yat-sen UniversityGuangzhou510630China Guangdong Provincial Key Laboratory of liver Disease Research Guangzhou510630China

As the most abundant liver-specific microRNA, microRNA-122 (miR122) played a crucial role in the differentiation of stem cells into hepatocytes. However, highly efficient miR122 delivery still confronts challenges including poor cellular uptake and easy biodegradation. Herein, we for the first time demonstrated that the tetrahedral DNA (TDN) nanoplatform had great potential in inducing the differentiation of human mesenchymal stem cells (hMSCs) into functional hepatocyte-like cells (HLCs) by transferring the liver-specific miR122 to hMSCs efficiently without any extrinsic factors. As compared with miR122, miR122-functionalized TDN (TDN-miR122) could significantly up-regulate the protein expression levels of mature hepatocyte markers and hepatocyte-specific marker genes in hMSCs, indicating that TDN-miR122 could particularly activate the hepatocyte-specific properties of hMSCs for developing cell-based therapies in vitro. The transcriptomic analysis further indicated the potential mechanism that TDN-miR122 assisted hMSCs differentiated into functional HLCs. The TDN-miR122-hMSCs exhibited hepatic cell morphology phenotype, significantly up-regulated specific hepatocyte genes and hepatic biofunctions in comparison with the undifferentiated MSCs. Preclinical in vivo transplantation appeared that TDN-miR122-hMSCs in combination with or without TDN could efficiently rescue acute liver failure injury through hepatocyte function supplement, anti-apoptosis, cellular proliferation promotion, and anti-inflammatory. Collectively, our findings may provide a new and facile approach for hepatic differentiation of hMSCs for acute liver failure therapy. Further large animal model explorations are needed to study their potential in clinical translation in the future.

关键词： Hepatocyte differentiation Tetrahedral framework nucleic acids Cell therapy Transcriptomics Acute liver failure treatment

Framework nucleic Acid-MicroRNA mediated hepatic differentiation and functional hepatic spheroid development for treating acute liver failure

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Bioactive Materials 2024年第11期41卷 611-626页

作者： Hongyan Wei Tiantian Xue Fenfang li Enguo Ju Haixia Wang mingqiang li Yu Tao Laboratory of Biomaterials and Translational Medicine Center for NanomedicineThe Third Affiliated HospitalSun Yat-sen UniversityGuangzhou510630GuangdongChina Guangdong Provincial Key Laboratory of liver Disease Research Sun Yat-sen UniversityGuangzhou510630GuangdongChina Department of Obstetrics and Gynecology Women and Children's Hospital of Chongqing Medical UniversityNo.120 Longshan RoadYubei DistrictChongqing401147China Department of Obstetrics and Gynecology Chongqing Health Center for Women and ChildrenNo.120 Longshan RoadYubei DistrictChongqing401147China

The specific induction of hepatic differentiation presents a significant challenge in developing alternative liver cell sources and viable strategies for clinical therapy of acute liver failure (ALF). The past decade has witnessed the blossom of microRNAs in regenerative medicine. Herein, microRNA 122-functionalized tetrahedral framework nucleic acid (FNA-miR-122) has emerged as an unprecedented and potential platform for directing the hepatic differentiation of adipose-derived mesenchymal stem cells (ADMSCs), which offers a straightforward and cost-effective method for generating functional hepatocyte-like cells (FNA-miR-122-iHep). Additionally, we have successfully established a liver organoid synthesis strategy by optimizing the co-culture of FNA-miR-122-iHep with endothelial cells (HUVECs), resulting in functional Hep:HUE-liver spheroids. Transcriptome analysis not only uncovered the potential molecular mechanisms through which miR-122 influences hepatic differentiation in ADMSCs, but also clarified that Hep:HUE-liver spheroids could further facilitate hepatocyte maturation and improved tissue-specific functions, which may provide new hints to be used to develop a hepatic organoid platform. Notably, compared to transplanted ADMSCs and Hep-liver spheroid, respectively, both FNA-miR-122-iHep-based single cell therapy and Hep:HUE-liver spheroid-based therapy showed high efficacy in treating ALF in vivo. Collectively, this research establishes a robust system using microRNA to induce ADMSCs into functional hepatocyte-like cells and to generate hepatic organoids in vitro, promising a highly efficient therapeutic approach for ALF.

关键词： Hepatic differentiation Framework nucleic acid Functional hepatic spheroids Transcriptome sequencing analysis Acute liver failure therapy

Applications of Nanobiomaterials in the Therapy and Imaging of Acute liver Failure

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Nano-Micro Letters 2021年第2期13卷 74-109页

作者： Yuanyuan Jin Haixia Wang Ke Yi Shixian Lv Hanze Hu mingqiang li Yu Tao Laboratory of Biomaterials and Translational Medicine The Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630People’s Republic of China Department of Bioengineering University of WashingtonSeattleWA 98195USA Department of Biomedical Engineering Columbia UniversityNew YorkNY 10027USA

Acute liver failure(ALF),a fatal clinical disease featured with overwhelming hepatocyte necrosis,is a grand challenge in global ***,a satisfactory therapeutic option for curing ALF is still absent,other than liver *** are currently being developed for the diagnosis and treatment of *** liver can sequester most of nanoparticles from blood circulation,which becomes an intrinsic superiority for nanobiomaterials targeting hepatic *** can enhance the bioavailability of free drugs,thereby significantly improving the therapeutic effects in *** can also increase the liver accumulation of therapeutic agents and enable more effective targeting of the liver or specific liver *** addition,stimuli-responsive,optical,or magnetic nanomaterials exhibit great potential in the therapeutical,diagnostic,and imaging applications in ***,therapeutic agents in combination with nanobiomaterials increase the specificity of ALF therapy,diminish adverse systemic effects,and offer a multifunctional theranostic *** holds excellent significance and prospects in ALF *** this review,we summarize the therapeutic mechanisms and targeting strategies of various nanobiomaterials in *** highlight recent developments of diverse nanomedicines for ALF therapy,diagnosis,and ***,the challenges and future perspectives in the theranostics of ALF are also discussed.

关键词： Acute liver failure Nanomaterials Drug/gene/cytokines delivery Targeted therapy Imaging

Tumor microenvironment-responsive hyaluronate-calcium carbonate hybrid nanoparticle enables effective chemo-therapy for primary and advanced osteosarcomas

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Nano Research 2018年第9期11卷 4806-4822页

作者： Yi Zhang Lulu Cai Di li Yeh-Hsing Lao Dingzhuo liu mingqiang li Jianxun Ding Xuesi Chen Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun 130022 China Department of Orthopedics the Fourth Affiliated Hospital of China Medical University Shenyang 110032 China Personalized Drug Therapy Key Laboratory of Sichuan Province Hospital of the University of Electronic Science and Technology of China Sichuan Provincial People's Hospital Chengdu 610072 China Department of Biomedical Engineering Columbia University New York NY 10027 USA Guangdong Provincial Key Laboratory of liver Disease The Third Affiliated Hospital of Sun Yat-sen University Guangzhou 510630 China

Osteosarcoma is the most common malignancy in the bone. Current chemotherapy offers limited efficacy with significant side effects, especially for advanced and relapsed osteosarcomas. Nanoparticle-formulated chemotherapeutic drugs may be used to resolve these issues, but several aspects of these formulations remain unsatisfactory, such as how to improve their stability in the bloodstream, prevent undesirable drug leakage, and enhance targeted drug accumulation in the tumor. In this study, a tumor microenvironment-responsive calcium carbonate （CaCO3）- crosslinked hyaluronate （HA） nanopartide was prepared via a ＂green＂ process to effectively deliver doxorubicin （DOX） for the treatment of various stages of osteosarcoma. The DOX-loaded hyaluronate-calcium carbonate hybrid nanoparfide （HA-DOX/CaCO3） demonstrated superior stability both in vitro and in vivo, and rapidly released DOX at the tumor site when triggered by the acidic tumor microenvironment. Compared with free DOX and a non-crosslinked nanoparficle （HA-DOX）, HA-DOX]CaCO3 exhibited the most potent inhibition efficacy toward both primary and advanced models of routine osteosarcoma, resulting in effective tumor inhibition, improved survival time, and reduced adverse effects. Most importantly, in the advanced osteosarcoma model, HA-DOX/CaCO3 potently suppressed tumor growth by 84.6%, which indicates the potential of this platform for osteosarcoma treatment, particularly for advanced and relapsed cases. The proposed polysaccharide nanopartide would be a promising drug delivery platform to advance osteosarcoma nanomedicine.

关键词： hybrid nanomedicine tumor-aridity responsiveness controlled drug delivery multi-stage osteosarcoma chemotherapy

Phase transferring luminescent gold nanoclusters via single-stranded DNA

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Science China Chemistry 2022年第6期65卷 1212-1220页

作者： Yu li Hui Lu Zhibei Qu mingqiang li Haoran Zheng Peilin Gu Jiye Shi Jiang li Qian li lihua Wang Jing Chen Chunhai Fan Jianlei Shen Division of Physical Biology CAS Key Laboratory of Interfacial Physics and TechnologyShanghai Institute of Applied PhysicsChinese Academy of SciencesShanghai201800China University of Chinese Academy of Sciences Beijing100049China School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules and National Center for Translational MedicineShanghai Jiao Tong UniversityShanghai200240China Shanghai Synchrotron Radiation Facility Zhangjiang LaboratoryShanghai Advanced Research InstituteChinese Academy of SciencesShanghai201210China Shanghai Key Laboratory of Green Chemistry and Chemical Processes School of Chemistry and Molecular EngineeringEast China Normal UniversityShanghai200127China

Atomically precise gold nanoclusters(Au NCs) are an emerging class of quantum-sized nanomaterials with discrete electronic energy levels, which has led to a range of attractive electronic and optical applications. Nevertheless, the lack of general methods to transfer Au NCs protected with hydrophobic ligands to an aqueous solution hampers their use in physiological settings. Here,we developed a single-stranded DNA-based approach that could transfer ~90% hydrophobic Au NCs into an aqueous *** experimentally and theoretically established that multivalent electrostatic and hydrophobic interactions between DNA strands and the hydrophobic ligand layer on Au NCs resulted in monodispersed DNA-coated Au NCs with high physical integrity in an aqueous solution. The fluorescence quantum yield of Au NCs was increased by ~13 fold, and surface-constrained DNA retained the specific recognition ability for biosensing. We further demonstrated the versatility of this phase-transfer approach, which thus holds great potential to advance biological and medical applications of Au NCs.

关键词： gold nanoclusters DNA monodispersed phase transfer biological application

Co-delivery of doxorubicin and paclitaxel with linear-dendritic block copolymer for enhanced anti-cancer efficacy

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Science China Chemistry 2014年第4期57卷 624-632页

作者： ZHANG Yu XIAO ChunSheng li mingqiang DING JianXun YANG ChenGuang ZHUANG Xiuli CHEN XueSi Key Laboratory of Polymer Ecomaterials Chanchun Institute of Applied Chemistry Chinese Academy of Sciences University of Chinese Academy of Sciences

A series of well-defined amphiphilic linear-dendritic block copolymers （telodendrimers, MPEG-b-PAMAM-cholesterol） with 1,2,4 or 8 cholesteryl groups （named as P1, P2, P4, P8, respectively） were synthesized. Their chemical structures were char- acterized with IH NMR and mass spectrum （MALDI-TOF MS）. The telodendrimers could self-assemble into micelles in aqueous solution, and encapsulate chemotherapeutic drug doxorubicin （DOX） and paclitaxel （PTX） for combination therapy. All the telodendrimers could encapsulate DOX with similar capability. However, their drug-loading capability of PTX is in- creased with the increasing number of cholesteryl groups. P8 exhibited much higher PTX loading efficiency than its counter- parts. Thus, P8 was selected for further application of drug delivery in the paper. The drug-loading micellar nanoparticles （NPs） of P8 were spherical in shape and their diameters were less than 150 nm which were determined by dynamic light scattering measurements （DLS） and transmission electron microscope （TEM）. In vitro drug release experiment demonstrated that P8 ex- hibited a controlled release manner for both DOX and PTX, and the two drugs were released simultaneously. In vitro cytotoxi- city experiment further demonstrated that the co-delivery of DOX and PTX in P8 exhibited better anti-cancer efficiency than the delivery systems encapsulated with single drug （DOX or PTX）. This indicates a synergistic effect. The co-delivery system showed potential in future anti-cancer treatment.

关键词： block copolymer linear-dendritic nanoparticle drug delivery combination therapy

Di-PEGylated insulin:A long-acting insulin conjugate with superior safety in reducing hypoglycemic events

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2761-2772页

作者： Zhipeng Zeng Runcheng Tan Shi Chen Haolin Chen Zhijia liu lixin liu mingqiang li Yongming Chen Laboratory of Biomaterials and Translational Medicine Center for NanomedicineThe Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630China School of Materials Science and Engineering Center of Functional BiomaterialsKey Laboratory of Polymeric Composite Materials and Functional Materials of Ministry of EducationSun Yat-sen UniversityGuangzhou 510275China

Although the discovery of insulin 100 years ago revolutionized the treatment of diabetes,its therapeutic potential is compromised by its short half-life and narrow therapeutic *** long-acting insulin analogs,such as insulin-polymer conjugates,are mainly used to improve pharmacokinetics by reducing renal ***,these conjugates are synthesized without sacrificing the bioactivity of insulin,thus retaining the narrow therapeutic index of native insulin,and exceeding the efficacious dose still leads to ***,we report a kind of di-PEGylated insulin that can simultaneously reduce renal clearance and receptor-mediated *** impairing the binding affinity to the receptor and the activation of the receptor,di-PEGylated insulin not only further prolongs the half-life of insulin compared to classical mono-PEGylated insulin but most importantly,increases its maximum tolerated dose *** target of long-term glycemic management in vivo has been achieved through improved pharmacokinetics and a high *** work represents an essential step towards long-acting insulin medication with superior safety in reducing hypoglycemic events.

关键词： Diabetes Insulin Therapeutic index Hypoglycemia PEGylation Receptor-mediated clearance Half-life Diabetic nephropathy

Spatiotemporal control of CRISPR/Cas9 gene editing

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Signal Transduction and Targeted Therapy 2021年第7期6卷 2088-2105页

作者： Chenya Zhuo Jiabin Zhang Jung-Hwan Lee Ju Jiao Du Cheng li liu Hae-Won Kim Yu Tao mingqiang li laboratory of Biomaterials and Translational Medicine Center for NanomedicineThe Third Affiliated HospitalSun Yat-sen UniversityGuangzhouChina lnstitute of Tissue Regeneration Engineering(ITREN) Dankook UniversityCheonanSouth Korea Department of Nuclear Medicine The Third Affiliated HospitalSun Yat-sen UniversityGuangzhouChina PCFM Lab of Ministry of Education School of Materials Science and EngineeringSun Yat-sen UniversityGuangzhouChina Department of Gynecology and Obstetrics The Third Affiliated HospitalSun Yat-sen UniversityGuangzhouChina Guangdong Provincial Key Laboratory of liver Disease Research GuangzhouChina

The clustered regularly interspaced short palindromic repeats(CRISPRJ/associated protein 9(CRISPR/Cas9)gene editing technology,as a revolutionary breakthrough in genetic engineering,offers a promising platform to improve the treatment of various genetic and infectious diseases because of its simple design and powerful ability to edit different loci ***,failure to conduct precise gene editing in specific tissues or cells within a certain time may result in undesirable consequences,such as serious off-target effects,representing a critical challenge for the clinical translation of the ***,some emerging strategies using genetic regulation,chemical and physical strategies to regulate the activity of CRISPR/Cas9 have shown promising results in the improvement of spatiotemporal ***,in this review,we first summarize the latest progress of these advanced strategies involving cell-specific promoters,small-molecule activation and inhibition,bioresponsive delivery carriers,and optical/thermal/ultrasonic/magnetic ***,we highlight the advantages and disadvantages of various strategies and discuss their obstacles and limitations in clinical ***,we propose viewpoints on directions that can be explored to further improve the spatiotemporal operability of CRISPR/Cas9.

关键词： activation breakthrough consequences

Stem cell-derived hepatocyte therapy using versatile biomimetic nanozyme incorporated nanofiber-reinforced decellularized extracellular matrix hydrogels for the treatment of acute liver failure

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Bioactive Materials 2023年第10期28卷 112-131页

作者： Yuanyuan Jin Jiabin Zhang Yanteng Xu Ke Yi Fenfang li Huicong Zhou Haixia Wang Hon Fai Chan Yeh-Hsing Lao Shixian Lv Yu Tao mingqiang li Laboratory of Biomaterials and Translational Medicine Center for NanomedicineThe Third Affiliated HospitalSun Yat-sen UniversityGuangzhou510630China Guangdong Provincial Key Laboratory of liver Disease Research Guangzhou510630China School of Materials Science and Engineering Peking UniversityBeijing100871China Institute for Tissue Engineering and Regenerative Medicine School of Biomedical ScienceThe Chinese University of Hong Kong999077Hong KongChina Department of Pharmaceutical Sciences University at BuffaloThe State University of New YorkBuffaloNY14214USA

Reactive oxygen species(ROS)-associated oxidative stress,inflammation storm,and massive hepatocyte necrosis are the typical manifestations of acute liver failure(ALF),therefore specific therapeutic interventions are essential for the devastating ***,we developed a platform consisting of versatile biomimetic copper oxide nanozymes(Cu NZs)-loaded PLGA nanofibers(Cu NZs@PLGA nanofibers)and decellularized extracellular matrix(dECM)hydrogels for delivery of human adipose-derived mesenchymal stem/stromal cells-derived hepatocyte-like cells(hADMSCs-derived HLCs)(HLCs/Cu NZs@fiber/dECM).Cu NZs@PLGA nanofibers could conspicuously scavenge excessive ROS at the early stage of ALF,and reduce the massive accumulation of pro-inflammatory cytokines,herein efficiently preventing the deterioration of hepatocytes ***,Cu NZs@PLGA nanofibers also exhibited a cytoprotection effect on the transplanted ***,HLCs with hepatic-specific biofunctions and anti-inflammatory activity acted as a promising alternative cell source for ALF *** dECM hydrogels further provided the desirable 3D environment and favorably improved the hepatic functions of *** addition,the pro-angiogenesis activity of Cu NZs@PLGA nanofibers also facilitated the integration of the whole implant with the host ***,HLCs/Cu NZs@fiber/dECM performed excellent synergistic therapeutic efficacy on ALF *** strategy using Cu NZs@PLGA nanofiber-reinforced dECM hydrogels for HLCs in situ delivery is a promising approach for ALF therapy and shows great potential for clinical translation.

关键词： Acute liver failure Nanozyme Hepatocyte-like cells Human adipose-derived mesenchymal stem/stromal cells Electrospun nanofiber