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Systemic delivery of gemcitabine analogue and STAT3 siRNA promotes antitumor immunity against melanoma

Nano research 2022年第10期15卷 9057-9072页

作者： Huan Yan Zhanyan Liu Guibin Lin Fei Gu Yan Liu Yuxiao Xu Xueli Kuang Yuan Zhang School of Biomedical Sciences and engineering South China University of TechnologyGuangzhou International CampusGuangzhou 511442China national engineering research center for tissue restoration and reconstruction South China University of TechnologyGuangzhou 510006China Guangdong Provincial Key Laboratory of Biomedical engineering South China University of TechnologyGuangzhou 510006China Key Laboratory of Biomedical Materials and engineering of the Ministry of Education South China University of TechnologyGuangzhou 510006China

Immunosuppressive myeloid cells in the tumor microenvironment(TME)inhibit T-cell-mediated immune response and promote tumor progression.Therapeutically targeting both tumor cells and myeloid cells such as myeloid-derived suppressor cells(MDSCs),is expected to promote antitumor immunity.Gemcitabine(Gem)can serve as a chemotherapeutic drug and a MDSCdepleting agent.Aberrant activation of STAT3 promotes tumor cell growth and orchestrates the immunosuppressive activity of tumor-associated myeloid cells.Here we describe a strategy to kill tumor cells as well as inhibit the expansion and suppressive function of myeloid cells through the systemic delivery of gemcitabine monophosphate(GMP)and STAT3 siRNA(siSTAT3).To enhance their in vivo delivery efficiency,we formulate GMP and siSTAT3 into a lipid-coated calcium phosphate(LCP)nanoparticle and a liposome-protamine-hyaluronic acid(LPH)nanoparticle,respectively.Compared to the control and monotherapy groups,combined GMP and siSTAT3 nanoparticles effectively induced tumor cell death,downregulated a wide range of pro-tumor signaling pathways and immunosuppressive mediators,eliminated MDSCs,enhanced T cell effector functions in tumors and lymphoid compartments,and led to superior therapeutic efficacy in a syngeneic mouse melanoma model.Additionally,these nanoparticles can serve as adjuvant treatment to improve the therapeutic response of anti-PD-1-based immune checkpoint blockade therapy.Thus,the combination of gemcitabine chemotherapy and STAT3 inhibition through nanotechnology could effectively kill tumor cells,alleviate the immunosuppressive TME,and enhance endogenous antitumor immunity.

关键词： immunosuppression tumor microenvironment nanoparticle gemcitabine STAT3 siRNA

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Modulation of Conformational Transition of Polypeptides under Slightly Acidic Environment

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Chinese Journal of Chemistry 2022年第24期40卷 2981-2987,I0002页

作者： Jie Li Jiajie Zhang Qi Long Weisheng Guo Menghua Xiong Guangzhou First People's Hospital School of Biomedical Sciences and EngineeringSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong511442 China national engineering research center for tissue restoration and reconstruction South China University of TechnologyGuangzhouGuangdong510006 China Translational Medicine center Key Laboratory of Molecular TargetClinical PharmacologySchool of Pharmaceutical SciencesThe Second Affiliated HospitalGuangzhou Medical UniversityGuangzhouGuangdong510260 China Key Laboratory of Biomedical engineering of Guangdong Province and Innovation Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhouGuangdong510006 China Key Laboratory of Biomedical Materials and engineering of the Ministry of Education South China University of TechnologyGuangzhouGuangdong510006 China

Controlling the conformational transition of polypeptides under slightly acidic environment is challenging.Herein,we report a class of pH-responsive helix-to-coil conformationally transitionable polypeptides(pCTPs)by simply conjugating tertiary amine groups(TAs)to polylysine.Their conformation is highly dependent on the charge state of TAs,showing a helical structure when most TAs are deprotonated and a non-helical structure when majority of TAs are protonated.The conformational transition pH can be modulated by tuning the hydrophobicity of TAs and the incorporation of hydrophobic monomers at a pH range of 7.2 to 6.0.Such pCTP showed a vesicle-to-micelle transition when their conformation transformed from helix to coil,facilitating controlled drug release.Our study provided an approach to control the conformational transition of polypeptides under slightly acidic condition.

关键词： Peptides Conformational transition Helical structures pH responsiveness Drug delivery

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Microgel assembly:Fabrication,characteristics and application in tissue engineering and regenerative medicine

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Bioactive Materials 2022年第3期7卷 105-119页

作者： Qi Feng Dingguo Li Qingtao Li Xiaodong Cao Hua Dong Department of Biomedical engineering School of Materials Science and EngineeringSouth China University of TechnologyGuangzhouChina national engineering research center for tissue restoration and reconstruction(NERC-TRR) GuangzhouChina Key Laboratory of Biomedical Materials and engineering of the Ministry of Education South China University of TechnologyGuangzhouChina Guangdong Province Key Laboratory of Biomedical engineering South China University of TechnologyGuangzhouChina School of Medicine South China University of TechnologyGuangzhouChina

Microgel assembly,a macroscopic aggregate formed by bottom-up assembly of microgels,is now emerging as prospective biomaterials for applications in tissue engineering and regenerative medicine(TERM).This mini-review first summarizes the fabrication strategies available for microgel assembly,including chemical reaction,physical reaction,cell-cell interaction and external driving force,then highlights its unique characteristics,such as microporosity,injectability and heterogeneity,and finally itemizes its applications in the fields of cell culture,tissue regeneration and biofabrication,especially 3D printing.The problems to be addressed for further applications of microgel assembly are also discussed.

关键词： Microgel assembly tissue engineering Regenerative medicine

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Phospholipid-grafted PLLA electrospun micro/nanofibers immobilized with small extracellular vesicles from rat adipose mesenchymal stem cells promote wound healing in diabetic rats

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Regenerative Biomaterials 2022年第1期9卷 827-843页

作者： Jing Li Shunshun Yan Weiju Han Zixuan Dong Junliang Li Qi Wu Xiaoling Fu School of Materials Science and engineering South China University of TechnologyGuangzhou 510006China national engineering research center for tissue restoration and reconstruction and Innovation center for tissue restoration and reconstruction Guangzhou 510006China Laboratory of Biomedical engineering of Guangdong Province South China University of TechnologyGuangzhou 510006China School of Biomedical Sciences and engineering South China University of TechnologyGuangzhou International CampusGuangzhou 511442China

Small extracellular vesicles(sEVs)derived from mesenchymal stem cells(MSCs)can deliver a variety of bioactive factors to create a favorable local microenvironment,thereby holding huge potential in chronic wound repair.However,free sEVs administrated intravenously or locally are usually cleared rapidly,resulting in an insufficient duration of the efficacy.Thus,strategies that enable optimized retention and release profiles of sEVs at wound sites are desirable.Herein,we fabricated novel functional phosphoethanolamine phospholipid-grafted poly-L-lactic acid micro/nanofibers(DSPE-PLLA)to carry and retain sEVs from rat adipose MSCs,enabling the slow local release of sEVs.Our results showed that sEVs@DSPE-PLLA promoted the proliferation,migration and gene expression(ColⅠ,ColⅢ,TGF-β,α-SMA,HIF-1α)of fibroblasts.It also promoted keratinocyte proliferation.In addition,sEVs@DSPE-PLLA helped polarize macrophages toward the M2 phenotype by increasing the expression of anti-inflammatory genes(Arginase 1,CD 206,IL-10)and inhibiting the expression of pro-inflammatory genes(IL-1β,TNF-α).Further in vivo study in diabetic rat models showed that sEVs@DSPE-PLLA improved the wound-healing process by alleviating the inflammatory responses,stimulating cell proliferation,collagen deposition and angiogenesis.These results highlight the potential of using DSPE-grafted scaffolds for extracellular vesicle immobilization and suggest sEVs@DSPE-PLLA micro/nanofibers as promising functional wound dressings for diabetic wounds.

关键词： chronic wound healing small extracellular vesicles sustained release DSPE-PLLA fibers

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A Redox-responsive Prodrug Nanogel of TLR7/8 Agonist for Improved Cancer Immunotherapy

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Chinese Journal of Polymer Science 2023年第1期41卷 32-39页

作者： Kai-Shuo Wang Yu-Feng Jin Qi-Song Tong Yong-Cong Huang Zhen-Lin Gao Sui-Juan Zheng Jing-Yang Zhang Jun Wang Jin-Zhi Du School of Medicine South China University of TechnologyGuangzhou510006China School of Biomedical Sciences and engineering Guangzhou International CampusSouth China University of TechnologyGuangzhou511442China national engineering research center for tissue restoration and reconstruction South China University of TechnologyGuangzhou510006China Key Laboratory of Biomedical Materials and engineering of the Ministry of Education and Guangdong Provincial Key Laboratory of Biomedical EngineeringSouth China University of TechnologyGuangzhou510006China

The existence of tumor immunosuppressive microenvironment(TIME)is the major determinant for the poor efficacy of current tumor immunotherapy.Tumor-associated macrophages(TAMs)tend to become tumor-promoting M2-like phenotype and hinder immune response in solid tumors.Repolarization of TAMs from M2 to anti-tumor M1 phenotype is robust for remodeling the TIME.Herein,we developed a redox-responsive nanogel as the delivery system of Toll-like receptor 7 and 8(TLR7/8)agonist(R848)prodrug for potent cancer immunotherapy.The nanogel(denoted as R848-Gel)was obtained by emulsion polymerization of HSEMA and R848 prodrug(R848-HSEMA),whose size was appropriate 100 nm.R848-Gel could be internalized by macrophages and dendritic cells in vitro,and effectively repolarized M2 into M1 macrophages and promoted the maturation of antigen-presenting cells.In vivo study indicated that the R848-Gel showed a stronger tumor inhibitory effect and no drastic body weight change compared with free drug.Immune cell analysis after the treatment indicated that R848-Gel was helpful to activating the TIME.In summary,this study provides a simple but effective vehicle for R848 to improve cancer immunotherapy.

关键词： Nanogel Drug delivery Tumor-associated macrophage Macrophage repolarization Cancer immunotherapy

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Progress in nanoparticle-based regulation of immune cells

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Medical Review 2023年第2期3卷 152-179页

作者： Ya-Nan Fan Gui Zhao Yue Zhang Qian-Ni Ye Yi-Qun Sun Song Shen Yang Liu Cong-Fei Xu Jun Wang School of Biomedical Sciences and engineering South China University of TechnologyGuangzhou International CampusGuangzhouGuangdong ProvinceChina national engineering research center for tissue restoration and reconstruction South China University of TechnologyGuangzhouGuangdong ProvinceChina Key Laboratory of Biomedical Materials and engineering of the Ministry of Education South China University of TechnologyGuangzhouGuangdong ProvinceChina Department of Biomedical engineering Wake Forest School of MedicineWinston-SalemNCUSA School of Biomedical Sciences and engineering South China University of TechnologyGuangzhou International CampusGuangzhou 511442Guangdong ProvinceChina national engineering research center for tissue restoration and reconstruction South China University of TechnologyGuangzhou 510006Guangdong ProvinceChina Guangdong Provincial Key Laboratory of Biomedical engineering South China University of TechnologyGuangzhou 510006Guangdong ProvinceChina

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.

关键词： biomaterial drug delivery immune cell immunotherapy nanoparticle

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Mucosal vaccine delivery:A focus on the breakthrough of specific barriers

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3456-3474页

作者： Mengwen Huang Miaomiao Zhang Hongbin Zhu Xiaojiao Du Jun Wang School of Medicine South China University of TechnologyGuangzhou 510006China School of Biomedical Sciences and engineering South China University of TechnologyGuangzhou International CampusGuangzhou 511442China national engineering research center for tissue restoration and reconstruction South China University of TechnologyGuangzhou 510006China Guangdong Provincial Key Laboratory of Biomedical engineering South China University of TechnologyGuangzhou 510006China Key Laboratory of Biomedical Materials and engineering of the Ministry of Education South China University of TechnologyGuangzhou 510006China

Mucosal vaccines can effectively induce an immune response at the mucosal site and form the first line of defense against microbial invasion.The induced mucosal immunity includes the proliferation of effector T cells and the production of IgG and IgA antibodies,thereby effectively blocking microbial infection and transmis sion.However,after a long period of development,the transformation of mucosal vaccines into clinical use is still relatively slow.To date,fewer than ten mucosal vaccines have been approved.Only seven mucosal vaccines against coronavirus disease 2019(COVID-19) are under investigation in clinical trials.A representative vaccine is the adenovirus type-5 vectored COVID-19 vaccine(Ad5-nCoV) developed by Chen and coworkers,which is currently in phase Ⅲ clinical trials.The reason for the limited progress of mucosal vaccines may be the complicated mucosal barriers.Therefore,this review summarizes the characteristics of mucosal barriers and highlights strategies to overcome these barriers for effective mucosal vaccine delivery.

关键词： Mucosal vaccine Mucosal barrier Mucosal immune response Vaccine delivery Nanocarriers

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3D printed pore morphology mediates bone marrow stem cell behaviors via RhoA/ROCK2 signaling pathway for accelerating bone regeneration

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Bioactive Materials 2023年第8期26卷 413-424页

作者： Qiji Lu Jingjing Diao Yingqu Wang Jianlang Feng Fansen Zeng Yan Yang Yudi Kuang Naru Zhao Yingjun Wang School of Materials Science and engineering South China University of TechnologyGuangzhou510641PR China national engineering research center for tissue restoration and reconstruction South China University of TechnologyGuangzhou510006PR China NMPA Key Laboratory for research and Evaluation of Innovative Biomaterials for Medical Devices.Guangzhou 510006PR China Medical Devices research&Testing center of SCUT Guangzhou510006PR China School of Biomedical Sciences and engineering South China University of TechnologyGuangzhou International CampusGuangzhou511442PR China Guangdong Institute of Advanced Biomaterials and Medical Devices Guangzhou510535PR China

Bone bionics and structural engineering have sparked a broad interest in optimizing artificial scaffolds for better bone regeneration.However,the mechanism behind scaffold pore morphology-regulated bone regeneration remains unclear,making the structure design of scaffolds for bone repair challenging.To address this issue,we have carefully assessed diverse cell behaviors of bone mesenchymal stem cells(BMSCs)on theβ-tricalcium phosphate(β-TCP)scaffolds with three representative pore morphologies(i.e.,cross column,diamond,and gyroid pore unit,respectively).Among the scaffolds,BMSCs on theβ-TCP scaffold with diamond pore unit(designated as D-scaffold)demonstrated enhanced cytoskeletal forces,elongated nucleus,faster cell mobility,and better osteogenic differentiation potential(for example,the alkaline phosphatase expression level in D-scaffold were 1.5-2 times higher than other groups).RNA-sequencing analysis and signaling pathway intervention revealed that Ras homolog gene family A(RhoA)/Rho-associated kinase-2(ROCK2)has in-depth participated in the pore morphology-mediated BMSCs behaviors,indicating an important role of mechanical signaling transduction in scaffold-cell interactions.Finally,femoral condyle defect repair results showed that D-scaffold could effectively promote endogenous bone regeneration,of which the osteogenesis rate was 1.2-1.8 times higher than the other groups.Overall,this work provides insights into pore morphology-mediated bone regeneration mechanisms for developing novel bioadaptive scaffold designs.

关键词： Bone mesenchymal stem cells 3D-printed scaffold Pore morphology Bone regeneration Structure-osteogenesis relationship

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Octacalcium Phosphate Fiber Synthesized by Homogeneous Precipitation Method

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Journal of Wuhan University of Technology(Materials Science) 2010年第5期25卷 747-752页

作者：王小俊方立明 School of Materials Science and engineering South China University of Technology national engineering research center for Human tissue restoration and Function reconstruction South China University of Technology

Calcium phosphate fiber was synthesized by homogeneous precipitation method using urea as precipitation agent. Effects of the reactant concentration and hydrothermal temperature on the calcium phosphate morphology and composition were studied using SEM, FTIR and XRD. It is found that fine octacalcium phosphate（OCP）fiber can be synthesized when the reactant concentrations are 0.167 mol/L for Ca（NO3）2, 0.1 mol/L for （NH4）2HPO4, and 0.6-0.7 mol/L for （NH2）2CO, respectively, with the initial reactant solution pH value around 2.2, hydrothermal temperature 90 ℃ and termination reaction at pH value around 5.0. At very low urea concentration, the product size distribution is highly inhomogeneous, however, at an excessively high concentration the product becomes larger and shorter and a mixture of OCP and hydroxyapatite （HA）. Increasing the hydrothermal temperature is favorable to the fast precipitation of OCP, higher productivity and finer product.

关键词： octacalcium phosphate fiber homogeneous precipitation

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Wireless electrical stimulation at the nanoscale interface induces tumor vascular normalization

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Bioactive Materials 2022年第12期7卷 399-408页

作者： Changhao Li Cairong Xiao Lizhen Zhan Zhekun Zhang Jun Xing Jinxia Zhai Zhengnan Zhou Guoxin Tan Jinhua Piao Yahong Zhou Suijian Qi Zhengao Wang Peng Yu Chengyun Ning School of Material Science and engineering National Engineering Research Center for Tissue Restoration and ReconstructionMetallic Materials Surface Functionalization Engineering Research Center of Guangdong ProvinceSouth China University of TechnologyGuangzhou510641China School of Food Science and engineering South China University of TechnologyGuangzhou510641China CAS Key Laboratory of Bio-inspired Materials and Interfacial Science Technical Institute of Physics and ChemistryChinese Academy of ScienceBeijing100190China School of Chemical engineering and Light Industry Guangdong University of TechnologyGuangzhou510006China China-Singapore International Joint research Institute Guangzhou511365China

Pathological angiogenesis frequently occurs in tumor tissue, limiting the efficiency of chemotherapeutic drug delivery and accelerating tumor progression. However, traditional vascular normalization strategies are not fully effective and limited by the development of resistance. Herein, inspired by the intervention of endogenous bioelectricity in vessel formation, we propose a wireless electrical stimulation therapeutic strategy, capable of breaking bioelectric homeostasis within cells, to achieve tumor vascular normalization. Polarized barium titanate nanoparticles with high mechano-electrical conversion performance were developed, which could generate pulsed open-circuit voltage under low-intensity pulsed ultrasound. We demonstrated that wireless electrical stimulation significantly inhibited endothelial cell migration and differentiation in vitro. Interestingly, we found that the angiogenesis-related eNOS/NO pathway was inhibited, which could be attributed to the destruction of the intracellular calcium ion gradient by wireless electrical stimulation. In vivo tumor-bearing mouse model indicated that wireless electrical stimulation normalized tumor vasculature by optimizing vascular structure, enhancing blood perfusion, reducing vascular leakage, and restoring local oxygenation. Ultimately, the anti-tumor efficacy of combination treatment was 1.8 times that of the single chemotherapeutic drug doxorubicin group. This work provides a wireless electrical stimulation strategy based on the mechano-electrical conversion performance of piezoelectric nanoparticles, which is expected to achieve safe and effective clinical adjuvant treatment of malignant tumors.

关键词： Calcium distribution Mechano-electrical conversion Piezoelectric barium titanate Tumor vascular normalization Wireless electrical stimulation

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