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Nanomedicine-mediated immunogenic cell death and its combination with immune checkpoint blockade therapy

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Science China(Technological sciences) 2024年第8期67卷 2350-2362页

作者： CHEN JunBin ZHANG YuXi SU Miao ZHU YueQiang YANG XianZhu school of biomedical sciences and engineering South China University of TechnologyGuangzhou International CampusGuangzhou 511442China National engineering Research Center for Tissue Restoration and Reconstruction Guangdong Provincial Key Laboratory of Biomedical EngineeringKey Laboratory of Biomedical Materials and Engineering of the Ministry of EducationSouth China University of TechnologyGuangzhou 510006China

Cancer immunotherapies, which train the natural immune system to specifically kill tumor cells while sparing the healthy cells,have helped revolutionize cancer treatments and demonstrated promising clinical therapeutic benefits for decades. However, the therapeutic outcome of immunotherapies, even for the most successful immune checkpoint blockade(ICB) therapy, remains unsatisfactory in the clinical practice, mainly due to the low immunogenicity of solid tumors and its immunosuppressive tumor microenvironment(TME). Notably, several cancer treatment modalities, including chemotherapy, radiotherapy, and phototherapy, have been revealed to evoke tumor immunogenicity and reverse immunosuppressive TME via inducing immunogenic cell death(ICD) of tumor cells, which synergistically sensitized tumors to ICB therapy. Nanomedicines have been extensively applied to augment ICD-inducing treatment modalities and potentiate ICB therapeutic efficacy therapy due to the opportune convergence of immunotherapy and nanotechnology. Here, we discuss the recent advances in nanomedicine-mediated ICD and its combination with ICB therapy.

关键词： cancer immunotherapy nanomedicine immunogenic cell death immune checkpoint blockade

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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 ***-associated macrophages(TAMs)tend to become tumor-promoting M2-like phenotype and hinder immune response in solid *** of TAMs from M2 to anti-tumor M1 phenotype is robust for remodeling the ***,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 *** 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 *** vivo study indicated that the R848-Gel showed a stronger tumor inhibitory effect and no drastic body weight change compared with free *** cell analysis after the treatment indicated that R848-Gel was helpful to activating the *** 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

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

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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 *** targeting both tumor cells and myeloid cells such as myeloid-derived suppressor cells(MDSCs),is expected to promote antitumor ***(Gem)can serve as a chemotherapeutic drug and a MDSCdepleting *** activation of STAT3 promotes tumor cell growth and orchestrates the immunosuppressive activity of tumor-associated myeloid *** 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,*** 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 ***,these nanoparticles can serve as adjuvant treatment to improve the therapeutic response of anti-PD-1-based immune checkpoint blockade ***,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

A polyamidoamine(PAMAM)derivative dendrimer with high loading capacity of TLR7/8 agonist for improved cancer immunotherapy

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Nano Research 2022年第1期15卷 510-518页

作者： Jia-Si Wu Jia-Xian Li Na Shu Qi-Jia Duan Qi-Song Tong Jing-Yang Zhang Yong-Cong Huang Si-Yu Yang Zhi-Bin Zhao Jin-Zhi Du Institutes for Life sciences School of MedicineSouth China University of TechnologyGuangzhou 510006China school of biomedical sciences and engineering Guangzhou International CampusSouth China University of TechnologyGuangzhou 511442China National engineering Research Center for Tissue Restoration and Reconstruction Key Laboratory of Biomedical Engineering oj Guangdong ProvinceSouth China University of TechnologyGuangzhou 510006China Key Laboratory of biomedical Materials and engineering of the Ministry of Education Innovation Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou 510006China

Tumor associated macrophages(TAMs)tend to exhibit tumor-promoting M2 phenotype and contribute to the development of immunosuppressive microenvironment of solid *** TAMs from M2 into tumoricidal M1 phenotype is robust for stimulating tumor immunosuppressive microenvironment(TIME).In this study,we developed a poly(amidoamine)(PAMAM)derivative dendrimer(denoted as fourth generation-N,N-diethylaminoethyl(G4-DEEA))for efficient loading of Toll-like receptor 7 and 8(TLR7/8)agonist(R848)to remodel the TIME for potent cancer immunotherapy,G4-DEEA exhibited a high loading capacity of R848 up to 35.9 wt%by taking advantage of its dendritic *** resulting formulation(designated as G4-DEEA@R848)effectively polarized M2 macrophages into M1 phenotype in vitro,and improved the maturation and activation of antigen-presenting *** the 4T1 orthotopic breast cancer model,G4-DEEA@R848 showed a stronger tumor inhibitory effect than free *** mechanistic studies suggested that G4-DEEA@R848 could significantly stimulate the TIME by repolarizing TAMs into M1 phenotype,reducing the presence of immunosuppressive myeloid cells and increasing the infiltration of tumor cytotoxic T *** study provides a simple but effective dendrimer-based strategy to improve the formulation of R848 for improved cancer immunotherapy.

关键词： poly(amidoamine)(PAMAM)dendrimer drug delivery tumor-associated macrophage macrophage repolarization cancer immunotherapy

Heterogenous glucose-stimulated insulin secretion at single islet level

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Engineered Regeneration 2023年第4期4卷 387-395页

作者： Jiaxiang Yin Hao Meng Haopeng Lin Meijun Mo Jingfang Lin Jingyi Chen Lihua Chen Xiaojun Xu Zonghong Li Wei Ji Tao Xu Huisheng Liu school of biomedical engineering Guangzhou Medical UniversityGuangzhouChina guangzhou National Laboratory GuangzhouGuangdongChina Bioland Laboratory GuangzhouGuangdongChina National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina school of biomedical sciences and engineering South China University of TechnologyGuangzhou International CampusGuangzhouChina

Insulin secretion by pancreatic islets plays a vital role in regulating blood glucose ***,the mech-anism responsible for this dynamic insulin secretion has not been completely understood,particularly at the single islet *** this study,we have successfully developed an easy microfluidic platform that allows for the exploration of dynamic glucose-stimulated insulin secretion(GSIS)at the single islet *** the utilization of this platform,we evaluated dynamic GSIS from single islets isolated from both normal and diabetic *** results demonstrate that islets can be categorized into three types based on their dynamic GSIS:Type Ⅰ exhibits a biphasic GSIS profile with a fast first phase and flat second phase;Type Ⅱ also has a biphasic GSIS profile with a fast first phase but a slow increased second phase;Type Ⅲ displays only a slowly increased second phase and lacks a fast first *** sequencing analysis demonstrated that the cell type and exocytosis-specific genes are consistent with the proportion of cells and insulin release kinetics among the three types of islets,***,our findings suggest that high expression of Atp5pb is anti-correlated with the first phase of insulin ***,we revealed that diabetic islets exhibit only the type Ⅰ GSIS response,indicating a deliberate impairment of the second phase of insulin ***,this device serves as a crucial tool in the research field of islets and diabetes,allowing researchers to investigate islet functional heterogeneity and identity at the single islet level.

关键词： Islet-on-a-chip Single islet Glucose-stimulated insulin secretion Heterogeneity Diabetes

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 ***,free sEVs administrated intravenously or locally are usually cleared rapidly,resulting in an insufficient duration of the ***,strategies that enable optimized retention and release profiles of sEVs at wound sites are ***,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 *** results showed that sEVs@DSPE-PLLA promoted the proliferation,migration and gene expression(ColⅠ,ColⅢ,TGF-β,α-SMA,HIF-1α)of *** also promoted keratinocyte *** 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 *** 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

Modification of adipose mesenchymal stem cells-derived small extracellular vesicles with fibrin-targeting peptide CREKA for enhanced bone repair

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Bioactive Materials 2023年第2期20卷 208-220页

作者： Qi Wu Xiaoling Fu Xian Li Jing Li Weiju Han Yingjun Wang school of biomedical sciences and engineering South China University of TechnologyGuangzhou International CampusGuangzhou511442PR China National engineering Research Center for Tissue Restoration and Reconstruction South China University of TechnologyGuangzhou510006PR China Key Laboratory of biomedical engineering of Guangdong Province South China University of TechnologyGuangzhou510006PR China Key Laboratory of biomedical Materials and engineering of the Ministry of Education South China University of TechnologyGuangzhou510006PR China

The process of bone repair is highly regulated by a large number of bioactive ***,a“cocktail”of bioactive factors supplemented to the defect sites is desirable for bone *** this regard,small extracellular vesicles(sEVs)derived from mesenchymal stem cells hold great potential in tissue ***,the poor homing and retention of sEVs greatly limited their possible clinical *** the present work,DMPE-PEG-CREKA was inserted into the membrane of sEVs released from adipose-derived mesenchymal stem cells to obtain CREKA functionalized sEVs(CREKA-sEVs),which could target fibrin to accumulate and retain in bone *** results showed that CREKA-sEVs,like sEVs,promoted the osteogenic differentiation of BMSCs,the angiogenic property of HUVECs,and modulated the polarization of macrophages in ***,due to the improved fibrin-binding and retention capacity of CREKA-sEVs,they enhanced the bone repair substantially in the rat femoral defect *** study provided a new strategy to improve the therapeutic efficiency of sEVs and showed that CREKA-sEVs had great application value in bone tissue repair.

关键词： MSCs-derived sEVs Fibrin-targeting CREKA Bone repair

Energy-Dissipative Hydrogels:A Promising Material for Tissue Regeneration

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Chinese Journal of Chemistry 2023年第20期41卷 2697-2714页

作者： Mingrui Li Youshi Lin Yuxiao Zhang Liming Bian Kunyu Zhang school of biomedical sciences and engineering South China University of TechnologyGuangzhou International CampusGuangzhouGuangdong511442 China National engineering Research Center for Tissue Restoration and Reconstruction South China University of TechnologyGuangzhouGuangdong510006 China Guangdong Provincial Key Laboratory of biomedical engineering South China University of TechnologyGuangzhouGuangdong510006 China Key Laboratory of biomedical Materials and engineering of the Ministry of Education South China University of TechnologyGuangzhouGuangdong510006 China

Hydrogels are promising candidates for mimicking native extracellular matrix(ECM)and are therefore widely adopted as scaffolds in tissue ***,conventional hydrogels composed of static networks are prone to permanent structural damages and lack the ability to provide the time-dependent mechanical cues,which are essential for cell development,ECM remodeling,and tissue *** recent substantial development in the structurally dynamic hydrogels with energy-dissipative ability has demonstrated the unique capability of such viscoelastic hydrogels to withstand extreme biomechanical loads and regulate cellular behaviors not present in classical *** review starts with the general design principles for energy-dissipative hydrogels,followed by recent advancements in fabrication approaches for energy-dissipative *** then highlight some applications of energy-dissipative hydrogels in tissue engineering,including bone and cartilage regeneration,vessel regeneration,nerve regeneration,and wound ***,we discuss about the key current challenges and future development of energy-dissipative hydrogels for biomedical applications.

关键词： Hydrogels Energy dissipation Interchain interactions Tissue engineering Crosslinking Supramolecular chemistry Viscoelasticity

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 *** 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 ***,after a long period of development,the transformation of mucosal vaccines into clinical use is still relatively *** date,fewer than ten mucosal vaccines have been *** 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 *** reason for the limited progress of mucosal vaccines may be the complicated mucosal ***,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