Long non-coding RNAs(lncRNAs)is a type of RNA over 200 nt long without any protein coding ability,which has been investigated relating to crucial biological function in cells.There are many key lncRNAs in tumor/normal...Long non-coding RNAs(lncRNAs)is a type of RNA over 200 nt long without any protein coding ability,which has been investigated relating to crucial biological function in cells.There are many key lncRNAs in tumor/normal cells that serve as a biological marker or a new target for tumor treatment.However,compared to some small non-coding RNA,lncRNA-based drugs are limited in clinical application.Different from other non-coding RNA,like microRNAs,most lncRNAs have a high molecular weight and conserved secondary structure,making the delivery of lncRNAs more complex than the small non-coding RNAs.Considering that lncRNAs constitute the most abundant part of the mammalian genome,it is critical to further explore lncRNA delivery and the subsequent functional studies for potential clinical application.In this review,we will discuss the function and mechanism of lncRNAs in diseases,especially cancer,and different approaches for lncRNA transfection using multiple biomaterials.展开更多
Cancer-associated fibroblasts(CAFs)are one of the most abundant stromal cells in the tumor microenvironment which mediate desmoplastic response and are the primary driver for an immunosuppressive microenvironment,lead...Cancer-associated fibroblasts(CAFs)are one of the most abundant stromal cells in the tumor microenvironment which mediate desmoplastic response and are the primary driver for an immunosuppressive microenvironment,leading to the failure of triple-negative breast cancer(TNBC)immunotherapy.Therefore,depleting CAFs may enhance the effect of immunotherapy(such as PD-L1 antibody).Relaxin(RLN)has been demonstrated to significantly improve transforming growth factor-β(TGF-β)induced CAFs activation and tumor immunosuppressive microenvironment.However,the short half-life and systemic vasodilation of RLN limit its in vivo efficacy.Here,plasmid encoding relaxin(pRLN)to locally express RLN was delivered with a new positively charged polymer named polymeric metformin(PolyMet),which could increase gene transfer efficiency significantly and have low toxicity that have been certified by our lab before.In order to improve the stability of pRLN in vivo,this complex was further formed lipid poly-γ-glutamic acid(PGA)/PolyMetpRLN nanoparticle(LPPR).The particle size of LPPR was 205.5±2.9 nm,and the zeta potential was+55.4±1.6 mV.LPPR displayed excellent tumor penetrating efficacy and weaken proliferation of CAFs in 4T1luc/CAFs tumor spheres in vitro.In vivo,it could reverse aberrantly activated CAFs by decreasing the expression of profibrogenic cytokine and remove the physical barrier to reshape the tumor stromal microenvironment,which enabled a 2.2-fold increase in cytotoxic T cell infiltration within the tumor and a decrease in immunosuppressive cells infiltration.Thus,LPPR was observed retarded tumor growth by itself in the 4T1 tumor bearing-mouse,and the reshaped immune microenvironment further led to facilitate antitumor effect when it combined with PD-L1 antibody(aPD-L1).Altogether,this study presented a novel therapeutic approach against tumor stroma using LPPR to achieve a combination regimen with immune checkpoint blockade therapy against the desmoplastic TNBC model.展开更多
Primary bile acids were reported to augment secretion of chemokine(C-X-C motif)ligand16(CXCL16)from liver sinusoidal endothelial cells(LSECs)and trigger natural killer T(NKT)cellbased immunotherapy for liver cancer.Ho...Primary bile acids were reported to augment secretion of chemokine(C-X-C motif)ligand16(CXCL16)from liver sinusoidal endothelial cells(LSECs)and trigger natural killer T(NKT)cellbased immunotherapy for liver cancer.However,abundant expression of receptors for primary bile acids across the gastrointestinal tract overwhelms the possibility of using agonists against these receptors for liver cancer control.Taking advantage of the intrinsic property of LSECs in capturing circulating nanoparticles in the circulation,we proposed a strategy using nanoemulsion-loaded obeticholic acid(OCA),a clinically approved selective farnesoid X receptor(FXR)agonist,for precisely manipulating LSECs for triggering NKT cell-mediated liver cancer immunotherapy.The OCA-nanoemulsion(OCA-NE)was prepared via ultrasonic emulsification method,with a diameter of 184 nm and good stability.In vivo biodistribution studies confirmed that the injected OCA-NE mainly accumulated in the liver and especially in LSECs and Kupffer cells.As a result,OCA-NE treatment significantly suppressed hepatic tumor growth in a murine orthotopic H22 tumor model,which performed much better than oral medication of free OCA.Immunologic analysis revealed that the OCA-NE resulted in augmented secretion of CXCL16 and IFN-g,as well as increased NKT cell populations inside the tumor.Overall,our research provides a new evidence for the antitumor effect of receptors for primary bile acids,and should inspire using nanotechnology for precisely manipulating LSECs for liver cancer therapy.展开更多
Routine exposure to inorganic nanoparticles （NPs） that are incorporated into consumer products such as foods/drinks, packaging materials, pharmaceuticals, and personal care products （e.g. cosmetics, sunscreens, sha...Routine exposure to inorganic nanoparticles （NPs） that are incorporated into consumer products such as foods/drinks, packaging materials, pharmaceuticals, and personal care products （e.g. cosmetics, sunscreens, shampoos） occurs on a daily basis. The standard everyday use of these products facilitates interactions between the incorporated inorganic NPs, mammalian tissues （e.g. skin, gastrointestinal tract, oral cavity）, and the community of microbes that resides on these tissues. Changes to the microbiome have been linked to the initiation/ progression of many diseases and there is a growing interest focused on understanding how inorganic NPs can initiate these changes. As these mechanisms are revealed and defined, it may be possible to rationally design microbiota- modulating therapies based on inorganic NPs. In this article, we will： （i） provide a background on inorganic NPs that are commonly found in consumer products such as those that incorporate titanium, zinc, silver, silica, or iron, （ii） discuss how NP properties, microbiota composition, and the physiological microenvironment can mediate the effects that inorganic NPs have on the microbiota, and （iii） highlight opportunities for inorganic NP therapies that are designed to interact with, and navigate, the microbiome.展开更多
Asherman’s syndrome(AS)is an endometrial disorder in which intrauterine adhesions crowd the uterine cavity and wall.The fibrotic adhesions are primarily the result of invasive uterine procedures that usually involve ...Asherman’s syndrome(AS)is an endometrial disorder in which intrauterine adhesions crowd the uterine cavity and wall.The fibrotic adhesions are primarily the result of invasive uterine procedures that usually involve the insertion of surgical equipment into the uterus.This syndrome is accompanied by a number of clinical manifestations,including irregular or painful menstruation and infertility.The most prevalent treatment is hysteroscopy,which involves the physical removal of the fibrous strands.Within the last decade,however,the field has been exploring the use of cellbased therapeutics,in conjunction with biomaterials,to treat AS.This review is a recapitulation of the literature focused on cellular therapies for treating AS.展开更多
Desmoplastic tumors have an abundance of stromal cells and the extracellular matrix which usually result in therapeutic resistance.Current treatment prescriptions for desmoplastic tumors are usually not sufficient to ...Desmoplastic tumors have an abundance of stromal cells and the extracellular matrix which usually result in therapeutic resistance.Current treatment prescriptions for desmoplastic tumors are usually not sufficient to eliminate the malignancy.Recently,through modulating cancer-associated fibroblasts(CAFs)which are the most abundant cell type among all stromal cells,natural products have improved chemotherapies and the delivery of nanomedicines to the tumor cells,showing promising ability to improve treatment effects on desmoplastic tumors.In this review,we discussed the latest advances in inhibiting desmoplastic tumors by modeling CAFs using natural products,highlighting the potential therapeutic abilities of natural products in targeting CAFs for cancer treatment.展开更多
The CRISPR-Cas system, especially the type II CRISPR-Cas9 system from Streptococcuspyogenes, has rapidly emerged as a popular genome editing tool. The development of Cas9 derivatives further expanded the toolbox of CR...The CRISPR-Cas system, especially the type II CRISPR-Cas9 system from Streptococcuspyogenes, has rapidly emerged as a popular genome editing tool. The development of Cas9 derivatives further expanded the toolbox of CRISPR- Cas9 based genome editing kit. However, therapeutic transla- tion of the CRISPR-Cas9 system in vivo is severely impeded by the absence of an appropriate delivery carrier. The complex- ity and high molecular weight of the CRISPR-Cas9 system, together with the physiological barriers for nucleus targeted cargo transportation have made it a huge challenge for in vivo therapeutic CRISPR-Cas9 delivery. Currently, the main stream carriers for systemic delivery of CRISPR-Cas9 are vi- ral based, such as adeno-associated virus. However, the safety concerns surrounding viral vectors call for the development of non-viral nanocarriers. In this review, we survey the recent advances in the development of non-viral delivery systems for CRISPR-Cas9. Challenges and future directions in this field are also discussed.展开更多
基金supported by Southern Medical University,Chinasupported by Fred Eshelman Distinguished Professorship。
文摘Long non-coding RNAs(lncRNAs)is a type of RNA over 200 nt long without any protein coding ability,which has been investigated relating to crucial biological function in cells.There are many key lncRNAs in tumor/normal cells that serve as a biological marker or a new target for tumor treatment.However,compared to some small non-coding RNA,lncRNA-based drugs are limited in clinical application.Different from other non-coding RNA,like microRNAs,most lncRNAs have a high molecular weight and conserved secondary structure,making the delivery of lncRNAs more complex than the small non-coding RNAs.Considering that lncRNAs constitute the most abundant part of the mammalian genome,it is critical to further explore lncRNA delivery and the subsequent functional studies for potential clinical application.In this review,we will discuss the function and mechanism of lncRNAs in diseases,especially cancer,and different approaches for lncRNA transfection using multiple biomaterials.
基金This work was funded by the Medical and Health Science and Technology Program of Zhejiang Province(2021KY813)the National Natural Science Foundation of China(82174095)the National Natural Science Foundation of Zhejiang Province(LZ22H290001).
文摘Cancer-associated fibroblasts(CAFs)are one of the most abundant stromal cells in the tumor microenvironment which mediate desmoplastic response and are the primary driver for an immunosuppressive microenvironment,leading to the failure of triple-negative breast cancer(TNBC)immunotherapy.Therefore,depleting CAFs may enhance the effect of immunotherapy(such as PD-L1 antibody).Relaxin(RLN)has been demonstrated to significantly improve transforming growth factor-β(TGF-β)induced CAFs activation and tumor immunosuppressive microenvironment.However,the short half-life and systemic vasodilation of RLN limit its in vivo efficacy.Here,plasmid encoding relaxin(pRLN)to locally express RLN was delivered with a new positively charged polymer named polymeric metformin(PolyMet),which could increase gene transfer efficiency significantly and have low toxicity that have been certified by our lab before.In order to improve the stability of pRLN in vivo,this complex was further formed lipid poly-γ-glutamic acid(PGA)/PolyMetpRLN nanoparticle(LPPR).The particle size of LPPR was 205.5±2.9 nm,and the zeta potential was+55.4±1.6 mV.LPPR displayed excellent tumor penetrating efficacy and weaken proliferation of CAFs in 4T1luc/CAFs tumor spheres in vitro.In vivo,it could reverse aberrantly activated CAFs by decreasing the expression of profibrogenic cytokine and remove the physical barrier to reshape the tumor stromal microenvironment,which enabled a 2.2-fold increase in cytotoxic T cell infiltration within the tumor and a decrease in immunosuppressive cells infiltration.Thus,LPPR was observed retarded tumor growth by itself in the 4T1 tumor bearing-mouse,and the reshaped immune microenvironment further led to facilitate antitumor effect when it combined with PD-L1 antibody(aPD-L1).Altogether,this study presented a novel therapeutic approach against tumor stroma using LPPR to achieve a combination regimen with immune checkpoint blockade therapy against the desmoplastic TNBC model.
基金financially supported by the National Natural Science Foundation of China(51673189,51973215,51833010and 51520105004)Ministry of Science and Technology of China(Project 2018ZX09711003-012)+1 种基金the Program of Scientific Development of Jilin Province(20170101100JC,20180520207JH,20190103112JH,China)supported by NIH grant CA198999(USA)
文摘Primary bile acids were reported to augment secretion of chemokine(C-X-C motif)ligand16(CXCL16)from liver sinusoidal endothelial cells(LSECs)and trigger natural killer T(NKT)cellbased immunotherapy for liver cancer.However,abundant expression of receptors for primary bile acids across the gastrointestinal tract overwhelms the possibility of using agonists against these receptors for liver cancer control.Taking advantage of the intrinsic property of LSECs in capturing circulating nanoparticles in the circulation,we proposed a strategy using nanoemulsion-loaded obeticholic acid(OCA),a clinically approved selective farnesoid X receptor(FXR)agonist,for precisely manipulating LSECs for triggering NKT cell-mediated liver cancer immunotherapy.The OCA-nanoemulsion(OCA-NE)was prepared via ultrasonic emulsification method,with a diameter of 184 nm and good stability.In vivo biodistribution studies confirmed that the injected OCA-NE mainly accumulated in the liver and especially in LSECs and Kupffer cells.As a result,OCA-NE treatment significantly suppressed hepatic tumor growth in a murine orthotopic H22 tumor model,which performed much better than oral medication of free OCA.Immunologic analysis revealed that the OCA-NE resulted in augmented secretion of CXCL16 and IFN-g,as well as increased NKT cell populations inside the tumor.Overall,our research provides a new evidence for the antitumor effect of receptors for primary bile acids,and should inspire using nanotechnology for precisely manipulating LSECs for liver cancer therapy.
文摘Routine exposure to inorganic nanoparticles （NPs） that are incorporated into consumer products such as foods/drinks, packaging materials, pharmaceuticals, and personal care products （e.g. cosmetics, sunscreens, shampoos） occurs on a daily basis. The standard everyday use of these products facilitates interactions between the incorporated inorganic NPs, mammalian tissues （e.g. skin, gastrointestinal tract, oral cavity）, and the community of microbes that resides on these tissues. Changes to the microbiome have been linked to the initiation/ progression of many diseases and there is a growing interest focused on understanding how inorganic NPs can initiate these changes. As these mechanisms are revealed and defined, it may be possible to rationally design microbiota- modulating therapies based on inorganic NPs. In this article, we will： （i） provide a background on inorganic NPs that are commonly found in consumer products such as those that incorporate titanium, zinc, silver, silica, or iron, （ii） discuss how NP properties, microbiota composition, and the physiological microenvironment can mediate the effects that inorganic NPs have on the microbiota, and （iii） highlight opportunities for inorganic NP therapies that are designed to interact with, and navigate, the microbiome.
基金the National Institutes of Health(R01HL123920 and R01HL137093 to K.C.).Final grammatical edits were made by Jhon Cores,PhD.
文摘Asherman’s syndrome(AS)is an endometrial disorder in which intrauterine adhesions crowd the uterine cavity and wall.The fibrotic adhesions are primarily the result of invasive uterine procedures that usually involve the insertion of surgical equipment into the uterus.This syndrome is accompanied by a number of clinical manifestations,including irregular or painful menstruation and infertility.The most prevalent treatment is hysteroscopy,which involves the physical removal of the fibrous strands.Within the last decade,however,the field has been exploring the use of cellbased therapeutics,in conjunction with biomaterials,to treat AS.This review is a recapitulation of the literature focused on cellular therapies for treating AS.
基金supported by National Institutes of Health(Grant No.CA198999,USA)the State Key Laboratory of Molecular Engineering of Polymers,Fudan University(China)+3 种基金the National Natural Science Foundation of China(Grant Nos.81202924 and81773909)Shanghai Rising-Star Program of China(Grant No.13QA1403400)Shanghai talent development funds(Grant No.201665,China)Shanghai municipal commission of health and family planning(Grant No.2017YQ060,China)
文摘Desmoplastic tumors have an abundance of stromal cells and the extracellular matrix which usually result in therapeutic resistance.Current treatment prescriptions for desmoplastic tumors are usually not sufficient to eliminate the malignancy.Recently,through modulating cancer-associated fibroblasts(CAFs)which are the most abundant cell type among all stromal cells,natural products have improved chemotherapies and the delivery of nanomedicines to the tumor cells,showing promising ability to improve treatment effects on desmoplastic tumors.In this review,we discussed the latest advances in inhibiting desmoplastic tumors by modeling CAFs using natural products,highlighting the potential therapeutic abilities of natural products in targeting CAFs for cancer treatment.
基金supported by the grants from North Carolina TraCS, NIH’s Clinical and Translational Science Awards (CTSA, 1UL1TR001111) at UNC-CHSloan Fellowship Award from the Alfred P. Sloan Foundation
文摘The CRISPR-Cas system, especially the type II CRISPR-Cas9 system from Streptococcuspyogenes, has rapidly emerged as a popular genome editing tool. The development of Cas9 derivatives further expanded the toolbox of CRISPR- Cas9 based genome editing kit. However, therapeutic transla- tion of the CRISPR-Cas9 system in vivo is severely impeded by the absence of an appropriate delivery carrier. The complex- ity and high molecular weight of the CRISPR-Cas9 system, together with the physiological barriers for nucleus targeted cargo transportation have made it a huge challenge for in vivo therapeutic CRISPR-Cas9 delivery. Currently, the main stream carriers for systemic delivery of CRISPR-Cas9 are vi- ral based, such as adeno-associated virus. However, the safety concerns surrounding viral vectors call for the development of non-viral nanocarriers. In this review, we survey the recent advances in the development of non-viral delivery systems for CRISPR-Cas9. Challenges and future directions in this field are also discussed.
