Early coagulation-inflammation interaction and late in-stent restenosis undermine the efficacy of vascular stents after implantation.Targeting the interplay between inflammation and coagulation,and smooth muscle cell(...Early coagulation-inflammation interaction and late in-stent restenosis undermine the efficacy of vascular stents after implantation.Targeting the interplay between inflammation and coagulation,and smooth muscle cell(SMC)proliferation,we presented a microenvironment-responsive coating designed to regulate tissue responses and vascular regeneration throughout the remodeling process.Coagulation was inhibited by incorporating anticoagulant tirofiban into the coating.MMP9-responsive nanoparticles embedded in the coating released salvianolic acid A to modulate inflammatory cell behavior and inhibit SMC dysfunction.By effectively interfering with clotting and inflammation,the coating suppressed platelet-fibrin interaction and formation of plateletmonocyte aggregates,thereby mitigating adverse effects on reendothelialization.Its ability to influence SMC proliferation and migration resulted in reduced intimal hyperplasia.Coated stents were shown to significantly regulate tissue regeneration,improve the vascular environment and even reduced the lipid content in the nar-rowed atherosclerotic vessels in vivo.This direct approach enhanced the vascular tissue regeneration after stent implantation,and offered promising insights for optimizing vascular stent design.展开更多
Dbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy(RT). However, there is no effective drug delivery system to effectively ov...Dbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy(RT). However, there is no effective drug delivery system to effectively overcome the blood–brain barrier(BBB). The aim of this study was to develop a gene delivery system by using the BBB and glioma dual-targeting and microenvironment-responsive micelles(ch-Kn(s-s)R8-An) to deliver Dbait into glioma for RT. Angiopep-2 can target the low-density lipoprotein receptor-related protein-1(LRP1) that is overexpressed on brain capillary endothelial cells(BCECs) and glioma cells. In particular, due to upregulated matrix metalloproteinase 2(MMP-2) in the tumor microenvironment, we utilized MMP-2-responsive peptides as the enzymatically degradable linkers to conjugate angiopep-2. The results showed that ch-Kn(s-s)R8-An micelles maintained a reasonable size(80–160 nm) with a moderate distribution and a decreased mean diameter from the cross-linking as well as exhibited low critical micelle concentration(CMC) with positive surface charge, ranging from 15 to40 mV. The ch-K5(s-s)R8-An/pEGFP showed high gene transfection efficiency in vitro, improved uptake in glioma cells and good biocompatibility in vitro and in vivo. In addition, the combination of ch-K5(s-s)R8-An/Dbait with RT significantly inhibited the growth of U251 cells in vitro. Thus, ch-K5(s-s)R8-An/Dbait may prove to be a promising gene delivery system to target glioma and enhance the efficacy of RT on U251 cells.展开更多
A light-switchable transgene system called LightOn gene expression system could regulate gene expression with a high on/off ratio under blue light,and have great potential for spatiotemporally controllable gene expres...A light-switchable transgene system called LightOn gene expression system could regulate gene expression with a high on/off ratio under blue light,and have great potential for spatiotemporally controllable gene expression.We developed a nanoparticle drug delivery system(NDDS)to achieve tumor microenvironment-responsive and targeted delivery of diphtheria toxin A(DTA)fragment-encoded plasmids to tumor sites.The expression of DTA was induced by exposure to blue light.Nanoparticles composed of polyethylenimine and vitamin E succinate linked by a disulfide bond,and PEGylated hyaluronic acid modified with RGD peptide,accumulated in tumor tissues and were actively internalized into 4 T1 cells via dual targeting to CD44 andαvβ3 receptors.The LightOn gene expression system was able to control target protein expression through regulation of the intensity or duration of blue light exposure.In vitro studies showed that lisht-induced DTA expression reduced 4 T1 cell viability and induced apoptosis.Furthermore,the LightOn gene expression system enabled spatiotemporal control of the expression of DTA in a mouse 4 T1 tumor xenogratt model,which resulted in excellent antitumor effects,reduced tumor angiogenesis,and no systemic toxicity.The combination of the LightOn gene expression system and NDDS may be an effective strategy for treatment of breast cancer.展开更多
The construction of an integrated nanoplatform with controlled fungicide delivery features in the specific microenvironment produced by fungal pathogens is a highly desirable strategy to improve the utilization of fun...The construction of an integrated nanoplatform with controlled fungicide delivery features in the specific microenvironment produced by fungal pathogens is a highly desirable strategy to improve the utilization of fungicides. Herein, we report a supramolecular fungicide delivery system based on benzimidazolemodified NH_(2)-MIL-101(Fe) metal–organic frameworks(B-MIL-101(Fe) MOFs) as carriers loaded with osthole(OS), and β-cyclodextrin(β-CD) as nanovalves to form β-CD@B-MIL-101(Fe)-OS. The nanoplatform can release the loaded OS for fungus control through self-degradation of the MOFs skeleton in an oxalic acid microenvironment produced by Botrytis cinerea. The experimental results exhibit that the constructed supramolecular fungicide delivery system could effectively inhibit mycelial growth and protect the tomatoes from infection by B. cinerea during the ripening stage. This strategy constructs a facile and integrated supramolecular drug delivery system for B. cinerea control and opens up a new avenue for the sustainable development of modern agriculture.展开更多
Carrier-free multi-component self-assembled nano-systems have attracted widespread attention owing to their easy preparation,high drug-loading efficiency,and excellent therapeutic efficacy.Herein,MnAs-ICG nanospike wa...Carrier-free multi-component self-assembled nano-systems have attracted widespread attention owing to their easy preparation,high drug-loading efficiency,and excellent therapeutic efficacy.Herein,MnAs-ICG nanospike was generated by self-assembly of indocyanine green(ICG),manganese ions(Mn^(2+)),and arsenate(AsO_(4)^(3−))based on electrostatic and coordination interactions,effectively integrating the bimodal imaging ability of magnetic resonance imaging(MRI)and fluorescence(FL)imaging-guided synergistic therapy of photothermal/chemo/chemodynamic therapy within an“all-in-one”theranostic nano-platform.The as-prepared MnAs-ICG nanospike had a uniform size,well-defined nanospike morphology,and impressive loading capacities.The MnAs-ICG nanospike exhibited sensitive responsiveness to the acidic tumor microenvironment with morphological transformation and dimensional variability,enabling deep penetration into tumor tissue and on-demand release of functional therapeutic components.In vitro and in vivo results revealed that MnAs-ICG nanospike showed synergistic tumor-killing effect,prolonged blood circulation and increased tumor accumulation compared to their individual components,effectively resulting in synergistic therapy of photothermal/chemo/chemodynamic therapy with excellent anti-tumor effect.Taken together,this new strategy might hold great promise for rationally engineering multifunctional theranostic nano-platforms for breast cancer treatment.展开更多
Rheumatoid arthritis(RA)is a systemic autoimmune disease that leads to the destruction of articular cartilage and bone.RA is characterized by immune cell infiltration and abnormal proliferation of synoviocytes in the ...Rheumatoid arthritis(RA)is a systemic autoimmune disease that leads to the destruction of articular cartilage and bone.RA is characterized by immune cell infiltration and abnormal proliferation of synoviocytes in the joints.Herein,we developed a biomimetic formulation via co-loading the anti-inflammatory agent Celastrol(Cel)along with the stabilizer Vitamin K(VK)in antirheumatic methotrexate(MTX)-conjugated Pluronic F127(F127)micelles.Micelles were then coated with B cell derived membrane,yielding MTX loaded Cel Micelle(CeViM)-micelle@B,which were investigated for RA treatment.VK,used at levels well within safety margins,was identified as a carrier compound that could stabilize Cel within micelles,increasing the encapsulation efficiency of Cel.In addition,MTX,a front-line RA therapeutic,was chemically grafted to F127 via a responsive linker sensitive to the chemically reducing environments.As such,CeViM-micelle@B released pristine MTX in response to the intracellular reducing environments,which combined with Cel to suppress pro-inflammatory responses.B cell membrane coating enhanced accumulation of CeViM-micelle@B in joints,leading to a 75%decrease of inflammatory cytokine secretion in vitro,and significantly ameliorated cartilage and bone structures in the collagen-induced arthritis murine model.Taken together,this biomimetic nanoparticle holds potential as a nextgeneration targeted RA treatment.展开更多
Myocardial infarction(MI)is characterized by a paucity of cardiomyocyte regeneration,leading to significant morbidity and mortality.Contemporary therapeutic modalities,while mitigating ischemic effects,fail to reconst...Myocardial infarction(MI)is characterized by a paucity of cardiomyocyte regeneration,leading to significant morbidity and mortality.Contemporary therapeutic modalities,while mitigating ischemic effects,fail to reconstitute the impaired electromechanical coupling within the infracted myocardium.Emerging evidence supports the utility of electroconductive hydrogels(ECHs)in facilitating post-MI cardiac function recovery by restoring the conductive microenvironment of the infarcted tissue.This comprehensive review delineates the taxonomy of ECHs predicated on their constituent conductive materials.It also encapsulates prevailing research trends in ECH-mediated MI repair,encompassing innovative design paradigms and microenvironment-sensitive strategies.The review also provides a critical appraisal of various implantation techniques,underscored by a thorough examination of the attendant considerations.It elucidates the mechanistic underpinnings by which hydrogels exert salutary effects on myocardial repair,namely by augmenting mechanical and electrical integrity,exerting anti-inflammatory actions,fostering angiogenesis,and curtailing adverse remodeling processes.Furthermore,the review engages with the pressing challenge of optimizing ECH functionality to achieve superior reparative outcomes post-MI.The discourse concludes with an anticipatory perspective on the evolution of ECH scaffolds,advocating for a tailored approach that integrates multifaceted physicochemical properties to cater to the nuances of personalized medicine.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.32301100,82270262)the Natural Science Foundation of Zhejiang Province,China(Grant No.LQ24C100003,LY23H020005).
文摘Early coagulation-inflammation interaction and late in-stent restenosis undermine the efficacy of vascular stents after implantation.Targeting the interplay between inflammation and coagulation,and smooth muscle cell(SMC)proliferation,we presented a microenvironment-responsive coating designed to regulate tissue responses and vascular regeneration throughout the remodeling process.Coagulation was inhibited by incorporating anticoagulant tirofiban into the coating.MMP9-responsive nanoparticles embedded in the coating released salvianolic acid A to modulate inflammatory cell behavior and inhibit SMC dysfunction.By effectively interfering with clotting and inflammation,the coating suppressed platelet-fibrin interaction and formation of plateletmonocyte aggregates,thereby mitigating adverse effects on reendothelialization.Its ability to influence SMC proliferation and migration resulted in reduced intimal hyperplasia.Coated stents were shown to significantly regulate tissue regeneration,improve the vascular environment and even reduced the lipid content in the nar-rowed atherosclerotic vessels in vivo.This direct approach enhanced the vascular tissue regeneration after stent implantation,and offered promising insights for optimizing vascular stent design.
基金the financial support received from the National Natural Science Foundation of China(No.81472349,81302714and 81201809,China)the Natural Science Foundation of Shanghai(No.14ZR1433300,China)+3 种基金the Interdisciplinary Program of Shanghai Jiao Tong University(No.0507N17014,China)the Innovation Program of Shanghai Municipal Education Commission(No.15ZZ041,China)Natural Science Foundation of Zhejiang Province(No.LQ12H30005,China)the Public Welfare Technology Application Research Project(No.LGF18H160034,China)
文摘Dbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy(RT). However, there is no effective drug delivery system to effectively overcome the blood–brain barrier(BBB). The aim of this study was to develop a gene delivery system by using the BBB and glioma dual-targeting and microenvironment-responsive micelles(ch-Kn(s-s)R8-An) to deliver Dbait into glioma for RT. Angiopep-2 can target the low-density lipoprotein receptor-related protein-1(LRP1) that is overexpressed on brain capillary endothelial cells(BCECs) and glioma cells. In particular, due to upregulated matrix metalloproteinase 2(MMP-2) in the tumor microenvironment, we utilized MMP-2-responsive peptides as the enzymatically degradable linkers to conjugate angiopep-2. The results showed that ch-Kn(s-s)R8-An micelles maintained a reasonable size(80–160 nm) with a moderate distribution and a decreased mean diameter from the cross-linking as well as exhibited low critical micelle concentration(CMC) with positive surface charge, ranging from 15 to40 mV. The ch-K5(s-s)R8-An/pEGFP showed high gene transfection efficiency in vitro, improved uptake in glioma cells and good biocompatibility in vitro and in vivo. In addition, the combination of ch-K5(s-s)R8-An/Dbait with RT significantly inhibited the growth of U251 cells in vitro. Thus, ch-K5(s-s)R8-An/Dbait may prove to be a promising gene delivery system to target glioma and enhance the efficacy of RT on U251 cells.
基金supportedby Shanghai Municipal Natural Science Foundation(No.17ZR1406600,China)Science and Technology Commission of Shanghai Municipality(No.10DZ2220500,China)+1 种基金The Shanghai Committee of Science and Technology(Grant No.11DZ2260600,China)National Natural Science Foundation of China(Grant No.81973700)
文摘A light-switchable transgene system called LightOn gene expression system could regulate gene expression with a high on/off ratio under blue light,and have great potential for spatiotemporally controllable gene expression.We developed a nanoparticle drug delivery system(NDDS)to achieve tumor microenvironment-responsive and targeted delivery of diphtheria toxin A(DTA)fragment-encoded plasmids to tumor sites.The expression of DTA was induced by exposure to blue light.Nanoparticles composed of polyethylenimine and vitamin E succinate linked by a disulfide bond,and PEGylated hyaluronic acid modified with RGD peptide,accumulated in tumor tissues and were actively internalized into 4 T1 cells via dual targeting to CD44 andαvβ3 receptors.The LightOn gene expression system was able to control target protein expression through regulation of the intensity or duration of blue light exposure.In vitro studies showed that lisht-induced DTA expression reduced 4 T1 cell viability and induced apoptosis.Furthermore,the LightOn gene expression system enabled spatiotemporal control of the expression of DTA in a mouse 4 T1 tumor xenogratt model,which resulted in excellent antitumor effects,reduced tumor angiogenesis,and no systemic toxicity.The combination of the LightOn gene expression system and NDDS may be an effective strategy for treatment of breast cancer.
基金supported by the National Natural Science Foundation of China(Nos.52173200,31470414,31870332)the Natural Science Foundation of Jilin Province(No.20230101052JC)+2 种基金the Special Fund Project of Shenzhen City for Local Science and Technology Development Guided by the Central Government(No.2021Szvup049)the National Major Increase or Decrease Project-Construction of the sustainable utilization capacity of famous traditional Chinese medicine resources(No.2060302)the Fundamental Research Funds for the Central Universities(No.2022-JCXK-13)。
文摘The construction of an integrated nanoplatform with controlled fungicide delivery features in the specific microenvironment produced by fungal pathogens is a highly desirable strategy to improve the utilization of fungicides. Herein, we report a supramolecular fungicide delivery system based on benzimidazolemodified NH_(2)-MIL-101(Fe) metal–organic frameworks(B-MIL-101(Fe) MOFs) as carriers loaded with osthole(OS), and β-cyclodextrin(β-CD) as nanovalves to form β-CD@B-MIL-101(Fe)-OS. The nanoplatform can release the loaded OS for fungus control through self-degradation of the MOFs skeleton in an oxalic acid microenvironment produced by Botrytis cinerea. The experimental results exhibit that the constructed supramolecular fungicide delivery system could effectively inhibit mycelial growth and protect the tomatoes from infection by B. cinerea during the ripening stage. This strategy constructs a facile and integrated supramolecular drug delivery system for B. cinerea control and opens up a new avenue for the sustainable development of modern agriculture.
基金supported by National Natural Science Foundation of China (81873014, 82074027, 81873018 and 82104405)Natural Science Foundation of Zhejiang Province (LZ21H280001 and LY21H280007, China)+2 种基金Zhejiang Chinese Medical University School-level Scientific Research Fund Project (2020ZG21, 2019ZG37, China)Traditional Chinese Medicine Science and Technology Plan of Zhejiang Province (2021ZQ036, China)Jinhua Science and Technology Research Plan Project (2019-4037, China)
文摘Carrier-free multi-component self-assembled nano-systems have attracted widespread attention owing to their easy preparation,high drug-loading efficiency,and excellent therapeutic efficacy.Herein,MnAs-ICG nanospike was generated by self-assembly of indocyanine green(ICG),manganese ions(Mn^(2+)),and arsenate(AsO_(4)^(3−))based on electrostatic and coordination interactions,effectively integrating the bimodal imaging ability of magnetic resonance imaging(MRI)and fluorescence(FL)imaging-guided synergistic therapy of photothermal/chemo/chemodynamic therapy within an“all-in-one”theranostic nano-platform.The as-prepared MnAs-ICG nanospike had a uniform size,well-defined nanospike morphology,and impressive loading capacities.The MnAs-ICG nanospike exhibited sensitive responsiveness to the acidic tumor microenvironment with morphological transformation and dimensional variability,enabling deep penetration into tumor tissue and on-demand release of functional therapeutic components.In vitro and in vivo results revealed that MnAs-ICG nanospike showed synergistic tumor-killing effect,prolonged blood circulation and increased tumor accumulation compared to their individual components,effectively resulting in synergistic therapy of photothermal/chemo/chemodynamic therapy with excellent anti-tumor effect.Taken together,this new strategy might hold great promise for rationally engineering multifunctional theranostic nano-platforms for breast cancer treatment.
基金This work was supported by the National Natural Science Foundation of China(22375144 and 32071384)the National Key Research and Development Program(2021YFC2102300)+1 种基金the basic research project of Shanxi Science and Technology Department(202103021224342)Key Research and Development(R&D)Projects of Shanxi Province(2021XM01).
文摘Rheumatoid arthritis(RA)is a systemic autoimmune disease that leads to the destruction of articular cartilage and bone.RA is characterized by immune cell infiltration and abnormal proliferation of synoviocytes in the joints.Herein,we developed a biomimetic formulation via co-loading the anti-inflammatory agent Celastrol(Cel)along with the stabilizer Vitamin K(VK)in antirheumatic methotrexate(MTX)-conjugated Pluronic F127(F127)micelles.Micelles were then coated with B cell derived membrane,yielding MTX loaded Cel Micelle(CeViM)-micelle@B,which were investigated for RA treatment.VK,used at levels well within safety margins,was identified as a carrier compound that could stabilize Cel within micelles,increasing the encapsulation efficiency of Cel.In addition,MTX,a front-line RA therapeutic,was chemically grafted to F127 via a responsive linker sensitive to the chemically reducing environments.As such,CeViM-micelle@B released pristine MTX in response to the intracellular reducing environments,which combined with Cel to suppress pro-inflammatory responses.B cell membrane coating enhanced accumulation of CeViM-micelle@B in joints,leading to a 75%decrease of inflammatory cytokine secretion in vitro,and significantly ameliorated cartilage and bone structures in the collagen-induced arthritis murine model.Taken together,this biomimetic nanoparticle holds potential as a nextgeneration targeted RA treatment.
基金supported by the National Natural Science Foundation of China(31860291,32430057,U21A20173)Guangdong Basic and Applied Basic Research Foundation(2023B1515120055,2024A1515011482)+1 种基金Major Research Project on Innovation Group of Education Department of Guizhou Province in 2018(KY character in Guizhou Education Cooperation[2018]025)Guangdong Basic and Applied Basic Research Foundation(2023B1515120055,2024A1515011482).J.W.Z.acknowledges National Natural Science Foundation of China(31860291)。
文摘Myocardial infarction(MI)is characterized by a paucity of cardiomyocyte regeneration,leading to significant morbidity and mortality.Contemporary therapeutic modalities,while mitigating ischemic effects,fail to reconstitute the impaired electromechanical coupling within the infracted myocardium.Emerging evidence supports the utility of electroconductive hydrogels(ECHs)in facilitating post-MI cardiac function recovery by restoring the conductive microenvironment of the infarcted tissue.This comprehensive review delineates the taxonomy of ECHs predicated on their constituent conductive materials.It also encapsulates prevailing research trends in ECH-mediated MI repair,encompassing innovative design paradigms and microenvironment-sensitive strategies.The review also provides a critical appraisal of various implantation techniques,underscored by a thorough examination of the attendant considerations.It elucidates the mechanistic underpinnings by which hydrogels exert salutary effects on myocardial repair,namely by augmenting mechanical and electrical integrity,exerting anti-inflammatory actions,fostering angiogenesis,and curtailing adverse remodeling processes.Furthermore,the review engages with the pressing challenge of optimizing ECH functionality to achieve superior reparative outcomes post-MI.The discourse concludes with an anticipatory perspective on the evolution of ECH scaffolds,advocating for a tailored approach that integrates multifaceted physicochemical properties to cater to the nuances of personalized medicine.
