Hepatic fibrosis is regulated by the synergistic actions of various cells and cytokines,with the activation and proliferation of hepatic stellate cells(HSCs) being considered the central event in this process.To achie...Hepatic fibrosis is regulated by the synergistic actions of various cells and cytokines,with the activation and proliferation of hepatic stellate cells(HSCs) being considered the central event in this process.To achieve specific targeting of activated hepatic stellate cells(a HSCs) and precise treatment of hepatic fibrosis,this study developed a dual-functional drug delivery system(SIL/c RGD-PEG-PPS PMs) with both targeting and responsive release capabilities.It aims to target the αvβ 3 receptor specifically expressed on the surface of a HSCs using the cyclic peptide c(RGDyk),and to exploit the high reactive oxygen species(ROS) level in the cellular microenvironment to achieve concentrated burst release of drugs at the pathological sites of hepatic fibrosis.Based on multiple assessments,SIL/c RGD-PEG-PPS PMs specifically enhanced the targeted delivery of silybin(SIL) to a HSCs,inhibited the proliferation and migration of a HSCs,and exhibited good biosafety.Additionally,it demonstrated excellent anti-fibrotic activity in fibrotic mice.In summary,this study shows great potential in targeted treatment of hepatic fibrosis and provides a multifunctional tool for advancing the research and therapeutic strategies of hepatic fibrosis.展开更多
Drug-loaded micelles for oral administration are desired for its conve nience,low cost and flexibility,but current designs rely on introducing pH responsiveness,leaving problems like drug leakage and low accuracy of t...Drug-loaded micelles for oral administration are desired for its conve nience,low cost and flexibility,but current designs rely on introducing pH responsiveness,leaving problems like drug leakage and low accuracy of targeted delivery un-solved.Herein,we reported an acid-resistant ROS-responsive hyperbranched polythioether which can self-assemble into micellar structure and pass through the gastrointestinal tract without leaking drugs.At the inflammatory lesions,the thioester bonds are oxidized to sulphone groups to significantly increase the hydrophilicity in response to accumulated ROS species and efficiently release the encapsulated drugs.Animal experiments,including the evaluation of bodyweight,colon length,MPO activity,spleen index,histology and quantitative reverse transcription PCR,evidenced that the drug-loaded micelles have improved therapeutic efficiency compared to bare drug administration for the treatment of DSS-induced colitis in mice.This study provides an example of oral administrated micellar system can be extended for the treatment of other intestinal tract diseases.展开更多
Plants must cope with a variety of environmental stresses. Most types of abiotic stresses, such as drought, salinity, flooding, heat and cold stress, disrupt the metabolic balance of cells, resulting in the enhanced p...Plants must cope with a variety of environmental stresses. Most types of abiotic stresses, such as drought, salinity, flooding, heat and cold stress, disrupt the metabolic balance of cells, resulting in the enhanced production of reactive oxygen species （ROS）. While being well-known as a toxic by-product, recent studies about ROS focus on their roles as signaling molecules.展开更多
The growing concern over bacterial multidrug resistance has led to a heightened interest in antimicrobial peptides(AMPs)known for their strong efficacy,albeit with high toxicity.In order to retain the potent antibacte...The growing concern over bacterial multidrug resistance has led to a heightened interest in antimicrobial peptides(AMPs)known for their strong efficacy,albeit with high toxicity.In order to retain the potent antibacterial activity of AMPs while minimizing their systemic toxicity,we introduce a conjugate strategy with selective infection-activatable and bacteria-targeting capabilities.A series of colistin prodrugs with well-defined structures were developed by attaching a reactive oxygen species-responsive phenylboronic acid linker to all amines of colistin,followed by covalent linkage to sugars through the reaction of boronic acid and a diol moiety.Among these prodrugs,a lactosyl-functionalized colistin prodrug,LaP-Col,was identified because of its minimal toxicity toward normal tissues and ability to target bacteria.It exhibits a maximum tolerated dose over 20 times greater than colistin and minimal nephrotoxicity.In a mouse model of bacterial pneumonia,intravenous administration of LaP-Col led to its accumulation in the infected lung.It effectively killed bacteria,significantly improving the therapeutic efficacy and mouse survival rates.Overall,this study presents a prodrug strategy that effectively reduces the inherent high toxicity of colistin and enhances its therapeutic targeting efficacy,which has promising implications for modifying other potent but toxic AMPs.展开更多
Myocardial ischemia reperfusion(IR)injury is closely related to the overwhelming inflammation in the myocardium.Herein,cardiomyocyte-targeted nanotherapeutics were developed for the reactive oxygen species(ROS)-ultras...Myocardial ischemia reperfusion(IR)injury is closely related to the overwhelming inflammation in the myocardium.Herein,cardiomyocyte-targeted nanotherapeutics were developed for the reactive oxygen species(ROS)-ultrasensitive co-delivery of dexamethasone(Dex)and RAGE small interfering RNA(siRAGE)to attenuate myocardial inflammation.PPTP,a ROSdegradable polycation based on PGE2-modified,PEGylated,ditellurium-crosslinked polyethylenimine(PEI)was developed to surface-decorate the Dex-encapsulated mesoporous silica nanoparticles(MSNs),which simultaneously condensed siRAGE and gated the MSNs to prevent the Dex pre-leakage.Upon intravenous injection to IR-injured rats,the nanotherapeutics could be efficiently transported into the inflamed cardiomyocytes via PGE2-assisted recognition of over-expressed E-series of prostaglandin(EP)receptors on the cell membranes.Intracellularly,the over-produced ROS degraded PPTP into small segments,promoting the release of siRAGE and Dex to mediate effective RAGE silencing(72%)and cooperative antiinflammatory effect.As a consequence,the nanotherapeutics notably suppressed the myocardial fibrosis and apoptosis,ultimately recovering the systolic function.Therefore,the current nanotherapeutics represent an effective example for the codelivery and on-demand release of nucleic acid and chemodrug payloads,and might find promising utilities toward the synergistic management of myocardial inflammation.展开更多
Poly-ion complex(PIC)integrating non-antibiotic theranostics holds great promise in the combat against drug-resistant bacteria.Photosensitizers with aggregation-induced emission(AIE)characteristic are particularly int...Poly-ion complex(PIC)integrating non-antibiotic theranostics holds great promise in the combat against drug-resistant bacteria.Photosensitizers with aggregation-induced emission(AIE)characteristic are particularly intriguing theranostic agents,but incorporating them into antibacterial PIC to enable both fluorescence and reactive oxygen species(ROS)generation turn-on is deemed a great challenge.Here we report the development of a PIC that can dually boost the fluorescence and ROS generation in the presence of pathogen bacteria.The PIC is constructed based on an anionic polydiacetylene poly(deca-4,6-diynedioic acid)(PDDA),which completely degrades in the presence of ROS.A cationic polymer quaternized poly(2-(dimethylamino)ethyl methacrylate)(PQDMA)that can disrupt bacterial membrane is co-loaded together with a highly efficient AIE photosensitizer TPCI in the PIC.PIC is nonfluorescent initially in that PDDA can quench the AIE of TPCI in PIC.When pathogenic bacteria are present,they can disturb the assembly of PIC to release TPCI,whose fluorescence turns on sensitively to indicate the existence of bacteria.The on-demand irradiation can be subsequently applied to excite TPCI,which generates ROS to degrade PDDA and deform the PIC.As a result,TPCI and PQDMA are completely released to eliminate bacteria through a synergy of turned-on photodynamic therapy(PDT)and membrane disruption.The highly efficient detection and inhibition against both Gramnegative and Gram-positive bacteria have validated this polydiacetylene-based PIC system as an effective non-antibiotic antibacterial theranostic platform as well as a new strategy to enable“turn-on”fluorescence sensing and imaging of AIE fluorophores.展开更多
Acute kidney injury(AKI),a prevalent and complex clinical condition associated with elevated risks of morbidity and mortality,necessitates the meticulous detection and monitoring of kidney damage globally.Biomedicine ...Acute kidney injury(AKI),a prevalent and complex clinical condition associated with elevated risks of morbidity and mortality,necessitates the meticulous detection and monitoring of kidney damage globally.Biomedicine has shown keen interest in molecular probes and detectors for AKI due to their sensitivity,rapidity,and cost-effectiveness.Bioimaging technologies play a significant role in identifying and quantifying AKI indicators,enhancing diagnostic approaches,and potentially refining clinical therapies for immediate injury control.Molecular probes serve as valuable tools for drug screening,uncovering renoprotective components,signaling pathways,and the nephrotoxic effects of drugs.This review comprehensively summarizes the latest advancements in molecular probes,emphasizing their exceptional efficacy in various characteristics,including renal cleanability,multichannel detection capability,near-infrared-II responsiveness,and reactivity toward reactive oxygen species.These probes offer enhanced benefits for assessing kidney damage and evaluating the therapeutic effects of medications while simultaneously reducing toxic effects.Additionally,the review delves into future potentials and challenges in this field,aiming to inspire the development and enhancement of molecular bioimaging for the early diagnosis and treatment of kidney diseases.展开更多
基金supported by the financial assistance from Natural Science Fund Project of Science and Technology Department of Jilin Province (Nos.YDZJ202301ZYTS141,YDZJ202501ZYTS793)。
文摘Hepatic fibrosis is regulated by the synergistic actions of various cells and cytokines,with the activation and proliferation of hepatic stellate cells(HSCs) being considered the central event in this process.To achieve specific targeting of activated hepatic stellate cells(a HSCs) and precise treatment of hepatic fibrosis,this study developed a dual-functional drug delivery system(SIL/c RGD-PEG-PPS PMs) with both targeting and responsive release capabilities.It aims to target the αvβ 3 receptor specifically expressed on the surface of a HSCs using the cyclic peptide c(RGDyk),and to exploit the high reactive oxygen species(ROS) level in the cellular microenvironment to achieve concentrated burst release of drugs at the pathological sites of hepatic fibrosis.Based on multiple assessments,SIL/c RGD-PEG-PPS PMs specifically enhanced the targeted delivery of silybin(SIL) to a HSCs,inhibited the proliferation and migration of a HSCs,and exhibited good biosafety.Additionally,it demonstrated excellent anti-fibrotic activity in fibrotic mice.In summary,this study shows great potential in targeted treatment of hepatic fibrosis and provides a multifunctional tool for advancing the research and therapeutic strategies of hepatic fibrosis.
基金the National Nature Science Foundation of China(NSFC,Nos.51803115,21636006,81773686)Nature Science Foundation of Shaanxi Province(No.2019JQ-528)+2 种基金the Fundamental Research Funds for the Central Universities(Nos.GK201801003,GK201802009,GK201901001)Young Talent Fund of University Association for Science and Technology in Shaanxi,China(No.20180602)the Program of Introducing Talents of Discipline to Universities(No.B14041)。
文摘Drug-loaded micelles for oral administration are desired for its conve nience,low cost and flexibility,but current designs rely on introducing pH responsiveness,leaving problems like drug leakage and low accuracy of targeted delivery un-solved.Herein,we reported an acid-resistant ROS-responsive hyperbranched polythioether which can self-assemble into micellar structure and pass through the gastrointestinal tract without leaking drugs.At the inflammatory lesions,the thioester bonds are oxidized to sulphone groups to significantly increase the hydrophilicity in response to accumulated ROS species and efficiently release the encapsulated drugs.Animal experiments,including the evaluation of bodyweight,colon length,MPO activity,spleen index,histology and quantitative reverse transcription PCR,evidenced that the drug-loaded micelles have improved therapeutic efficiency compared to bare drug administration for the treatment of DSS-induced colitis in mice.This study provides an example of oral administrated micellar system can be extended for the treatment of other intestinal tract diseases.
文摘Plants must cope with a variety of environmental stresses. Most types of abiotic stresses, such as drought, salinity, flooding, heat and cold stress, disrupt the metabolic balance of cells, resulting in the enhanced production of reactive oxygen species （ROS）. While being well-known as a toxic by-product, recent studies about ROS focus on their roles as signaling molecules.
基金supported by the National Key R&D Program of China(2023YFB3809904)the National Natural Science Foundation of China(U22A20156,52073102,51873070,32171319,52203165,52403183)+4 种基金the Guangdong Provincial Pearl River Talents Program(2019QN01Y090)the Guangdong Basic and Applied Basic Research Foundation(2023B1515020086)the Science and Technology Planning Project of Guangdong Province(2023B1212060013)the Guangzhou Innovation and Entrepreneurship Team Projects(2024A03J1055)the Guangdong Provincial Key Laboratory of Cancer Pathogenesis and Precision Diagnosis and Treatment(2024B1212030002)。
文摘The growing concern over bacterial multidrug resistance has led to a heightened interest in antimicrobial peptides(AMPs)known for their strong efficacy,albeit with high toxicity.In order to retain the potent antibacterial activity of AMPs while minimizing their systemic toxicity,we introduce a conjugate strategy with selective infection-activatable and bacteria-targeting capabilities.A series of colistin prodrugs with well-defined structures were developed by attaching a reactive oxygen species-responsive phenylboronic acid linker to all amines of colistin,followed by covalent linkage to sugars through the reaction of boronic acid and a diol moiety.Among these prodrugs,a lactosyl-functionalized colistin prodrug,LaP-Col,was identified because of its minimal toxicity toward normal tissues and ability to target bacteria.It exhibits a maximum tolerated dose over 20 times greater than colistin and minimal nephrotoxicity.In a mouse model of bacterial pneumonia,intravenous administration of LaP-Col led to its accumulation in the infected lung.It effectively killed bacteria,significantly improving the therapeutic efficacy and mouse survival rates.Overall,this study presents a prodrug strategy that effectively reduces the inherent high toxicity of colistin and enhances its therapeutic targeting efficacy,which has promising implications for modifying other potent but toxic AMPs.
基金funding support from the National Natural Science Foundation of China(No.52033006 and 51873142)Suzhou Science and Technology Development Project(No.SYS2019072) Science Foundation of China (No. 52033006 and 51873142)+1 种基金Suzhou Science and Technology Development Project (No.SYS2019072), Collaborative Innovation Center of Suzhou NanoScience & Technology, the 111 project, Suzhou Key Laboratory ofNanotechnology and BiomedicineJoint InternationalResearch Laboratory of Carbon-Based Functional Materials andDevices。
文摘Myocardial ischemia reperfusion(IR)injury is closely related to the overwhelming inflammation in the myocardium.Herein,cardiomyocyte-targeted nanotherapeutics were developed for the reactive oxygen species(ROS)-ultrasensitive co-delivery of dexamethasone(Dex)and RAGE small interfering RNA(siRAGE)to attenuate myocardial inflammation.PPTP,a ROSdegradable polycation based on PGE2-modified,PEGylated,ditellurium-crosslinked polyethylenimine(PEI)was developed to surface-decorate the Dex-encapsulated mesoporous silica nanoparticles(MSNs),which simultaneously condensed siRAGE and gated the MSNs to prevent the Dex pre-leakage.Upon intravenous injection to IR-injured rats,the nanotherapeutics could be efficiently transported into the inflamed cardiomyocytes via PGE2-assisted recognition of over-expressed E-series of prostaglandin(EP)receptors on the cell membranes.Intracellularly,the over-produced ROS degraded PPTP into small segments,promoting the release of siRAGE and Dex to mediate effective RAGE silencing(72%)and cooperative antiinflammatory effect.As a consequence,the nanotherapeutics notably suppressed the myocardial fibrosis and apoptosis,ultimately recovering the systolic function.Therefore,the current nanotherapeutics represent an effective example for the codelivery and on-demand release of nucleic acid and chemodrug payloads,and might find promising utilities toward the synergistic management of myocardial inflammation.
基金supported by the National Natural Science Foundation of China(21877042,22077038,22107032)the National Basic Research Plan of China(2018YFA0208903)+1 种基金Postdoctoral Research Foundation of China(2017M622454,2020T130038ZX)Huazhong University Startup Fund。
文摘Poly-ion complex(PIC)integrating non-antibiotic theranostics holds great promise in the combat against drug-resistant bacteria.Photosensitizers with aggregation-induced emission(AIE)characteristic are particularly intriguing theranostic agents,but incorporating them into antibacterial PIC to enable both fluorescence and reactive oxygen species(ROS)generation turn-on is deemed a great challenge.Here we report the development of a PIC that can dually boost the fluorescence and ROS generation in the presence of pathogen bacteria.The PIC is constructed based on an anionic polydiacetylene poly(deca-4,6-diynedioic acid)(PDDA),which completely degrades in the presence of ROS.A cationic polymer quaternized poly(2-(dimethylamino)ethyl methacrylate)(PQDMA)that can disrupt bacterial membrane is co-loaded together with a highly efficient AIE photosensitizer TPCI in the PIC.PIC is nonfluorescent initially in that PDDA can quench the AIE of TPCI in PIC.When pathogenic bacteria are present,they can disturb the assembly of PIC to release TPCI,whose fluorescence turns on sensitively to indicate the existence of bacteria.The on-demand irradiation can be subsequently applied to excite TPCI,which generates ROS to degrade PDDA and deform the PIC.As a result,TPCI and PQDMA are completely released to eliminate bacteria through a synergy of turned-on photodynamic therapy(PDT)and membrane disruption.The highly efficient detection and inhibition against both Gramnegative and Gram-positive bacteria have validated this polydiacetylene-based PIC system as an effective non-antibiotic antibacterial theranostic platform as well as a new strategy to enable“turn-on”fluorescence sensing and imaging of AIE fluorophores.
基金supported by grants from the National Natural Science Foundation of China(21775166)China Postdoctoral Science Foundation(2023TQ0380)+3 种基金Natural Science Foundation for Distinguished Young Scholars of Jiangsu Province(BK20180026)China Postdoctoral Science Foundation(2023TQ0380)Postdoctoral Fellowship Program of CPSF(GZB20230867)Jiangsu Excellent Postdoctoral Program(2023ZB388)。
文摘Acute kidney injury(AKI),a prevalent and complex clinical condition associated with elevated risks of morbidity and mortality,necessitates the meticulous detection and monitoring of kidney damage globally.Biomedicine has shown keen interest in molecular probes and detectors for AKI due to their sensitivity,rapidity,and cost-effectiveness.Bioimaging technologies play a significant role in identifying and quantifying AKI indicators,enhancing diagnostic approaches,and potentially refining clinical therapies for immediate injury control.Molecular probes serve as valuable tools for drug screening,uncovering renoprotective components,signaling pathways,and the nephrotoxic effects of drugs.This review comprehensively summarizes the latest advancements in molecular probes,emphasizing their exceptional efficacy in various characteristics,including renal cleanability,multichannel detection capability,near-infrared-II responsiveness,and reactivity toward reactive oxygen species.These probes offer enhanced benefits for assessing kidney damage and evaluating the therapeutic effects of medications while simultaneously reducing toxic effects.Additionally,the review delves into future potentials and challenges in this field,aiming to inspire the development and enhancement of molecular bioimaging for the early diagnosis and treatment of kidney diseases.
