Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxyge...Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxygen species(ROS),and aggregation-induced ROS quenching.To address these challenges,we present a molecular self-assembly strategy utilizing aggregation-induced emission(AIE)conjugates for metal complexes.As a proof of concept,we synthesized a mitochondrial-targeting cyclometalated Ir(Ⅲ)photosensitizer Ir-TPE.This approach significantly enhances the photodynamic effect while mitigating the dark toxicity associated with AIE groups.Ir-TPE readily self-assembles into nanoaggregates in aqueous solution,leading to a significant production of ROS upon light irradiation.Photoirradiated Ir-TPE triggers multiple modes of death by excessively accumulating ROS in the mitochondria,resulting in mitochondrial DNA damage.This damage can lead to ferroptosis and autophagy,two forms of cell death that are highly cytotoxic to cancer cells.The aggregation-enhanced photodynamic effect of Ir-TPE significantly enhances the production of ROS,leading to a more pronounced cytotoxic effect.In vitro and in vivo experiments demonstrate this aggregation-enhanced PDT approach achieves effective in situ tumor eradication.This study not only addresses the limitations of metal complexes in terms of low ROS production due to aggregation but also highlights the potential of this strategy for enhancing ROS production in PDT.展开更多
Hepatocellular carcinoma is a common and fatal malignancy for which there is no effective systemic therapeutic strategy.Dihydroartemisinin(DHA),a derivative of artemisinin,has been shown to exert anti-tumor effects th...Hepatocellular carcinoma is a common and fatal malignancy for which there is no effective systemic therapeutic strategy.Dihydroartemisinin(DHA),a derivative of artemisinin,has been shown to exert anti-tumor effects through the production of reactive oxygen species(ROS)and resultant mitochondrial damage.However,clinical translation is limited by several drawbacks,such as insolubility,instability and low bioavailability.Here,based on a nanomedicine-based delivery strategy,we fabricated mitochondria-targeted carrier-free nanoparticles coupling DHA and triphenylphosphonium(TPP),aiming to improve bioavailability and mitochondrial targeting.DHA-TPP nanoparticles can be passively delivered to the tumor site by enhanced penetration and retention and then internalized.Flow cytometry and Western blot analysis showed that DHA-TPP nanoparticles increased intracellular ROS,which increased mitochondrial stress and in turn upregulated the downstream Bcl-2 pathway,leading to apoptosis.In vivo experiments showed that DHA-TPP nanoparticles exhibited anti-tumor effects in a mouse model of hepatocellular carcinoma.These findings suggest carrier-free DHA-TPP nanoparticles as a potential therapeutic strategy for hepatocellular carcinoma.展开更多
Mitochondrial damage is closely related to the occurrence of many diseases.However,accurate monitoring and reporting of mitochondrial damage are not easy.Here,we developed a small molecule fluorescent probe named CB-C...Mitochondrial damage is closely related to the occurrence of many diseases.However,accurate monitoring and reporting of mitochondrial damage are not easy.Here,we developed a small molecule fluorescent probe named CB-Cl,which has splendid spectral properties(large Stokes shift,strong affinity for RNA,etc.)and excellent targeting ability to intracellular mitochondria.After mitochondria were damaged by external stimuli,CB-Cl would light up the nucleolus as a signal reporter.The cascade imaging of mitochondria and nucleolus using CB-Cl can monitor and visualize the mitochondrial status in living cells in real-time.Based on the above advantages,the probe CB-Cl has reference significance for the related research of mitochondrial damage and the prevention and treatment of related diseases.展开更多
Considering that hydrogen peroxide(H2O2)plays significant roles in oxidative stress,the cellular signal transduction and essential biological process regulation,the detection and imaging of H2O2 in living systems unde...Considering that hydrogen peroxide(H2O2)plays significant roles in oxidative stress,the cellular signal transduction and essential biological process regulation,the detection and imaging of H2O2 in living systems undertakes critical responsibility.Herein,we have developed a novel two-photon fluorescence turn on probe,named as Pyp-B for mitochondria H2O2 detection in living systems.Selectivity studies show that probe Pyp-B exhibit highly sensitive response toward H2O2 than other reactive oxygen species(ROS)and reactive nitrogen species(RNS)as well as biologically relevant species.The fluorescence colocalization studies demonstrate that the probe can localize in the mitochondria solely.Furthermore,as a bio-compatibility molecule,the highly selective and sensitive of fluorescence probe Pyp-B have been confirmed by its cell imaging application of H2O2 in living A549 cells and zebrafishes under the physiological conditions.展开更多
Well-developed mitochondria-targeted nanocarriers for function regulation are highly desirable.Numerous studies have been conducted on the treatment of mitochondria-related diseases;however,further improvements are re...Well-developed mitochondria-targeted nanocarriers for function regulation are highly desirable.Numerous studies have been conducted on the treatment of mitochondria-related diseases;however,further improvements are required to develop more effective drug delivery methods.Herein,we comprehensively introduce recent developments progress in rational design of mitochondria-targeted nanocarriers,and discuss the different strategies of available nanocarriers for targeting mitochondria.We also highlight the advantages and disadvantages of various carrier systems that are currently in use.Finally,perspective on new generation for mitochondria-targeted delivery systems in the emerging area of drug-based therapeutics is also discussed.展开更多
Photodynamic therapy(PDT)is an effective treatment method for tumors.But the specifically accumulated of photosensitizer was very difficult in the tumor site,which greatly limited the efficacy of PDT.Here,mitochondria...Photodynamic therapy(PDT)is an effective treatment method for tumors.But the specifically accumulated of photosensitizer was very difficult in the tumor site,which greatly limited the efficacy of PDT.Here,mitochondria-targeted Janus mesoporous nanoplatform(JPMO-Pt-CTPP-ZnPc)for PDT was prepared,the nanoplatform has uniform size(275 nm)and good dispersion and biocompatibility.The confocal laser scanning microscopy(CLSM)revealed the signal of ZnPc of JPMO-Pt-CTPP-ZnPc were higher than JPMO-Pt-ZnPc in tumor cells,and flow cytometry results showed the cell uptake efficiency of JPMO-Pt-CTPP-ZnPc was 2.5-fold higher than that of JPMO-Pt-ZnPc.This revealed the modification of CTPP significantly improves the targeting ability of the nanoplatform.In vitro anti-tumor experiment showed the JPMO-Pt-CTPP-ZnPc significantly inhibited the growth of tumor cells upon the irradiation of low-power laser,and the survival rate of cells incubated with 60μg/mL JPMO-Pt-CTPP-ZnPc was only 3%.Simultaneously,compared with JPMO-Pt-ZnPc(not modified with mitochondria targeting molecules CTPP),the PDT efficacy of JPMO-Pt-CTPP-ZnPc was significantly better,as it has targeted mitochondria in cells.展开更多
Formation of Lewy body inclusions（LBs）in the substantia nigra（SN）is a very well-characterized pathological hallmark of Parkinson’s disease（PD）.LBs are aggregates of many biologically inactive proteins including...Formation of Lewy body inclusions（LBs）in the substantia nigra（SN）is a very well-characterized pathological hallmark of Parkinson’s disease（PD）.LBs are aggregates of many biologically inactive proteins including structural elements,alpha-synuclein（asyn）-binding proteins,synphilin-1-binding proteins,and components of the ubiquitin-proteasome system.展开更多
Neuronal mitochondrial dysfunction caused by excessive reactive oxygen species(ROS)is an early event of sporadic Alzheimer's disease(AD),and considered to be a key pathologic factor in the progression of AD.The ta...Neuronal mitochondrial dysfunction caused by excessive reactive oxygen species(ROS)is an early event of sporadic Alzheimer's disease(AD),and considered to be a key pathologic factor in the progression of AD.The targeted delivery of the antioxidants to mitochondria of injured neurons in brain is a promising therapeutic strategy for AD.A safe and effective drug delivery system(DDS)which is able to cross the blood-brain barrier(BBB)and target neuronal mitochondria is necessary.Recently,bioactive materials-based DDS has been widely investigated for the treatment of AD.Herein,we developed macrophage(MA)membrane-coated solid lipid nanoparticles(SLNs)by attaching rabies virus glycoprotein(RVG29)and triphenylphosphine cation(TPP)molecules to the surface of MA membrane(RVG/TPP-MASLNs)for functional antioxidant delivery to neuronal mitochondria.According to the results,MA membranes camouflaged the SLNs from being eliminated by RESrich organs by inheriting the immunological characteristics of macrophages.The unique properties of the DDS after decoration with RVG29 on the surface was demonstrated by the ability to cross the BBB and the selective targeting to neurons.After entering the neurons in CNS,TPP further lead the DDS to mitochondria driven by electric charge.The Genistein(GS)-encapsulated DDS(RVG/TPP-MASLNs-GS)exhibited the most favorable effects on reliveing AD symptoms in vitro and in vivo by the synergies gained from the combination of MA membranes,RVG29 and TPP.These results demonstrated a promising therapeutic candidate for delaying the progression of AD via neuronal mitochondria-targeted delivery by the designed biomimetic nanosystems.展开更多
Hybrid lipid-nanoparticle complexes have shown attractive characteristics as drug carriers due to their integrated advantages from liposomes and nanoparticles.Here we developed a kind of lipid-small molecule hybrid na...Hybrid lipid-nanoparticle complexes have shown attractive characteristics as drug carriers due to their integrated advantages from liposomes and nanoparticles.Here we developed a kind of lipid-small molecule hybrid nanoparticles(LPHNPs) for imaging and treatment in an ortho topic glioma model.LPHNPs were prepared by engineering the co-assembly of lipids and an amphiphilic pheophorbide a-quinolinium conjugate(PQC),a mitochondria-targeting small molecule.Compared with the pure nanofiber self-assembled by PQC,LPHNPs not only preserve the comparable antiproliferative potency,but also possess a spherical nanostructure that allows the PQC molecules to be administrated through intravenous injection.Also,this co-assembly remarkably improved the drug-loading capacity and formulation stability against the physical encapsulation using conventional liposomes.By integrating the advantages from liposome and PQC molecule,LPHNPs have minimal system toxicity,enhanced potency of photodynamic therapy(PDT) and visualization capacities of drug biodistribution and tumor imaging.The hybrid nanoparticle demonstrates excellent curative effects to significantly prolong the survival of mice with the orthotopic glioma.The unique co-assembly of lipid and small molecule provides new potential for constructing new liposome-derived nanoformulations and improving cancer treatment.展开更多
Immunogenic cell death(ICD) plays a major role in cancer immunotherapy by stimulating specific T cell responses and restoring the antitumor immune system.However,effective type Ⅱ ICD inducers without biotoxicity are ...Immunogenic cell death(ICD) plays a major role in cancer immunotherapy by stimulating specific T cell responses and restoring the antitumor immune system.However,effective type Ⅱ ICD inducers without biotoxicity are still very limited.Herein,a tentative drug-or photo sensitizer-free strategy was developed by employing enzymatic self-assembly of the peptide F-pY-T to induce mitochondrial oxidative stress in cancer cells.Upon dephosphorylation catalyzed by alkaline phosphatase overexpressed on cancer cells,the peptide F-pY-T self-assembled to form nanoparticles,which were subsequently internalized.These affected the morphology of mitochondria and induced serious reactive oxygen species production,causing the ICD characterized by the release of danger-associated molecular patterns(DAMPs).DAMPs enhanced specific immune responses by promoting the maturation of DCs and the intratumoral infiltration of tumor-specific T cells to eradicate tumor cells.The dramatic immunotherapeutic capacity could be enhanced further by combination therapy of F-pY-T and anti-PD-L1 agents without visible biotoxicity in the main organs.Thus,our results revealed an alternative strategy to induce efficient ICD by physically promoting mitochondrial oxidative stress.展开更多
Mitochondria are the power plants of the cell and play key roles in activating the apoptotic pathway in cancer cells,which are readily susceptible to cytotoxic reactive oxygen species and temperature elevations.Herein...Mitochondria are the power plants of the cell and play key roles in activating the apoptotic pathway in cancer cells,which are readily susceptible to cytotoxic reactive oxygen species and temperature elevations.Herein,we develop a"nanomissile"that targets mitochondria to enhance tumor treatment effects by facilitating mitochondrial dysfunction and releasing cytochrome C to activate the apoptotic pathway of cancer cells under 650-nm laser irradiation.Porphyringrafted polydopamine nanomaterial(PTPF-MitP)is designed as a nanomissile,with integrated O;-evolving photodynamic therapy and moderate photothermal therapy,which can selectively deliver to the mitochondria through a targeting unit,MitP.The cytotoxicity of PTPF-MitP to human lung tumor cells is twice as high as that of PTPF that does not have mitochondrial targeting units.In addition,it represents a realtime visualization and highly efficient treatment for tumor sites in vivo.This development represents a viable strategy for cancer therapy.展开更多
Targeted-delivery is of great importance to molecular probes and drugs for cell biology study. Herein we reported 11 sulfur-containing coumarins as cell imaging probes. Different sulfur speciation of the 4 representat...Targeted-delivery is of great importance to molecular probes and drugs for cell biology study. Herein we reported 11 sulfur-containing coumarins as cell imaging probes. Different sulfur speciation of the 4 representative coumarins SC1-SC4 renders them significantly different subcellular localizations and cellular uptake pathways： SC1 containing thioether group located in lysosomes, while sulfoxide and sulfone compounds SC2 and SC3 distributed in the whole cell. Furthermore, the cationic sulfonium containing compound SC4 was internalized by clathrin-mediated endocytosis and localized at mitochondria. By analyzing the molecular parameters of all 11 coumarins, we found that different sulfur speciation affected their lipophilicity and electrostatic surface potential. These two key factors play roles in altering biological behaviors of the coumarins. The results revealed the importance of sulfur speciation on the physicochemical properties and thus subcellular localization of bioprobes. This is useful for designing new functional bioprobes.展开更多
Protein biogenesis is a complex process,and complexity is greatly increased in eukaryotic cells through specific targeting of proteins to different organelles.To direct targeting,organellar proteins carry an organelle...Protein biogenesis is a complex process,and complexity is greatly increased in eukaryotic cells through specific targeting of proteins to different organelles.To direct targeting,organellar proteins carry an organelle-specific targeting signal for recognition by organelle-specific import machinery.However,the situation is confusing for transmembrane domain(TMD)-containing signalanchored(SA)proteins of various organelles because TMDs function as an endoplasmic reticulum(ER)targeting signal.Although ER targeting of SA proteins is well understood,how they are targeted to mitochondria and chloroplasts remains elusive.Here,we investigated how the targeting specificity of SA proteins is determined for specific targeting to mitochondria and chloroplasts.Mitochondrial targeting requires multiple motifs around and within TMDs:a basic residue and an arginine-rich region flanking the N-and C-termini of TMDs,respectively,and an aromatic residue in the C-terminal side of the TMD that specify mitochondrial targeting in an additive manner.These motifs play a role in slowing down the elongation speed during translation,thereby ensuring mitochondrial targeting in a cotranslational manner.By contrast,the absence of any of these motifs individually or together causes at varying degrees chloroplast targeting that occurs in a post-translational manner.展开更多
Prostate cancer(PC)biomarker-citrate detection is clinically important to diagnose PC in early stages.Methylquinolinium iodide(Q)conjugated indole-phenylboronic acid(IB)was designed as a red-emissive QIB probe for the...Prostate cancer(PC)biomarker-citrate detection is clinically important to diagnose PC in early stages.Methylquinolinium iodide(Q)conjugated indole-phenylboronic acid(IB)was designed as a red-emissive QIB probe for the detection of citrate through Lewis acid-base reaction and intramolecular charge transfer(ICT)sensing mechanisms.Boronic acid acts as Lewis acid as well as citrate(Lewis base)recognition unit.The probe reacted with citrate,showing enhanced red emissions.Since the probe has excellent water solubility and great biocompatibility,practical application in biological systems is possible.Citrate was monitored precisely in the mitochondria organelle(in vitro)of living cells with a positive charge on QIB.Also,endogenous(in situ)citrate was detected quantitatively to discriminate non-cancerous and PC mice,observed strong and lower(negligible)emission intensity on non-cancerous and cancerous prostate tissues,respectively.Because,the concentration of citrate is higher in healthy prostate compared with PC prostate.Furthermore,the analysis of sliced prostate tissues can give PC-related information for clinical diagnosis to prevent and treat PC in the initial stages.Therefore,we believe that the present probe is a promising biochemical reagent in diagnosing PC.展开更多
Development of effective treatments for neurodegenerative disorders is a clinical conundrum that has puzzled many researchers.Currently available drugs target symptomatic relief rather than suppressing,ceasing or repa...Development of effective treatments for neurodegenerative disorders is a clinical conundrum that has puzzled many researchers.Currently available drugs target symptomatic relief rather than suppressing,ceasing or repairing the devastating neural damages.For Alzheimer’s disease,two classes of procognitive compounds are approved as a treatment.展开更多
Acute kidney injury(AKI)progression is driven by mitochondrial redox collapse in proximal tubular epithelial cells(PTECs),where reactive oxygen species(ROS)surge and molybdenum(Mo)metabolic dysregulation create an“ox...Acute kidney injury(AKI)progression is driven by mitochondrial redox collapse in proximal tubular epithelial cells(PTECs),where reactive oxygen species(ROS)surge and molybdenum(Mo)metabolic dysregulation create an“oxidative storm-defense collapse”cycle.Conventional antioxidant therapies fail to halt AKI chronicity due to their inability to restore Mo-dependent detoxification enzymes(e.g.,Mo-containing Amidoxime Reducing Component,mARC).To address this dual pathology,we developed N-acetylcysteine(NAC)-modified molybde-num disulfide quantum dots(NMDs)that implement an endo-exogenous antioxidant collaborative strategy,synergizing exogenous ROS elimination with endogenous Mo enzyme restoration.NMDs achieve triple-tiered targeting:1)Organ-selective accumulation leveraging NMDs’hydrophilicity and ultrasmall size;2)Cell-specific internalization through Organic Anion Transporter 1(OAT1)-mediated active uptake into PTECs;3)Mitochondrial precision delivery guided by NAC’s intrinsic mitochondrial affinity.Within pathological micro-environments,NMDs exhibit multidimensional therapeutic superiority:exposed Mo(IV)directly quenches mitochondrial ROS via electron transfer(external clearance),while released Mo ions reactivate mARC and NAC supplies glutathione precursors,synergistically rebuilding endogenous antioxidant defenses(internal rein-forcement).In vivo validation demonstrated NMDs’superior therapeutic efficacy,outperforming clinical anti-oxidant NAC.This work pioneers a“scavenging-fortification”strategy through Mo-centric metabolic regulation and nanotechnology integration,validating Mo-based materials’therapeutic potential and establishing a para-digm for mitochondrial-targeted AKI treatment.展开更多
This study demonstrated the design of whey protein isolate(WPI)-mannose(Man)conjugates with triphenylphosphonium bromide(TPP)through self-assembly to prepare macrophage and mitochondrion dual-targeting astaxanthin(AXT...This study demonstrated the design of whey protein isolate(WPI)-mannose(Man)conjugates with triphenylphosphonium bromide(TPP)through self-assembly to prepare macrophage and mitochondrion dual-targeting astaxanthin(AXT)nanoparticles(AXT@TPP-WPI-Man).The nanoparticles displayed spherical structures with a well-dispersed size of approximately 206.1±39.2 nm,with good biocompatibility,stability,and targeting capabilities.In vitro experiments demonstrated the specific accumulation of AXT@TPP-WPI-Man in mitochondria and exhibited good targeting ability toward macrophages.The AXT@TPP-WPI-Man effectively reduced reactive oxygen species and preserved the normal mitochondrial membrane potential.The AXT@TPP-WPI-Man treated ulcerative colitis mice exhibited a 52.32%increase in colon length with significant improvement in weight loss,disease activity index scores,and reduced release of inflammatory cytokines.Immunofluorescence staining indicated AXT@TPP-WPI-Man alleviated ulcerative colitis by reducing M1 polarization in colonic macrophages while promoting M2 polarization.The dual-targeting AXT@TPP-WPI-Man has the potential to improve astaxanthin bioavailability,presenting a promising delivery method for the treatment of ulcerative colitis.展开更多
In order to explore the complex interaction between H_(2)S and the development of related diseases,it is urgently necessary to develop effective visualization methods to monitor the dynamic changes of H_(2)S in real t...In order to explore the complex interaction between H_(2)S and the development of related diseases,it is urgently necessary to develop effective visualization methods to monitor the dynamic changes of H_(2)S in real time.Herein,we constructed the NIR fluorescent probe HCy-SSPy based on disulfide cleavage for the rapid imaging of H_(2)S.The hemicyanine(HCy-NH_(2))unit was used as a NIR fluorophore,and asymmetric pyridyl disulfides(SSPy)acted as the specific recognition receptor for H_(2)S.The synthesized HCy-SSPy showed a remarkable NIR turn-on signal at 765 nm activated by H_(2)S.This probe also possessed excellent selectivity and high sensitivity,as well as rapid detection ability for H_(2)S(-5s).Moreover,the low cytotoxicity,mitochondrial localization,and excellent cell imaging performance of HCy-SSPy were discussed.Further biological experiments revealed that the probe not only imaged H_(2)S in tumor-bearing mice but also showed great potential for H_(2)S detection in inflammatory processes.展开更多
Alzheimer’s disease(AD),the most prominent form of dementia in the elderly,has no cure.Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials.Nov...Alzheimer’s disease(AD),the most prominent form of dementia in the elderly,has no cure.Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials.Novel therapeutic targets and strategies are urgently needed.Emerging data suggest that in response to environmental stress,mitochondria initiate an integrated stress response(ISR)shown to be beneficial for healthy aging and neuroprotection.Here,we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR.Specifically,partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions,including AD,with several small molecules being tested in clinical trials.We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach.Since this strategy has also been shown to enhance health and life span,the development of safe and efficacious complex Ⅰ inhibitors could promote healthy aging,delaying the onset of age-related neurodegenerative diseases.展开更多
Cardiac arrhythmias are among the most common causes of death in the world. Foundational studies established the critical role of ion channel disorders in arrhythmias, yet defects in ion channels themselves, such as m...Cardiac arrhythmias are among the most common causes of death in the world. Foundational studies established the critical role of ion channel disorders in arrhythmias, yet defects in ion channels themselves, such as mutations, may not account for all arrhythmias. Despite the progress made in recent decades, the antiarrhythmic drugs currently available have limited effectiveness,and the majority of these drugs can have proarrhythmic effects. This review describes novel knowledge on cellular mechanisms that cause cardiac arrhythmias, focuses on the dysfunction of subcellular organelles and intracellular logistics, and discusses potential strategies and challenges for developing novel, safe and effective treatments for arrhythmias.展开更多
基金support from the National Natural Science Foundation of China(Nos.22277056,21977052)the Distinguished Young Scholars of Jiangsu Province(No.BK20230006)+2 种基金the Natural Science Foundation of Jiangsu Province(Nos.BK20230977,BK20231090)the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province(No.23KJB150020)the Jiangsu Excellent Postdoctoral Program(No.2022ZB758)。
文摘Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxygen species(ROS),and aggregation-induced ROS quenching.To address these challenges,we present a molecular self-assembly strategy utilizing aggregation-induced emission(AIE)conjugates for metal complexes.As a proof of concept,we synthesized a mitochondrial-targeting cyclometalated Ir(Ⅲ)photosensitizer Ir-TPE.This approach significantly enhances the photodynamic effect while mitigating the dark toxicity associated with AIE groups.Ir-TPE readily self-assembles into nanoaggregates in aqueous solution,leading to a significant production of ROS upon light irradiation.Photoirradiated Ir-TPE triggers multiple modes of death by excessively accumulating ROS in the mitochondria,resulting in mitochondrial DNA damage.This damage can lead to ferroptosis and autophagy,two forms of cell death that are highly cytotoxic to cancer cells.The aggregation-enhanced photodynamic effect of Ir-TPE significantly enhances the production of ROS,leading to a more pronounced cytotoxic effect.In vitro and in vivo experiments demonstrate this aggregation-enhanced PDT approach achieves effective in situ tumor eradication.This study not only addresses the limitations of metal complexes in terms of low ROS production due to aggregation but also highlights the potential of this strategy for enhancing ROS production in PDT.
基金funded and supported by the Department of Science and Technology of Guangdong Province(No.2022B1111020005)Key Laboratory of Guangdong Provincial Food and Drug Administration(No.2021ZDB03)+3 种基金the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund(Guangdong-Hong Kong-Macao Joint Lab,No.2020B1212030006)Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme(No.Guochao Liao,2019)Guangdong Basic and Applied Basic Research Foundation(Nos.2020B1515130005,2022A1515110270,202201011563)The Bureau of Science and Technology of Guangzhou City(No.HMJH_(2)019000)。
文摘Hepatocellular carcinoma is a common and fatal malignancy for which there is no effective systemic therapeutic strategy.Dihydroartemisinin(DHA),a derivative of artemisinin,has been shown to exert anti-tumor effects through the production of reactive oxygen species(ROS)and resultant mitochondrial damage.However,clinical translation is limited by several drawbacks,such as insolubility,instability and low bioavailability.Here,based on a nanomedicine-based delivery strategy,we fabricated mitochondria-targeted carrier-free nanoparticles coupling DHA and triphenylphosphonium(TPP),aiming to improve bioavailability and mitochondrial targeting.DHA-TPP nanoparticles can be passively delivered to the tumor site by enhanced penetration and retention and then internalized.Flow cytometry and Western blot analysis showed that DHA-TPP nanoparticles increased intracellular ROS,which increased mitochondrial stress and in turn upregulated the downstream Bcl-2 pathway,leading to apoptosis.In vivo experiments showed that DHA-TPP nanoparticles exhibited anti-tumor effects in a mouse model of hepatocellular carcinoma.These findings suggest carrier-free DHA-TPP nanoparticles as a potential therapeutic strategy for hepatocellular carcinoma.
基金the Shenzhen Science and Technology Research and Development Funds(No.JCYJ20190806155409104)National Natural Science Foundation of China(Nos.52150222,21672130 and 52073163)+1 种基金Guangdong Basic and Applied Basic Research Foundation(No.2019A1515110356)the Qilu Young Scholars Program of Shandong University.
文摘Mitochondrial damage is closely related to the occurrence of many diseases.However,accurate monitoring and reporting of mitochondrial damage are not easy.Here,we developed a small molecule fluorescent probe named CB-Cl,which has splendid spectral properties(large Stokes shift,strong affinity for RNA,etc.)and excellent targeting ability to intracellular mitochondria.After mitochondria were damaged by external stimuli,CB-Cl would light up the nucleolus as a signal reporter.The cascade imaging of mitochondria and nucleolus using CB-Cl can monitor and visualize the mitochondrial status in living cells in real-time.Based on the above advantages,the probe CB-Cl has reference significance for the related research of mitochondrial damage and the prevention and treatment of related diseases.
基金the financial support from the National Natural Science Foundation of China(No.81860630)the China Postdoctoral Science Foundation(No.2019M662968)GuangdongBasic and Applied Basic Research Foundation(Nos.2019A1515110356,2019A1515110877)。
文摘Considering that hydrogen peroxide(H2O2)plays significant roles in oxidative stress,the cellular signal transduction and essential biological process regulation,the detection and imaging of H2O2 in living systems undertakes critical responsibility.Herein,we have developed a novel two-photon fluorescence turn on probe,named as Pyp-B for mitochondria H2O2 detection in living systems.Selectivity studies show that probe Pyp-B exhibit highly sensitive response toward H2O2 than other reactive oxygen species(ROS)and reactive nitrogen species(RNS)as well as biologically relevant species.The fluorescence colocalization studies demonstrate that the probe can localize in the mitochondria solely.Furthermore,as a bio-compatibility molecule,the highly selective and sensitive of fluorescence probe Pyp-B have been confirmed by its cell imaging application of H2O2 in living A549 cells and zebrafishes under the physiological conditions.
基金financial support from the National Key Research and Development Project (No. 2020YFA0709900)the Key University Science Research Project of Jiangsu Province (No. 19KJA520005)+1 种基金the National Natural Science Foundation of China (No. 22077101)the Open Project Program of State Key Laboratory of Coordination Chemistry (No. 202008)
文摘Well-developed mitochondria-targeted nanocarriers for function regulation are highly desirable.Numerous studies have been conducted on the treatment of mitochondria-related diseases;however,further improvements are required to develop more effective drug delivery methods.Herein,we comprehensively introduce recent developments progress in rational design of mitochondria-targeted nanocarriers,and discuss the different strategies of available nanocarriers for targeting mitochondria.We also highlight the advantages and disadvantages of various carrier systems that are currently in use.Finally,perspective on new generation for mitochondria-targeted delivery systems in the emerging area of drug-based therapeutics is also discussed.
基金financial support from the National Natural Science Foundation of China(Nos.81971675,22275099)Project of State Key Laboratory of Organic Electronics and Information Displays,Nanjing University of Posts&Telecommunications(No.GDX2022010014)Natural Science Research Start up Foundation of Recruiting Talents of Nanjing University of Posts and Telecommunications(No.NY222067).
文摘Photodynamic therapy(PDT)is an effective treatment method for tumors.But the specifically accumulated of photosensitizer was very difficult in the tumor site,which greatly limited the efficacy of PDT.Here,mitochondria-targeted Janus mesoporous nanoplatform(JPMO-Pt-CTPP-ZnPc)for PDT was prepared,the nanoplatform has uniform size(275 nm)and good dispersion and biocompatibility.The confocal laser scanning microscopy(CLSM)revealed the signal of ZnPc of JPMO-Pt-CTPP-ZnPc were higher than JPMO-Pt-ZnPc in tumor cells,and flow cytometry results showed the cell uptake efficiency of JPMO-Pt-CTPP-ZnPc was 2.5-fold higher than that of JPMO-Pt-ZnPc.This revealed the modification of CTPP significantly improves the targeting ability of the nanoplatform.In vitro anti-tumor experiment showed the JPMO-Pt-CTPP-ZnPc significantly inhibited the growth of tumor cells upon the irradiation of low-power laser,and the survival rate of cells incubated with 60μg/mL JPMO-Pt-CTPP-ZnPc was only 3%.Simultaneously,compared with JPMO-Pt-ZnPc(not modified with mitochondria targeting molecules CTPP),the PDT efficacy of JPMO-Pt-CTPP-ZnPc was significantly better,as it has targeted mitochondria in cells.
基金funded by MJ FOX Foundation Rapid Response Innovation Award Grant to AR
文摘Formation of Lewy body inclusions（LBs）in the substantia nigra（SN）is a very well-characterized pathological hallmark of Parkinson’s disease（PD）.LBs are aggregates of many biologically inactive proteins including structural elements,alpha-synuclein（asyn）-binding proteins,synphilin-1-binding proteins,and components of the ubiquitin-proteasome system.
基金We are grateful for the financial support from National Science and Technology Major Projects for Major New Drugs Innovation and Development(Grant No.2018ZX09711003-008-001)Beijing Natural Science Foundation(Grant No.7172162).
文摘Neuronal mitochondrial dysfunction caused by excessive reactive oxygen species(ROS)is an early event of sporadic Alzheimer's disease(AD),and considered to be a key pathologic factor in the progression of AD.The targeted delivery of the antioxidants to mitochondria of injured neurons in brain is a promising therapeutic strategy for AD.A safe and effective drug delivery system(DDS)which is able to cross the blood-brain barrier(BBB)and target neuronal mitochondria is necessary.Recently,bioactive materials-based DDS has been widely investigated for the treatment of AD.Herein,we developed macrophage(MA)membrane-coated solid lipid nanoparticles(SLNs)by attaching rabies virus glycoprotein(RVG29)and triphenylphosphine cation(TPP)molecules to the surface of MA membrane(RVG/TPP-MASLNs)for functional antioxidant delivery to neuronal mitochondria.According to the results,MA membranes camouflaged the SLNs from being eliminated by RESrich organs by inheriting the immunological characteristics of macrophages.The unique properties of the DDS after decoration with RVG29 on the surface was demonstrated by the ability to cross the BBB and the selective targeting to neurons.After entering the neurons in CNS,TPP further lead the DDS to mitochondria driven by electric charge.The Genistein(GS)-encapsulated DDS(RVG/TPP-MASLNs-GS)exhibited the most favorable effects on reliveing AD symptoms in vitro and in vivo by the synergies gained from the combination of MA membranes,RVG29 and TPP.These results demonstrated a promising therapeutic candidate for delaying the progression of AD via neuronal mitochondria-targeted delivery by the designed biomimetic nanosystems.
基金support from NIH/NCI(R01CA199668,R01CA232845)NIH/NIDCR(1R01DE029237,USA)+1 种基金NIH/NICHD(R01HD086195,USA)UC Davis Comprehensive Cancer Centre Support Grant(CCSG,USA)awarded by the National Cancer Institute(NCI P30CA093373,USA)。
文摘Hybrid lipid-nanoparticle complexes have shown attractive characteristics as drug carriers due to their integrated advantages from liposomes and nanoparticles.Here we developed a kind of lipid-small molecule hybrid nanoparticles(LPHNPs) for imaging and treatment in an ortho topic glioma model.LPHNPs were prepared by engineering the co-assembly of lipids and an amphiphilic pheophorbide a-quinolinium conjugate(PQC),a mitochondria-targeting small molecule.Compared with the pure nanofiber self-assembled by PQC,LPHNPs not only preserve the comparable antiproliferative potency,but also possess a spherical nanostructure that allows the PQC molecules to be administrated through intravenous injection.Also,this co-assembly remarkably improved the drug-loading capacity and formulation stability against the physical encapsulation using conventional liposomes.By integrating the advantages from liposome and PQC molecule,LPHNPs have minimal system toxicity,enhanced potency of photodynamic therapy(PDT) and visualization capacities of drug biodistribution and tumor imaging.The hybrid nanoparticle demonstrates excellent curative effects to significantly prolong the survival of mice with the orthotopic glioma.The unique co-assembly of lipid and small molecule provides new potential for constructing new liposome-derived nanoformulations and improving cancer treatment.
基金supported by the National Natural Science Foundation of China (31870949,21875116,31961143004,81921004,81100942,81472081)the National Science Fund for Distinguished Young Scholars (31825012,China)the Tianjin Science Fund for Distinguished Young Scholars (17JCJQJC44900,China)。
文摘Immunogenic cell death(ICD) plays a major role in cancer immunotherapy by stimulating specific T cell responses and restoring the antitumor immune system.However,effective type Ⅱ ICD inducers without biotoxicity are still very limited.Herein,a tentative drug-or photo sensitizer-free strategy was developed by employing enzymatic self-assembly of the peptide F-pY-T to induce mitochondrial oxidative stress in cancer cells.Upon dephosphorylation catalyzed by alkaline phosphatase overexpressed on cancer cells,the peptide F-pY-T self-assembled to form nanoparticles,which were subsequently internalized.These affected the morphology of mitochondria and induced serious reactive oxygen species production,causing the ICD characterized by the release of danger-associated molecular patterns(DAMPs).DAMPs enhanced specific immune responses by promoting the maturation of DCs and the intratumoral infiltration of tumor-specific T cells to eradicate tumor cells.The dramatic immunotherapeutic capacity could be enhanced further by combination therapy of F-pY-T and anti-PD-L1 agents without visible biotoxicity in the main organs.Thus,our results revealed an alternative strategy to induce efficient ICD by physically promoting mitochondrial oxidative stress.
基金supported by the National Natural Science Foundation of China(21705117,22174110,21904095 and 22004089)the Elite Scholar Program of Tianjin University(2019XRG-0065)+2 种基金the Program of Tianjin Science and Technology Major Project and Engineering(19ZXYXSY00090)the Program for Chang Jiang Scholars and Innovative Research Team,Ministry of Education,China(IRT-16R61)the Special Fund Project for the Central Government to Guide Local Science and Technology Development(2020)。
文摘Mitochondria are the power plants of the cell and play key roles in activating the apoptotic pathway in cancer cells,which are readily susceptible to cytotoxic reactive oxygen species and temperature elevations.Herein,we develop a"nanomissile"that targets mitochondria to enhance tumor treatment effects by facilitating mitochondrial dysfunction and releasing cytochrome C to activate the apoptotic pathway of cancer cells under 650-nm laser irradiation.Porphyringrafted polydopamine nanomaterial(PTPF-MitP)is designed as a nanomissile,with integrated O;-evolving photodynamic therapy and moderate photothermal therapy,which can selectively deliver to the mitochondria through a targeting unit,MitP.The cytotoxicity of PTPF-MitP to human lung tumor cells is twice as high as that of PTPF that does not have mitochondrial targeting units.In addition,it represents a realtime visualization and highly efficient treatment for tumor sites in vivo.This development represents a viable strategy for cancer therapy.
基金financial support from the National Key Basic Research Support Foundation of China(No. 2015CB856301)the National Natural Scientific Foundation of China (Nos. 21571007, 21271013,21321001)
文摘Targeted-delivery is of great importance to molecular probes and drugs for cell biology study. Herein we reported 11 sulfur-containing coumarins as cell imaging probes. Different sulfur speciation of the 4 representative coumarins SC1-SC4 renders them significantly different subcellular localizations and cellular uptake pathways： SC1 containing thioether group located in lysosomes, while sulfoxide and sulfone compounds SC2 and SC3 distributed in the whole cell. Furthermore, the cationic sulfonium containing compound SC4 was internalized by clathrin-mediated endocytosis and localized at mitochondria. By analyzing the molecular parameters of all 11 coumarins, we found that different sulfur speciation affected their lipophilicity and electrostatic surface potential. These two key factors play roles in altering biological behaviors of the coumarins. The results revealed the importance of sulfur speciation on the physicochemical properties and thus subcellular localization of bioprobes. This is useful for designing new functional bioprobes.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(No.2022R1A2C1091844)。
文摘Protein biogenesis is a complex process,and complexity is greatly increased in eukaryotic cells through specific targeting of proteins to different organelles.To direct targeting,organellar proteins carry an organelle-specific targeting signal for recognition by organelle-specific import machinery.However,the situation is confusing for transmembrane domain(TMD)-containing signalanchored(SA)proteins of various organelles because TMDs function as an endoplasmic reticulum(ER)targeting signal.Although ER targeting of SA proteins is well understood,how they are targeted to mitochondria and chloroplasts remains elusive.Here,we investigated how the targeting specificity of SA proteins is determined for specific targeting to mitochondria and chloroplasts.Mitochondrial targeting requires multiple motifs around and within TMDs:a basic residue and an arginine-rich region flanking the N-and C-termini of TMDs,respectively,and an aromatic residue in the C-terminal side of the TMD that specify mitochondrial targeting in an additive manner.These motifs play a role in slowing down the elongation speed during translation,thereby ensuring mitochondrial targeting in a cotranslational manner.By contrast,the absence of any of these motifs individually or together causes at varying degrees chloroplast targeting that occurs in a post-translational manner.
基金financially supported by the National Natural Science Foundation of China(No.22150410327)the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT&Future Planning(No.2020R1A2C1102741).
文摘Prostate cancer(PC)biomarker-citrate detection is clinically important to diagnose PC in early stages.Methylquinolinium iodide(Q)conjugated indole-phenylboronic acid(IB)was designed as a red-emissive QIB probe for the detection of citrate through Lewis acid-base reaction and intramolecular charge transfer(ICT)sensing mechanisms.Boronic acid acts as Lewis acid as well as citrate(Lewis base)recognition unit.The probe reacted with citrate,showing enhanced red emissions.Since the probe has excellent water solubility and great biocompatibility,practical application in biological systems is possible.Citrate was monitored precisely in the mitochondria organelle(in vitro)of living cells with a positive charge on QIB.Also,endogenous(in situ)citrate was detected quantitatively to discriminate non-cancerous and PC mice,observed strong and lower(negligible)emission intensity on non-cancerous and cancerous prostate tissues,respectively.Because,the concentration of citrate is higher in healthy prostate compared with PC prostate.Furthermore,the analysis of sliced prostate tissues can give PC-related information for clinical diagnosis to prevent and treat PC in the initial stages.Therefore,we believe that the present probe is a promising biochemical reagent in diagnosing PC.
文摘Development of effective treatments for neurodegenerative disorders is a clinical conundrum that has puzzled many researchers.Currently available drugs target symptomatic relief rather than suppressing,ceasing or repairing the devastating neural damages.For Alzheimer’s disease,two classes of procognitive compounds are approved as a treatment.
基金supported by the National Natural Science Foundation of China(No.82373871,82574405)Key Research and Development Program of Hunan Province(No.2024JK2114)+2 种基金Key Research Project of Ningxia Hui Autonomous Region of China(Major Project)(No.2023BEG02038)Central South University Research Programme of Advanced Interdisciplinary Studies(No.2023QYJC017)The Project Program of National Clinical Research Center for Geriatric Disorders(Xiangya Hospital,Grant No.2023LNJJ12).
文摘Acute kidney injury(AKI)progression is driven by mitochondrial redox collapse in proximal tubular epithelial cells(PTECs),where reactive oxygen species(ROS)surge and molybdenum(Mo)metabolic dysregulation create an“oxidative storm-defense collapse”cycle.Conventional antioxidant therapies fail to halt AKI chronicity due to their inability to restore Mo-dependent detoxification enzymes(e.g.,Mo-containing Amidoxime Reducing Component,mARC).To address this dual pathology,we developed N-acetylcysteine(NAC)-modified molybde-num disulfide quantum dots(NMDs)that implement an endo-exogenous antioxidant collaborative strategy,synergizing exogenous ROS elimination with endogenous Mo enzyme restoration.NMDs achieve triple-tiered targeting:1)Organ-selective accumulation leveraging NMDs’hydrophilicity and ultrasmall size;2)Cell-specific internalization through Organic Anion Transporter 1(OAT1)-mediated active uptake into PTECs;3)Mitochondrial precision delivery guided by NAC’s intrinsic mitochondrial affinity.Within pathological micro-environments,NMDs exhibit multidimensional therapeutic superiority:exposed Mo(IV)directly quenches mitochondrial ROS via electron transfer(external clearance),while released Mo ions reactivate mARC and NAC supplies glutathione precursors,synergistically rebuilding endogenous antioxidant defenses(internal rein-forcement).In vivo validation demonstrated NMDs’superior therapeutic efficacy,outperforming clinical anti-oxidant NAC.This work pioneers a“scavenging-fortification”strategy through Mo-centric metabolic regulation and nanotechnology integration,validating Mo-based materials’therapeutic potential and establishing a para-digm for mitochondrial-targeted AKI treatment.
基金supported by the National Natural Science Fund for Distinguished Young Scholars of China(31925031).
文摘This study demonstrated the design of whey protein isolate(WPI)-mannose(Man)conjugates with triphenylphosphonium bromide(TPP)through self-assembly to prepare macrophage and mitochondrion dual-targeting astaxanthin(AXT)nanoparticles(AXT@TPP-WPI-Man).The nanoparticles displayed spherical structures with a well-dispersed size of approximately 206.1±39.2 nm,with good biocompatibility,stability,and targeting capabilities.In vitro experiments demonstrated the specific accumulation of AXT@TPP-WPI-Man in mitochondria and exhibited good targeting ability toward macrophages.The AXT@TPP-WPI-Man effectively reduced reactive oxygen species and preserved the normal mitochondrial membrane potential.The AXT@TPP-WPI-Man treated ulcerative colitis mice exhibited a 52.32%increase in colon length with significant improvement in weight loss,disease activity index scores,and reduced release of inflammatory cytokines.Immunofluorescence staining indicated AXT@TPP-WPI-Man alleviated ulcerative colitis by reducing M1 polarization in colonic macrophages while promoting M2 polarization.The dual-targeting AXT@TPP-WPI-Man has the potential to improve astaxanthin bioavailability,presenting a promising delivery method for the treatment of ulcerative colitis.
基金supported by the National Natural Science Foundation of China(No.22264013)Hainan Province Science and Technology Special Fund(No.ZDKJ2021038)+1 种基金Key Research and Development Project of Hainan Province(No.ZDYF2025SHFZ043)High-level Talents Project of Hainan Provincial Natural Science Foundation(No.825RC763)。
文摘In order to explore the complex interaction between H_(2)S and the development of related diseases,it is urgently necessary to develop effective visualization methods to monitor the dynamic changes of H_(2)S in real time.Herein,we constructed the NIR fluorescent probe HCy-SSPy based on disulfide cleavage for the rapid imaging of H_(2)S.The hemicyanine(HCy-NH_(2))unit was used as a NIR fluorophore,and asymmetric pyridyl disulfides(SSPy)acted as the specific recognition receptor for H_(2)S.The synthesized HCy-SSPy showed a remarkable NIR turn-on signal at 765 nm activated by H_(2)S.This probe also possessed excellent selectivity and high sensitivity,as well as rapid detection ability for H_(2)S(-5s).Moreover,the low cytotoxicity,mitochondrial localization,and excellent cell imaging performance of HCy-SSPy were discussed.Further biological experiments revealed that the probe not only imaged H_(2)S in tumor-bearing mice but also showed great potential for H_(2)S detection in inflammatory processes.
基金supported by grants from the National Institutes of Health [grant numbers RF1AG55549, R01NS107265, RO1AG062135, AG59093, AG072899, UG3/ UH3NS 113776, all to Eugenia Trushina, USA]。
文摘Alzheimer’s disease(AD),the most prominent form of dementia in the elderly,has no cure.Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials.Novel therapeutic targets and strategies are urgently needed.Emerging data suggest that in response to environmental stress,mitochondria initiate an integrated stress response(ISR)shown to be beneficial for healthy aging and neuroprotection.Here,we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR.Specifically,partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions,including AD,with several small molecules being tested in clinical trials.We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach.Since this strategy has also been shown to enhance health and life span,the development of safe and efficacious complex Ⅰ inhibitors could promote healthy aging,delaying the onset of age-related neurodegenerative diseases.
基金supported by the National Key Basic Research Program of China (2013CB531100 to Yi-Han Chen)the Major International Joint Research Program of China (81120108004 to Yi-Han Chen)+3 种基金the Key Program of National Natural Science Foundation of China (81530017 to Yi-Han Chen)the National Innovative Research Groups Program of the National Natural Science Foundation of China (81221001 to Yi-Han Chen)the General Program of National Natural Science Foundation of China (81170224, 81270313 to Jun Li, 31271214 to Yi-Han Chen)the National Natural Science Foundation of China (81670295 to Li Lin)
文摘Cardiac arrhythmias are among the most common causes of death in the world. Foundational studies established the critical role of ion channel disorders in arrhythmias, yet defects in ion channels themselves, such as mutations, may not account for all arrhythmias. Despite the progress made in recent decades, the antiarrhythmic drugs currently available have limited effectiveness,and the majority of these drugs can have proarrhythmic effects. This review describes novel knowledge on cellular mechanisms that cause cardiac arrhythmias, focuses on the dysfunction of subcellular organelles and intracellular logistics, and discusses potential strategies and challenges for developing novel, safe and effective treatments for arrhythmias.
