The occurrence and progression of liver cancer are closely associated with mitochondrial dysfunction.Mitochondria exhibit characteristics,such as decreased oxidative phosphorylation efficiency,abnormal accumulation of...The occurrence and progression of liver cancer are closely associated with mitochondrial dysfunction.Mitochondria exhibit characteristics,such as decreased oxidative phosphorylation efficiency,abnormal accumulation of reactive oxygen species in liver cancer and promoting tumor proliferation and drug resistance through the Warburg effect,as the core of energy metabolism and apoptosis regulation.Mutations in mitochondrial DNA(mtDNA)and dysregulation of mitochondrial autophagy(mitophagy)further enhance the invasive and metastatic capabilities of liver cancer.Current targeted therapeutic strategies focus on modulating the activity of respiratory chain complexes,regulating calcium homeostasis,repairing mtDNA,and activating mitochondrial apoptotic pathways.Although these approaches have shown therapeutic effects,challenges persist,such as tumor heterogeneity,insufficient drug specificity,and drug resistance.Future research needs to integrate the concept of precision medicine by focusing on breakthroughs in the molecular mechanisms underlying mitochondrial dysfunction,development of targeted delivery systems,optimization of combination therapy regimens,and screening of biomarkers to provide new pathways for individualized treatment.With advances in technology,targeting mitochondrial dysfunction is expected to become an important breakthrough for improving the prognosis of liver cancer.展开更多
Oxidation of self-stored carbohydrates and lipids provides the energy for the rapid morphogenetic transformation during asexual and infection-related development in Pyricularia oryzae,which results in intracellular ac...Oxidation of self-stored carbohydrates and lipids provides the energy for the rapid morphogenetic transformation during asexual and infection-related development in Pyricularia oryzae,which results in intracellular accumulation of reducing equivalents NADH and FADH_(2),requiring a cytosolic shuttling machinery towards mitochondria.Our previous studies identified the mitochondrial D-lactate dehydrogenase MoDld1 as a regulator to channel the metabolite flow in conjunction with redox homeostasis.However,the regulator(s)facilitating the cytosolic redox balance and the importance in propelling nutrient metabolite flow remain unknown.The G-3-P shuttle is a conserved machinery transporting the cytosolic reducing power to mitochondria.In P.oryzae,the mitochondrial G-3-P dehydrogenase Gpd2 was required for cellular NAD^(+)/NADH balance and fungal virulence.In this study,we relocate the mitochondrial G-3-P dehydrogenase Gpd2 to the cytosol for disturbing cytosolic redox status.Our results showed overexpression of cytosolic gpd2^(Δmts)without the mitochondrial targeted signal(MTS)driven by Ribosomal protein 27 promoter(PR27)exerted conflicting regulation of cellular oxidoreductase activities compared to theΔModld1 deletion mutant by RNA-seq and prevented the conidiation and pathogenicity of P.oryzae.Moreover,overexpression of gpd2^(Δmts)caused defects in glycogen and lipid mobilization underlying asexual and infectious structural development associated with decreased cellular NADH production and weakened anti-oxidation activities.RNA-seq and non-targeted metabolic profiling revealed down-regulated transcriptional activities of carbohydrate metabolism and lower abundance of fatty acids and secondary metabolites in RP27:gpd2^(Δmts).Thus,our studies indicate the essential role of cytosolic redox control in nutrient metabolism fueling the asexual and infection-related development in P.oryzae.展开更多
Mitochondria play a crucial role in maintaining the normal physiological state of cells.Hence,ensuring mitochondrial quality control is imperative for the prevention and treatment of numerous diseases.Previous reviews...Mitochondria play a crucial role in maintaining the normal physiological state of cells.Hence,ensuring mitochondrial quality control is imperative for the prevention and treatment of numerous diseases.Previous reviews on this topic have however been inconsistencies and lack of systematic organization.Therefore,this review aims to provide a comprehensive and systematic overview of mitochondrial quality control and explore the possibility of targeting the same for the treatment of major diseases.This review systematically summarizes three fundamental characteristics of mitochondrial quality control,including mitochondrial morphology and dynamics,function and metabolism,and protein expression and regulation.It also extensively examines how imbalances in mitochondrial quality are linked to major diseases,such as ischemia-hypoxia,inflammatory disorders,viral infections,metabolic dysregulations,degenerative conditions,and tumors.Additionally,the review explores innovative approaches to target mitochondrial quality control,including using small molecule drugs that regulate critical steps in maintaining mitochondrial quality,nanomolecular materials designed for precise targeting of mitochondria,and novel cellular therapies,such as vesicle therapy and mitochondrial transplantation.This review offers a novel perspective on comprehending the shared mechanisms underlying the occurrence and progression of major diseases and provides theoretical support and practical guidance for the clinical implementation of innovative therapeutic strategies that target mitochondrial quality control for treating major diseases.展开更多
Iron-sulfur clusters(ISC)are essential cofactors for proteins involved in various biological processes,such as electron transport,biosynthetic reactions,DNA repair,and gene expression regulation.ISC assembly protein I...Iron-sulfur clusters(ISC)are essential cofactors for proteins involved in various biological processes,such as electron transport,biosynthetic reactions,DNA repair,and gene expression regulation.ISC assembly protein IscA1(or MagR)is found within the mitochondria of most eukaryotes.Magnetoreceptor(MagR)is a highly conserved A-type iron and iron-sulfur cluster-binding protein,characterized by two distinct types of iron-sulfur clusters,[2Fe-2S]and[3Fe-4S],each conferring unique magnetic properties.MagR forms a rod-like polymer structure in complex with photoreceptive cryptochrome(Cry)and serves as a putative magnetoreceptor for retrieving geomagnetic information in animal navigation.Although the N-terminal sequences of MagR vary among species,their specific function remains unknown.In the present study,we found that the N-terminal sequences of pigeon MagR,previously thought to serve as a mitochondrial targeting signal(MTS),were not cleaved following mitochondrial entry but instead modulated the efficiency with which iron-sulfur clusters and irons are bound.Moreover,the N-terminal region of MagR was required for the formation of a stable MagR/Cry complex.Thus,the N-terminal sequences in pigeon MagR fulfil more important functional roles than just mitochondrial targeting.These results further extend our understanding of the function of MagR and provide new insights into the origin of magnetoreception from an evolutionary perspective.展开更多
Insulin resistance is an important feature of type 2 diabetes and obesity. The underlying mechanisms of insulin resistance are still unclear. Mitochondrial dysfunction,
Focal ischemic stroke（FIS）results from the lack of blood flow in a particular region of the brain and accounts for about 80%of all human strokes.Although tremendous efforts have been made in translational research,t...Focal ischemic stroke（FIS）results from the lack of blood flow in a particular region of the brain and accounts for about 80%of all human strokes.Although tremendous efforts have been made in translational research,the treatment strategies are still limited.Tissue plasminogen activator is the only FDA-approved drug currently available for acute stroke treatment,展开更多
The purpose of this article is to review current literature and data regarding treatment options for age-related macular degeneration(AMD)related to mitochondrial therapy.This article considers the presence of flavopr...The purpose of this article is to review current literature and data regarding treatment options for age-related macular degeneration(AMD)related to mitochondrial therapy.This article considers the presence of flavoprotein fluorescence as a potential biomarker to test the effectiveness of the treatments.We focus primarily on two major mitochondrial targets,nuclear factor erythroid 2-related factor(NFE2L2)and PGC-1α,that function in controlling the production and effects of reactive oxidative species(ROS)directly in the mitochondria.PU-91 is an FDA approved drug that directly targets and upregulates PGC-1αin AMD cybrid cell lines.Although neither NFE2L2 nor PGC1-αhave yet been tested in clinical trials,their effects have been studied in rodent models and offer promising results.MTP-131,or elamipretide®,and metformin are two drugs in phase II clinical trials that focus on the treatment of advanced,non-exudative AMD.MTP-131 functions by associating with cardiolipin(CL)whereas metformin targets adenosine-monophosphate protein kinase(AMPK)in the mitochondria.The current results of their clinical trials are elucidated in this article.The molecular targets and drugs reviewed in this article show promising results in the treatment of AMD.These targets can be further pursued to improve and refine treatment practices of this diagnosis.展开更多
Parkinson＇s disease （PD） is a progressive neurodegenerative disease, which is generally considered a multifactorial disorder that arises owing to a combination of genes and environmental factors. While most cases a...Parkinson＇s disease （PD） is a progressive neurodegenerative disease, which is generally considered a multifactorial disorder that arises owing to a combination of genes and environmental factors. While most cases are idiopathic, in about 10% of the patients a genetic cause can be detected, ascribable to mutations in more than a dozen genes. PD is characterized clinically by tremor, rigidity, reduced mo- tor activity （bradykinesia）, and postural instability and pathological- ly by loss of dopaminergic （DA） neurons in the substantia nigra pars compacta, loss of DA innervation in the striatum, and the presence of a-synuclein positive aggregates in the form of Lewy bodies. The symptomatic treatment of PD with levodopa, which aims at replac- ing dopamine, remains the gold standard, and no neuroprotective or disease-modifying therapy is available. During treatment, the disease continues to progress, and long-term use of levodopa has import- ant limitations including motor complications termed dyskinesias. Therefore, a pharmacological therapy able to prevent or halt the neu- rodegenerative process is urgently required.展开更多
The accurate delivery of nanoparticles and organic small molecule drugs remains a serious challenge in nanoparticle-based tumor therapy.Dual-targeted therapy combining tumor cell targeting and organelle targeting is a...The accurate delivery of nanoparticles and organic small molecule drugs remains a serious challenge in nanoparticle-based tumor therapy.Dual-targeted therapy combining tumor cell targeting and organelle targeting is an effective solution.Here,an anticancer nanoformulation accurate delivery system was prepared using hyaluronic acid (HA) targeting CD44 receptors on the surface of tumor cells and IR780iodine (IR780) targeting mitochondrial for delivery.The system is based on an ultra-small Janus structured inorganic sensitizer TiO_(2-x)@NaGdF_(4) nanoparticles (TN NPs) prepared by one-step pyrolysis,further loaded with organic small molecule acoustic sensitizer IR780 and mitochondrial hexokinase Ⅱ inhibitor lonidamine (LND),followed by encapsulation of HA.Ultra-small size nanoparticles exhibit strong tissue penetration,tumor inhibition and in vivo metabolism.Under ultrasound radiation,TN NPs and IR780could produce a synergistic effect,effectively increased the efficiency of reactive oxygen species (ROS)production.Meanwhile,the released IR780 could smoothly target the mitochondria,and the ROS produced by IR780 can destroy the mitochondrial structure and disrupt the mitochondrial respiration.LND could inhibit the energy metabolism of tumor cells by reducing the activity of hexokinase Ⅱ (HK Ⅱ),which further accelerates the process of apoptosis.Furthermore,since the Janus structure allows the integration of multifunctional components into a single system,TN NPs can not only serve as an acoustic sensitizer to generate ROS,but the Gd element contained can also act as the nuclear magnetic resonance (MR)imaging contrast agent,suggesting that the nanoformulation can enable imaging-guided diagnosis and therapy.In conclusion,a new scheme to enhance sonodynamic therapy (SDT) and chemotherapy synergistically is proposed here based on ultra-small dual-targeted nanoformulation with Janus structure in the ultrasound radiation environment.展开更多
Nanotechnology has changed the entire paradigm of drug targeting and has shown tremendous potential in the area of cancer therapy due to its specificity. In cancer, several targets have been explored which could be ut...Nanotechnology has changed the entire paradigm of drug targeting and has shown tremendous potential in the area of cancer therapy due to its specificity. In cancer, several targets have been explored which could be utilized for the better treatment of disease. Mitochondria, the so-called powerhouse of cell, portrays significant role in the survival and death of cells, and has emerged as potential target for cancer therapy. Direct targeting and nanotechnology based approaches can be tailor-made to target mitochondria and thus improve the survival rate of patients suffering from cancer. With this backdrop, in present review, we have reemphasized the role of mitochondria in cancer progression and inhibition, highlighting the different targets that can be explored for targeting of disease. Moreover, we have also summarized different nanoparticulate systems that have been used for treatment of cancer via mitochondrial targeting.展开更多
Carbon dots(CDs), a new building unit, have been revolutionizing the fields of biomedicine, bioimaging, and optoelectronics with their excellent physical, chemical, and biological properties. However, the difficulty o...Carbon dots(CDs), a new building unit, have been revolutionizing the fields of biomedicine, bioimaging, and optoelectronics with their excellent physical, chemical, and biological properties. However, the difficulty of preparing excitation-dependent full-spectrum fluorescent CDs has seriously hindered their further research in fluorescence emission mechanisms and biomedicine. Here, we report full-spectrum fluorescent CDs that exhibit controlled emission changes from purple(380 nm) to red(613 nm) at room temperature by changing the excitation wavelength, and the excitation dependence was closely related to the regulation of sp2 and sp3 hybrid carbon structures by β-cyclodextrin-related groups. In addition,by regulating the content of β-cyclodextrin, the optimal quantum yields of full-spectrum fluorescent CDs were 8.97%, 8.35%, 7.90%, 9.69% and 17.4% at the excitation wavelengths of 340, 350, 390, 410 and 540 nm,respectively. Due to their excellent biocompatibility and color tunability, full-spectrum fluorescent CDs emitted bright and steady purple, blue, green, yellow, and red fluorescence in MCF-7 cells. Moreover, we optimized the imaging conditions of CDs and mitochondrial-specific dyes;and realized the mitochondrialtargeted co-localization imaging of purple, blue and green fluorescence. After that, we also explored the effect of full-spectrum fluorescent CDs in vivo fluorescence imaging through the intratumorally, subcutaneously, and caudal vein, and found that full-spectrum fluorescent CDs had good fluorescence imaging ability in vivo.展开更多
Oxidative stress injury and mitochondrial dysfunction are major obstacles to neurological functional recovery after ischemic stroke.The development of new approaches to simultaneously diminish oxidative stress and res...Oxidative stress injury and mitochondrial dysfunction are major obstacles to neurological functional recovery after ischemic stroke.The development of new approaches to simultaneously diminish oxidative stress and resist mitochondrial dysfunction is urgently needed.Inspired by the overproduced reactive oxygen species(ROS)at ischemic neuron mitochondria,multifunctional nanoparticles with ROS-responsiveness and mitochondrial-targeted(SPNPs)were engineered,achieving specific targeting delivery and controllable drug release at ischemic penumbra.Due to the nose-to-brain pathway.SPNPs which were encapsulated in a thermo-sensitive gel by intranasal administration were directly delivered to the ischemic penumbra bypassing the blood-brain barrier(BBB)and enhancing delivery efficiency.The potential of SPNPs for ischemic stroke treatment was systematically evaluated in vitro and in rat models of middle cerebral artery occlusion(MCAO).Results demonstrated the mitochondrialtargeted and protective effects of SPNPs on H2O2-induced oxidative damage in SH-SY5Y cells.In vivo distribution analyzed by fuorescence imaging proved the rapid and enhanced active targeting of SPNPs to the ischemic area in MCAO rats.SPNPs by intranasal administration exhibited superior therapeutic efficacy by alleviating oxidative stress,diminishing infammation,repairing mitochondrial function,and decreasing apoptosis.This strategy provided a multifunctional delivery system for the effective treatment of ischemic injury,which also implies a potential application prospect for other central nervous diseases.展开更多
Heterocyclic compound quinoline and its derivatives exist in natural compounds and have a broad spectrum of biological activity.They play an important role in the design of new structural entities for medical applicat...Heterocyclic compound quinoline and its derivatives exist in natural compounds and have a broad spectrum of biological activity.They play an important role in the design of new structural entities for medical applications.Similarly,indoles and their derivatives are found widely in nature.Amino acids,alkaloids and auxin are all derivatives of indoles,as are dyes,and their condensation with aldehydes makes it easy to construct reaction sites for nucleophilic addition agents.In this work,we combine these two groups organically to construct a rapid response site(within 30 s)for H_(2)S,and at the same time,a ratiometric fluorescence response is presented throughout the process of H_(2)S detection.As such,the lower detection limit can reach 55.7 nmol/L for H_(2)S.In addition,cell imaging shows that this probe can be used for the mitochondrial targeted detection of endogenous and exogenous H_(2)S.Finally,this probe application was verified by imaging H_(2)S in nude mice.展开更多
Mitochondrial disease was a clinically and genetically heterogeneous group of diseases, thus the diagnosis was very difficult to clinicians. Our objective was to analyze clinical and genetic characteristics of childre...Mitochondrial disease was a clinically and genetically heterogeneous group of diseases, thus the diagnosis was very difficult to clinicians. Our objective was to analyze clinical and genetic characteristics of children with mitochondrial disease in China. We tested 141 candidate patients who have been suspected of mitochondrial disorders by using targeted next-generation sequencing(NGS), and summarized the clinical and genetic data of gene confirmed cases from Neurology Department, Beijing Children's Hospital, Capital Medical University from October 2012 to January 2015. In our study, 40 cases of gene confirmed mitochondrial disease including eight kinds of mitochondrial disease, among which Leigh syndrome was identified to be the most common type, followed by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes(MELAS). The age-of-onset varies among mitochondrial disease, but early onset was common. All of 40 cases were gene confirmed, among which 25 cases(62.5%)with mitochondrial DNA(mtDNA) mutation, and 15 cases(37.5%) with nuclear DNA(nDNA) mutation. M.3243A>G(n=7)accounts for a large proportion of mtDNA mutation. The nDNA mutations include SURF1(n=7),PDHA1(n=2),and NDUFV1,NDUFAF6, SUCLA2, SUCLG1, RRM2 B, and C12orf65, respectively.展开更多
Organelle-targeted imaging can provide information on cellular functions and intracellular interactions,being significant for disease diagnosis.The use of room-temperature phosphorescence(RTP)in organelle-targeted ima...Organelle-targeted imaging can provide information on cellular functions and intracellular interactions,being significant for disease diagnosis.The use of room-temperature phosphorescence(RTP)in organelle-targeted imaging can fully utilize its unique characteristics of long wavelength and deep penetration.However,this technology has long been plagued by insufficient probe targeting and limited luminous intensity.In this work,we prepared a series of complexes composed of multicationic persulfurated arenes and biomacromolecules via electrostatic interactions in 1:1 stoichiometry for high-contrast mitochondrial-targeted RTP imaging.Such an electrostatic interaction design effectively prevented the self-aggregation of the probes,which is not conducive to mitochondrial targeting.Simultaneously,it suppressed the non-radiative decay to the maximum extent,enabling the probes to exhibit strong RTP signals both in aqueous solution and at the cellular level.Furthermore,the biomacromolecules can serve as carriers for an electrostatic interaction transfer of the persulfurated arenes to mitochondria.This leads to high mitochondrial targeting Pearson's correlation coefficients of the probes and high-contrast RTP imaging effects,as well as the independence of the co-incubated probe concentration.These results provide new insights for the development of targeted imaging technologies.展开更多
The mitochondrion is a promising target for diagnosis and therapy. Mitochondrial-targeting silica-coated manganese oxide nanoparticles(Mn O@Si O2-PPh3+ NPs) were successfully synthesized to explore the mitochondrial c...The mitochondrion is a promising target for diagnosis and therapy. Mitochondrial-targeting silica-coated manganese oxide nanoparticles(Mn O@Si O2-PPh3+ NPs) were successfully synthesized to explore the mitochondrial cytotoxicity of nanoparticles. The mitochondrial targeting property was confirmed by a laser scanning confocal microscopy experiment. Even after incubation for only 4 h, the cytotoxicity of Mn O@Si O2-PPh3+ NPs against cancer cells was obvious; the ATP content was significantly decreased to 40%; and the mitochondrial membrane potential was depleted. All of these results indicated the collapse of mitochondrial function and the start of a cell apoptosis pathway. Our findings suggest that mitochondrial-mediated apoptosis could be strengthened by targeting to the subcellular compartment.展开更多
Reduction of endogenous hydrogen sulfide(H_(2)S)is considered to have an important impact on the progress of Parkinson’s disease(PD),thus exogenous H_(2)S supplementation is expected to become one of the key means to...Reduction of endogenous hydrogen sulfide(H_(2)S)is considered to have an important impact on the progress of Parkinson’s disease(PD),thus exogenous H_(2)S supplementation is expected to become one of the key means to treat PD.However,at present,it is difficult for H_(2)S donors to effectively penetrate the blood brain barrier(BBB),selectively release H_(2)S in brain,and effectively target the mitochondria of neuron cells.Herein,we report a kind of nanomotor-based H_(2)S donor,which is obtained by free radical polymerization reaction between L-cysteine derivative modified-polyethylene glycol(PEG-Cys)and 2-methacryloyloxyethyl phosphorylcholine(MPC).This kind of H_(2)S donor can not only effectively break through BBB,but also be specifically catalyzed by cystathionineβ-synthase(CBS)in neurons of PD site in brain and 3-mercaptopyruvate sulfurtransferase(3-MST)in mitochondria to produce H_(2)S,endowing it with chemotaxis/motion ability.Moreover,the unique chemotaxis effect of nanomotor can realize the purpose of precisely targeting brain and the mitochondria of damaged neuron cytopathic diseases.This kind of nanomotor-based H_(2)S donor is expected to enrich the current types of H_(2)S donors and provide new ideas for the treatment of PD.展开更多
Photodynamic therapy (PDT) has been attracted a surge of research interest. However, there are several obstacles to limit the efficacy of PDT, such as hypoxic tumor microenvironment (TME), overexpressed glutathione (G...Photodynamic therapy (PDT) has been attracted a surge of research interest. However, there are several obstacles to limit the efficacy of PDT, such as hypoxic tumor microenvironment (TME), overexpressed glutathione (GSH), inefficient reactive oxygen species (ROS) generation, and so on. Herein, a smart responsive nanosystem was constructed, which was composed of Au25 modified with triphenylphosphine (Au25-TPP), catalase (CAT) and GSH-responsive diselenide-bridged mesoporous silica nanoparticles (Se-MSN). When the nanosystem arrived at tumor site, Se-MSN was degraded by the intracellular overexpressed GSH to release Au25-TPP and CAT. The Au25-TPP was targeted to mitochondria and generated ROS under the 808 nm NIR laser irradiation to kill tumor cells. Simultaneously, CAT could catalyze hydrogen peroxide to provide oxygen for relieving the hypoxia of TME. Besides, GSH was consumed by the diselenide bond to diminish the ROS loss. The above tactics (mitochondria targeting, hypoxia relieving and GSH consuming) jointly enhanced the PDT efficacy. The nanosystem showed distinct in vitro anticancer effect significantly stronger than other groups containing one or two assistance. Moreover, the in vivo results suggested that the tumors could be restrained obviously. The current study provides a new inspiration for constructing novel inorganic nanomedicines with multiple enhancement effect of PDT efficacy.展开更多
Incorporation of multiple functions into one nanoplatform can improve cancer diagnostic efficacy and enhance anti-cancer outcomes. Here, we constructed doxorubicin(DOX)-loaded silk fibroinbased nanoparticles(NPs) with...Incorporation of multiple functions into one nanoplatform can improve cancer diagnostic efficacy and enhance anti-cancer outcomes. Here, we constructed doxorubicin(DOX)-loaded silk fibroinbased nanoparticles(NPs) with surface functionalization by photosensitizer(N770). The obtained nanotheranostics(N770-DOX@NPs) had desirable particle size(157 nm) and negative surface charge(-25 m V). These NPs presented excellent oxygen-generating capacity and responded to a quadruple of stimuli(acidic solution, reactive oxygen species, glutathione, and hyperthermia). Surface functionalization of DOX@NPs with N770 could endow them with active internalization by cancerous cell lines, but not by normal cells. Furthermore, the intracellular NPs were found to be preferentially retained in mitochondria, which were also efficient for near-infrared(NIR) fluorescence imaging, photothermal imaging,and photoacoustic imaging. Meanwhile, DOX could spontaneously accumulate in the nucleus. Importantly, a mouse test group treated with N770-DOX@NPs plus NIR irradiation achieved the best tumorretardation effect among all treatment groups based on tumor-bearing mouse models and a patientderived xenograft model, demonstrating the unprecedented therapeutic effects of trimodal imagingguided mitochondrial phototherapy(photothermal therapy and photodynamic therapy) and chemotherapy.Therefore, the present study brings new insight into the exploitation of an easy-to-use, versatile, and robust nanoplatform for programmable targeting, imaging, and applying synergistic therapy to tumors.展开更多
Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted d...Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted delivery of doxorubicin(DOX) massively amplified ICD via substantial generation of reactive oxygen species(ROS) after mitochondrial damage. The underlying mechanism behind increased ICD was further demonstrated to be ascribed to two pathways:(1) ROS elevated endoplasmic reticulum(ER) stress, leading to surface exposure of calreticulin;(2) ROS promoted release of various mitochondriaassociated damage molecules including mitochondrial transcription factor A. Nevertheless, adaptive upregulation of PD-L1 was found after such ICD-inducing treatment. To overcome such immunosuppressive feedback,we developed a tumor stimuli-responsive nano vehicle to simultaneously exert mitochondrial targeted ICD induction and PD-L1 blockade. The nano vehicle was self-assembled from ICD-inducing copolymer and PD-L1 blocking copolymer, and possessed long-circulating property which contributed to better tumor accumulation and mitochondrial targeting. As a result, the nano vehicle remarkably activated antitumor immune responses and exhibited robust antitumor efficacy in both immunogenic and non-immunogenic tumor mouse models.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.81860653)Qiankehe Foundation[Grant No.QN(2025)383].
文摘The occurrence and progression of liver cancer are closely associated with mitochondrial dysfunction.Mitochondria exhibit characteristics,such as decreased oxidative phosphorylation efficiency,abnormal accumulation of reactive oxygen species in liver cancer and promoting tumor proliferation and drug resistance through the Warburg effect,as the core of energy metabolism and apoptosis regulation.Mutations in mitochondrial DNA(mtDNA)and dysregulation of mitochondrial autophagy(mitophagy)further enhance the invasive and metastatic capabilities of liver cancer.Current targeted therapeutic strategies focus on modulating the activity of respiratory chain complexes,regulating calcium homeostasis,repairing mtDNA,and activating mitochondrial apoptotic pathways.Although these approaches have shown therapeutic effects,challenges persist,such as tumor heterogeneity,insufficient drug specificity,and drug resistance.Future research needs to integrate the concept of precision medicine by focusing on breakthroughs in the molecular mechanisms underlying mitochondrial dysfunction,development of targeted delivery systems,optimization of combination therapy regimens,and screening of biomarkers to provide new pathways for individualized treatment.With advances in technology,targeting mitochondrial dysfunction is expected to become an important breakthrough for improving the prognosis of liver cancer.
基金funded by the National Natural Science Foundation of China(32272513 and 31770156)the Natural Sciences and Engineering Research Council of Canada(Discovery Grant,RGPIN-2016-05356)the Canadian Foundation for Innovation(Discovery Grant,227398-2011)。
文摘Oxidation of self-stored carbohydrates and lipids provides the energy for the rapid morphogenetic transformation during asexual and infection-related development in Pyricularia oryzae,which results in intracellular accumulation of reducing equivalents NADH and FADH_(2),requiring a cytosolic shuttling machinery towards mitochondria.Our previous studies identified the mitochondrial D-lactate dehydrogenase MoDld1 as a regulator to channel the metabolite flow in conjunction with redox homeostasis.However,the regulator(s)facilitating the cytosolic redox balance and the importance in propelling nutrient metabolite flow remain unknown.The G-3-P shuttle is a conserved machinery transporting the cytosolic reducing power to mitochondria.In P.oryzae,the mitochondrial G-3-P dehydrogenase Gpd2 was required for cellular NAD^(+)/NADH balance and fungal virulence.In this study,we relocate the mitochondrial G-3-P dehydrogenase Gpd2 to the cytosol for disturbing cytosolic redox status.Our results showed overexpression of cytosolic gpd2^(Δmts)without the mitochondrial targeted signal(MTS)driven by Ribosomal protein 27 promoter(PR27)exerted conflicting regulation of cellular oxidoreductase activities compared to theΔModld1 deletion mutant by RNA-seq and prevented the conidiation and pathogenicity of P.oryzae.Moreover,overexpression of gpd2^(Δmts)caused defects in glycogen and lipid mobilization underlying asexual and infectious structural development associated with decreased cellular NADH production and weakened anti-oxidation activities.RNA-seq and non-targeted metabolic profiling revealed down-regulated transcriptional activities of carbohydrate metabolism and lower abundance of fatty acids and secondary metabolites in RP27:gpd2^(Δmts).Thus,our studies indicate the essential role of cytosolic redox control in nutrient metabolism fueling the asexual and infection-related development in P.oryzae.
基金supported by the National Natural Science Foundation of China (82272252 and 82372192)the Senior Medical Talents Program of Chongqing for Young and Middle-AgedKuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University
文摘Mitochondria play a crucial role in maintaining the normal physiological state of cells.Hence,ensuring mitochondrial quality control is imperative for the prevention and treatment of numerous diseases.Previous reviews on this topic have however been inconsistencies and lack of systematic organization.Therefore,this review aims to provide a comprehensive and systematic overview of mitochondrial quality control and explore the possibility of targeting the same for the treatment of major diseases.This review systematically summarizes three fundamental characteristics of mitochondrial quality control,including mitochondrial morphology and dynamics,function and metabolism,and protein expression and regulation.It also extensively examines how imbalances in mitochondrial quality are linked to major diseases,such as ischemia-hypoxia,inflammatory disorders,viral infections,metabolic dysregulations,degenerative conditions,and tumors.Additionally,the review explores innovative approaches to target mitochondrial quality control,including using small molecule drugs that regulate critical steps in maintaining mitochondrial quality,nanomolecular materials designed for precise targeting of mitochondria,and novel cellular therapies,such as vesicle therapy and mitochondrial transplantation.This review offers a novel perspective on comprehending the shared mechanisms underlying the occurrence and progression of major diseases and provides theoretical support and practical guidance for the clinical implementation of innovative therapeutic strategies that target mitochondrial quality control for treating major diseases.
基金supported by the National Natural Science Foundation of China(31640001 and T2350005 to C.X.,U21A20148 to X.Z.and C.X.)Ministry of Science and Technology of China(2021ZD0140300 to C.X.)+2 种基金Natural Science Foundation of Hainan Province(No.822RC703 for J.L.)Foundation of Hainan Educational Committee(No.Hnky2022-27 for J.L.)Presidential Foundation of Hefei Institutes of Physical Science,Chinese Academy of Sciences(Y96XC11131,E26CCG27,and E26CCD15 to C.X.,E36CWGBR24B and E36CZG14132 to T.C.)。
文摘Iron-sulfur clusters(ISC)are essential cofactors for proteins involved in various biological processes,such as electron transport,biosynthetic reactions,DNA repair,and gene expression regulation.ISC assembly protein IscA1(or MagR)is found within the mitochondria of most eukaryotes.Magnetoreceptor(MagR)is a highly conserved A-type iron and iron-sulfur cluster-binding protein,characterized by two distinct types of iron-sulfur clusters,[2Fe-2S]and[3Fe-4S],each conferring unique magnetic properties.MagR forms a rod-like polymer structure in complex with photoreceptive cryptochrome(Cry)and serves as a putative magnetoreceptor for retrieving geomagnetic information in animal navigation.Although the N-terminal sequences of MagR vary among species,their specific function remains unknown.In the present study,we found that the N-terminal sequences of pigeon MagR,previously thought to serve as a mitochondrial targeting signal(MTS),were not cleaved following mitochondrial entry but instead modulated the efficiency with which iron-sulfur clusters and irons are bound.Moreover,the N-terminal region of MagR was required for the formation of a stable MagR/Cry complex.Thus,the N-terminal sequences in pigeon MagR fulfil more important functional roles than just mitochondrial targeting.These results further extend our understanding of the function of MagR and provide new insights into the origin of magnetoreception from an evolutionary perspective.
文摘Insulin resistance is an important feature of type 2 diabetes and obesity. The underlying mechanisms of insulin resistance are still unclear. Mitochondrial dysfunction,
基金supported by NIH NS069726 and NS094539America Heart Association 13GRANT17020004(to SD)
文摘Focal ischemic stroke（FIS）results from the lack of blood flow in a particular region of the brain and accounts for about 80%of all human strokes.Although tremendous efforts have been made in translational research,the treatment strategies are still limited.Tissue plasminogen activator is the only FDA-approved drug currently available for acute stroke treatment,
文摘The purpose of this article is to review current literature and data regarding treatment options for age-related macular degeneration(AMD)related to mitochondrial therapy.This article considers the presence of flavoprotein fluorescence as a potential biomarker to test the effectiveness of the treatments.We focus primarily on two major mitochondrial targets,nuclear factor erythroid 2-related factor(NFE2L2)and PGC-1α,that function in controlling the production and effects of reactive oxidative species(ROS)directly in the mitochondria.PU-91 is an FDA approved drug that directly targets and upregulates PGC-1αin AMD cybrid cell lines.Although neither NFE2L2 nor PGC1-αhave yet been tested in clinical trials,their effects have been studied in rodent models and offer promising results.MTP-131,or elamipretide®,and metformin are two drugs in phase II clinical trials that focus on the treatment of advanced,non-exudative AMD.MTP-131 functions by associating with cardiolipin(CL)whereas metformin targets adenosine-monophosphate protein kinase(AMPK)in the mitochondria.The current results of their clinical trials are elucidated in this article.The molecular targets and drugs reviewed in this article show promising results in the treatment of AMD.These targets can be further pursued to improve and refine treatment practices of this diagnosis.
基金supported by the Ministry of Health and Department of Educational Assistance,University and Research of the Autonomous Province of Bolzano
文摘Parkinson＇s disease （PD） is a progressive neurodegenerative disease, which is generally considered a multifactorial disorder that arises owing to a combination of genes and environmental factors. While most cases are idiopathic, in about 10% of the patients a genetic cause can be detected, ascribable to mutations in more than a dozen genes. PD is characterized clinically by tremor, rigidity, reduced mo- tor activity （bradykinesia）, and postural instability and pathological- ly by loss of dopaminergic （DA） neurons in the substantia nigra pars compacta, loss of DA innervation in the striatum, and the presence of a-synuclein positive aggregates in the form of Lewy bodies. The symptomatic treatment of PD with levodopa, which aims at replac- ing dopamine, remains the gold standard, and no neuroprotective or disease-modifying therapy is available. During treatment, the disease continues to progress, and long-term use of levodopa has import- ant limitations including motor complications termed dyskinesias. Therefore, a pharmacological therapy able to prevent or halt the neu- rodegenerative process is urgently required.
基金financially supported by the National Natural Science Foundation of China (Nos. 52250077, 52272156, 51872263 and 52202175)Taishan Scholars Project (No. ts20190911)+1 种基金Shandong Natural Science Foundation (No. ZR2020ZD36)Guangdong Basic and Applied Basic Research Foundation (No. 2022A1515010461)。
文摘The accurate delivery of nanoparticles and organic small molecule drugs remains a serious challenge in nanoparticle-based tumor therapy.Dual-targeted therapy combining tumor cell targeting and organelle targeting is an effective solution.Here,an anticancer nanoformulation accurate delivery system was prepared using hyaluronic acid (HA) targeting CD44 receptors on the surface of tumor cells and IR780iodine (IR780) targeting mitochondrial for delivery.The system is based on an ultra-small Janus structured inorganic sensitizer TiO_(2-x)@NaGdF_(4) nanoparticles (TN NPs) prepared by one-step pyrolysis,further loaded with organic small molecule acoustic sensitizer IR780 and mitochondrial hexokinase Ⅱ inhibitor lonidamine (LND),followed by encapsulation of HA.Ultra-small size nanoparticles exhibit strong tissue penetration,tumor inhibition and in vivo metabolism.Under ultrasound radiation,TN NPs and IR780could produce a synergistic effect,effectively increased the efficiency of reactive oxygen species (ROS)production.Meanwhile,the released IR780 could smoothly target the mitochondria,and the ROS produced by IR780 can destroy the mitochondrial structure and disrupt the mitochondrial respiration.LND could inhibit the energy metabolism of tumor cells by reducing the activity of hexokinase Ⅱ (HK Ⅱ),which further accelerates the process of apoptosis.Furthermore,since the Janus structure allows the integration of multifunctional components into a single system,TN NPs can not only serve as an acoustic sensitizer to generate ROS,but the Gd element contained can also act as the nuclear magnetic resonance (MR)imaging contrast agent,suggesting that the nanoformulation can enable imaging-guided diagnosis and therapy.In conclusion,a new scheme to enhance sonodynamic therapy (SDT) and chemotherapy synergistically is proposed here based on ultra-small dual-targeted nanoformulation with Janus structure in the ultrasound radiation environment.
基金the Department of Science and Technology and SERB (INSPIRE Grant no: IFA-LSBM-13 and EMR/2016/007966/HS) for project funds。
文摘Nanotechnology has changed the entire paradigm of drug targeting and has shown tremendous potential in the area of cancer therapy due to its specificity. In cancer, several targets have been explored which could be utilized for the better treatment of disease. Mitochondria, the so-called powerhouse of cell, portrays significant role in the survival and death of cells, and has emerged as potential target for cancer therapy. Direct targeting and nanotechnology based approaches can be tailor-made to target mitochondria and thus improve the survival rate of patients suffering from cancer. With this backdrop, in present review, we have reemphasized the role of mitochondria in cancer progression and inhibition, highlighting the different targets that can be explored for targeting of disease. Moreover, we have also summarized different nanoparticulate systems that have been used for treatment of cancer via mitochondrial targeting.
基金supported by the National Natural Science Foundation of China(No.U2230123)the Science Foundation of the Science and Technology Department of Sichuan Province(No.22ZYZYTS0159)+4 种基金Science Foundation of China University of Petroleum(Nos.2462019QNXZ02,2462019BJRC007)Science Foundation of China University of Petroleum(East China)(No.2462020YXZZ018)Science and Technology Innovation Commission of Shenzhen(No.JSGG20210802153410031)Science and Technology Project of Nanshan District(No.NS_(2)021016)the Scientific Research Startup Fund for Discipline Leader of Huazhong University of Science and Technology Union Shenzhen Hospital(Nanshan Hospital)(No.YN2021002)。
文摘Carbon dots(CDs), a new building unit, have been revolutionizing the fields of biomedicine, bioimaging, and optoelectronics with their excellent physical, chemical, and biological properties. However, the difficulty of preparing excitation-dependent full-spectrum fluorescent CDs has seriously hindered their further research in fluorescence emission mechanisms and biomedicine. Here, we report full-spectrum fluorescent CDs that exhibit controlled emission changes from purple(380 nm) to red(613 nm) at room temperature by changing the excitation wavelength, and the excitation dependence was closely related to the regulation of sp2 and sp3 hybrid carbon structures by β-cyclodextrin-related groups. In addition,by regulating the content of β-cyclodextrin, the optimal quantum yields of full-spectrum fluorescent CDs were 8.97%, 8.35%, 7.90%, 9.69% and 17.4% at the excitation wavelengths of 340, 350, 390, 410 and 540 nm,respectively. Due to their excellent biocompatibility and color tunability, full-spectrum fluorescent CDs emitted bright and steady purple, blue, green, yellow, and red fluorescence in MCF-7 cells. Moreover, we optimized the imaging conditions of CDs and mitochondrial-specific dyes;and realized the mitochondrialtargeted co-localization imaging of purple, blue and green fluorescence. After that, we also explored the effect of full-spectrum fluorescent CDs in vivo fluorescence imaging through the intratumorally, subcutaneously, and caudal vein, and found that full-spectrum fluorescent CDs had good fluorescence imaging ability in vivo.
基金supported by National Natural Science Foundation(82272154,China)Tianjin Science Fund for Distinguished Young Scholars(22JCJQJC00120,China)+2 种基金Natural Science Foundation of Tianjin(The Basic Research Cooperation Special Foundation of Beijing-Tianjin-Hebei Region,H2022205047,22JCZXJC00060,and E3B33911DF,China)the Fundamental Research Funds for the Central Universities(3332021068,,3332020059,2019PT320028,and 2021-RC310-005,China)the CAMS Innovation Fund for Medical Sciences(2021-I2M-1-058,and 2022-I2M-2-003,China).
文摘Oxidative stress injury and mitochondrial dysfunction are major obstacles to neurological functional recovery after ischemic stroke.The development of new approaches to simultaneously diminish oxidative stress and resist mitochondrial dysfunction is urgently needed.Inspired by the overproduced reactive oxygen species(ROS)at ischemic neuron mitochondria,multifunctional nanoparticles with ROS-responsiveness and mitochondrial-targeted(SPNPs)were engineered,achieving specific targeting delivery and controllable drug release at ischemic penumbra.Due to the nose-to-brain pathway.SPNPs which were encapsulated in a thermo-sensitive gel by intranasal administration were directly delivered to the ischemic penumbra bypassing the blood-brain barrier(BBB)and enhancing delivery efficiency.The potential of SPNPs for ischemic stroke treatment was systematically evaluated in vitro and in rat models of middle cerebral artery occlusion(MCAO).Results demonstrated the mitochondrialtargeted and protective effects of SPNPs on H2O2-induced oxidative damage in SH-SY5Y cells.In vivo distribution analyzed by fuorescence imaging proved the rapid and enhanced active targeting of SPNPs to the ischemic area in MCAO rats.SPNPs by intranasal administration exhibited superior therapeutic efficacy by alleviating oxidative stress,diminishing infammation,repairing mitochondrial function,and decreasing apoptosis.This strategy provided a multifunctional delivery system for the effective treatment of ischemic injury,which also implies a potential application prospect for other central nervous diseases.
基金the National Natural Science Foundation of China(Grant Nos.21775096 and 21878180)One hundred people plan of Shanxi Province,Shanxi Province“1331 project”key innovation team construction plan cultivation team(No.2018-CT-1)+7 种基金2018 Xiangyuan County Solid Waste Comprehensive Utilization Science and Technology Project(No.2018XYSDJS-05)Key R&D Program of Shanxi Province(No.201903D421069)the Shanxi Province Science Foundation(No.201901D111015)Shanxi Collaborative Innovation Center of High Valueadded Utilization of Coal-related Wastes(No.2015-10-B3)the Shanxi Province Foundation for Selected Returnee(No.2019),Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi(No.2019L0031)Project of Graduate Innovation of Shanxi Province(No.2020)Key R&D and transformation plan of Qinghai Province(No.2020-GX-101)Scientific Instrument Center of Shanxi University(No.201512).
文摘Heterocyclic compound quinoline and its derivatives exist in natural compounds and have a broad spectrum of biological activity.They play an important role in the design of new structural entities for medical applications.Similarly,indoles and their derivatives are found widely in nature.Amino acids,alkaloids and auxin are all derivatives of indoles,as are dyes,and their condensation with aldehydes makes it easy to construct reaction sites for nucleophilic addition agents.In this work,we combine these two groups organically to construct a rapid response site(within 30 s)for H_(2)S,and at the same time,a ratiometric fluorescence response is presented throughout the process of H_(2)S detection.As such,the lower detection limit can reach 55.7 nmol/L for H_(2)S.In addition,cell imaging shows that this probe can be used for the mitochondrial targeted detection of endogenous and exogenous H_(2)S.Finally,this probe application was verified by imaging H_(2)S in nude mice.
文摘Mitochondrial disease was a clinically and genetically heterogeneous group of diseases, thus the diagnosis was very difficult to clinicians. Our objective was to analyze clinical and genetic characteristics of children with mitochondrial disease in China. We tested 141 candidate patients who have been suspected of mitochondrial disorders by using targeted next-generation sequencing(NGS), and summarized the clinical and genetic data of gene confirmed cases from Neurology Department, Beijing Children's Hospital, Capital Medical University from October 2012 to January 2015. In our study, 40 cases of gene confirmed mitochondrial disease including eight kinds of mitochondrial disease, among which Leigh syndrome was identified to be the most common type, followed by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes(MELAS). The age-of-onset varies among mitochondrial disease, but early onset was common. All of 40 cases were gene confirmed, among which 25 cases(62.5%)with mitochondrial DNA(mtDNA) mutation, and 15 cases(37.5%) with nuclear DNA(nDNA) mutation. M.3243A>G(n=7)accounts for a large proportion of mtDNA mutation. The nDNA mutations include SURF1(n=7),PDHA1(n=2),and NDUFV1,NDUFAF6, SUCLA2, SUCLG1, RRM2 B, and C12orf65, respectively.
基金supported by the National Natural Science Foundation of China(22275038)partially funded by the Swedish Research Council(2022-06725)+1 种基金the support from the Swedish Research Council(2020-04600)funded by the European Union(ERC,LUMOR,101077649)the support from the Swedish Science Research Council(2022-03405)。
文摘Organelle-targeted imaging can provide information on cellular functions and intracellular interactions,being significant for disease diagnosis.The use of room-temperature phosphorescence(RTP)in organelle-targeted imaging can fully utilize its unique characteristics of long wavelength and deep penetration.However,this technology has long been plagued by insufficient probe targeting and limited luminous intensity.In this work,we prepared a series of complexes composed of multicationic persulfurated arenes and biomacromolecules via electrostatic interactions in 1:1 stoichiometry for high-contrast mitochondrial-targeted RTP imaging.Such an electrostatic interaction design effectively prevented the self-aggregation of the probes,which is not conducive to mitochondrial targeting.Simultaneously,it suppressed the non-radiative decay to the maximum extent,enabling the probes to exhibit strong RTP signals both in aqueous solution and at the cellular level.Furthermore,the biomacromolecules can serve as carriers for an electrostatic interaction transfer of the persulfurated arenes to mitochondria.This leads to high mitochondrial targeting Pearson's correlation coefficients of the probes and high-contrast RTP imaging effects,as well as the independence of the co-incubated probe concentration.These results provide new insights for the development of targeted imaging technologies.
基金supported by the National Natural Science Foundation of China(21271130,21371122)the Program for Changjiang Scholars and Innovative Research Team in University(IRT1269)+4 种基金the Shanghai Science and Technology Development Fund(12ZR1421800,13520502800)the Shanghai Pujiang Program(13PJ1406600)the Shanghai Municipal Education Commission(13ZZ110)Shanghai Normal University(SK201339)the International Joint Laboratory on Resource Chemistry
文摘The mitochondrion is a promising target for diagnosis and therapy. Mitochondrial-targeting silica-coated manganese oxide nanoparticles(Mn O@Si O2-PPh3+ NPs) were successfully synthesized to explore the mitochondrial cytotoxicity of nanoparticles. The mitochondrial targeting property was confirmed by a laser scanning confocal microscopy experiment. Even after incubation for only 4 h, the cytotoxicity of Mn O@Si O2-PPh3+ NPs against cancer cells was obvious; the ATP content was significantly decreased to 40%; and the mitochondrial membrane potential was depleted. All of these results indicated the collapse of mitochondrial function and the start of a cell apoptosis pathway. Our findings suggest that mitochondrial-mediated apoptosis could be strengthened by targeting to the subcellular compartment.
基金supported by National Natural Science Foundation of China(No:22175096,No:22275095)Qinglan Project Foundation of Colleges and Universities of Jiangsu Province,Jiangsu Collaborative Innovation Center of Biomedical Functional Materials,Priority Academic Program Development of Jiangsu Higher Education Institution.
文摘Reduction of endogenous hydrogen sulfide(H_(2)S)is considered to have an important impact on the progress of Parkinson’s disease(PD),thus exogenous H_(2)S supplementation is expected to become one of the key means to treat PD.However,at present,it is difficult for H_(2)S donors to effectively penetrate the blood brain barrier(BBB),selectively release H_(2)S in brain,and effectively target the mitochondria of neuron cells.Herein,we report a kind of nanomotor-based H_(2)S donor,which is obtained by free radical polymerization reaction between L-cysteine derivative modified-polyethylene glycol(PEG-Cys)and 2-methacryloyloxyethyl phosphorylcholine(MPC).This kind of H_(2)S donor can not only effectively break through BBB,but also be specifically catalyzed by cystathionineβ-synthase(CBS)in neurons of PD site in brain and 3-mercaptopyruvate sulfurtransferase(3-MST)in mitochondria to produce H_(2)S,endowing it with chemotaxis/motion ability.Moreover,the unique chemotaxis effect of nanomotor can realize the purpose of precisely targeting brain and the mitochondria of damaged neuron cytopathic diseases.This kind of nanomotor-based H_(2)S donor is expected to enrich the current types of H_(2)S donors and provide new ideas for the treatment of PD.
基金financially supported by the National Natural Science Foundation of China(21771058 and 21877027)the Natural Science Foundation of Henan Province(242300421205,212300410009,and 232300421302)+1 种基金the 111 Project(D17007),the Program for Science&Technology Innovation Talents in Universities of Henan Province(23HASTIT002)the Foundation of Henan Educational Committee(23A150021).
文摘Photodynamic therapy (PDT) has been attracted a surge of research interest. However, there are several obstacles to limit the efficacy of PDT, such as hypoxic tumor microenvironment (TME), overexpressed glutathione (GSH), inefficient reactive oxygen species (ROS) generation, and so on. Herein, a smart responsive nanosystem was constructed, which was composed of Au25 modified with triphenylphosphine (Au25-TPP), catalase (CAT) and GSH-responsive diselenide-bridged mesoporous silica nanoparticles (Se-MSN). When the nanosystem arrived at tumor site, Se-MSN was degraded by the intracellular overexpressed GSH to release Au25-TPP and CAT. The Au25-TPP was targeted to mitochondria and generated ROS under the 808 nm NIR laser irradiation to kill tumor cells. Simultaneously, CAT could catalyze hydrogen peroxide to provide oxygen for relieving the hypoxia of TME. Besides, GSH was consumed by the diselenide bond to diminish the ROS loss. The above tactics (mitochondria targeting, hypoxia relieving and GSH consuming) jointly enhanced the PDT efficacy. The nanosystem showed distinct in vitro anticancer effect significantly stronger than other groups containing one or two assistance. Moreover, the in vivo results suggested that the tumors could be restrained obviously. The current study provides a new inspiration for constructing novel inorganic nanomedicines with multiple enhancement effect of PDT efficacy.
基金supported by the National Natural Science Foundation of China(82072060,81773685,and 81571807)the Fundamental Research Funds for the Central Universities(XDJK2019TY002,China)+3 种基金the Chengdu Science and Technology Program(2018-CY02-00042-GX,China)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYYC21002,ZYJC18032 and ZY2016101,China)the Natural Scienceof Chongqing(cstc2020jcyj-msxm X0292,China)the Venture&Innovation Support Program for Chongqing Overseas Returnees(cx2018029,China)。
文摘Incorporation of multiple functions into one nanoplatform can improve cancer diagnostic efficacy and enhance anti-cancer outcomes. Here, we constructed doxorubicin(DOX)-loaded silk fibroinbased nanoparticles(NPs) with surface functionalization by photosensitizer(N770). The obtained nanotheranostics(N770-DOX@NPs) had desirable particle size(157 nm) and negative surface charge(-25 m V). These NPs presented excellent oxygen-generating capacity and responded to a quadruple of stimuli(acidic solution, reactive oxygen species, glutathione, and hyperthermia). Surface functionalization of DOX@NPs with N770 could endow them with active internalization by cancerous cell lines, but not by normal cells. Furthermore, the intracellular NPs were found to be preferentially retained in mitochondria, which were also efficient for near-infrared(NIR) fluorescence imaging, photothermal imaging,and photoacoustic imaging. Meanwhile, DOX could spontaneously accumulate in the nucleus. Importantly, a mouse test group treated with N770-DOX@NPs plus NIR irradiation achieved the best tumorretardation effect among all treatment groups based on tumor-bearing mouse models and a patientderived xenograft model, demonstrating the unprecedented therapeutic effects of trimodal imagingguided mitochondrial phototherapy(photothermal therapy and photodynamic therapy) and chemotherapy.Therefore, the present study brings new insight into the exploitation of an easy-to-use, versatile, and robust nanoplatform for programmable targeting, imaging, and applying synergistic therapy to tumors.
基金financial support from the National Natural Science Foundation for Distinguished Young Scholars (81625023,China)。
文摘Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted delivery of doxorubicin(DOX) massively amplified ICD via substantial generation of reactive oxygen species(ROS) after mitochondrial damage. The underlying mechanism behind increased ICD was further demonstrated to be ascribed to two pathways:(1) ROS elevated endoplasmic reticulum(ER) stress, leading to surface exposure of calreticulin;(2) ROS promoted release of various mitochondriaassociated damage molecules including mitochondrial transcription factor A. Nevertheless, adaptive upregulation of PD-L1 was found after such ICD-inducing treatment. To overcome such immunosuppressive feedback,we developed a tumor stimuli-responsive nano vehicle to simultaneously exert mitochondrial targeted ICD induction and PD-L1 blockade. The nano vehicle was self-assembled from ICD-inducing copolymer and PD-L1 blocking copolymer, and possessed long-circulating property which contributed to better tumor accumulation and mitochondrial targeting. As a result, the nano vehicle remarkably activated antitumor immune responses and exhibited robust antitumor efficacy in both immunogenic and non-immunogenic tumor mouse models.
