Nanomaterial-based drug delivery systems are susceptible to premature drug leakage and systemic toxicity due to lack of specific targeting,and live-cell drug delivery is also prone to be restricted by drug carrier-cel...Nanomaterial-based drug delivery systems are susceptible to premature drug leakage and systemic toxicity due to lack of specific targeting,and live-cell drug delivery is also prone to be restricted by drug carrier-cellinteractions.Here,a method is established to adsorb drug-loaded nanomaterials externally to the live cells,which reduces cytotoxicity caused by drug uptake and improves the bioactivity of the carrier cells and drug release at the lesion site.It was found that polyphenols act like"doublesided tape"to bridge metal-organic framework(MOF)nanoparticles with live macrophages(Mop),attaching MOFs to the Mp surface and minimizing intracellular uptake,with no negative effect on cell proliferation.On this basis,a"macrophage missile"with peroxymonosulfate(PMS)-loaded MOF nanoparticles on the cell surface was constructed.As a"propellant",the Mo,in which bioactivity is preserved,can selectively identify and target tumor cells,precisely bringing nanomedicines to the lesion.MOF nanoparticles are used to load and catalyze PMS,which acts as an exogenous source of reactive oxygen species,showing higher efficacy and lower toxicity in an oxygen-independent manner.The primary study results demonstrate that this innovative combination of biology and nanomaterials remarkably enhances tumor targeting and therapeutic efficacy while reducing systemic side effects.This approach is expected to provide a more effective and safer treatment for lung cancer and holds promise for broader applications in other cancer therapies.展开更多
The alterations in glucose metabolism flux induced by mitochondrial function changes are crucial for regulating bone immune homeostasis.The restoration of mitochondrial homeostasis,serving as a pivotal rheostat for ba...The alterations in glucose metabolism flux induced by mitochondrial function changes are crucial for regulating bone immune homeostasis.The restoration of mitochondrial homeostasis,serving as a pivotal rheostat for balancing glucose metabolism in immune cells,can effectively mitigate inflammation and initiate osteogenesis.Herein,an ion-activated mitochondrial rheostat fiber-microsphere polymerization system(FM@CeZnHA)was innovatively constructed.Physical-chemical and molecular biological methods confirmed that CeZnHA,char-acterized by a rapid degradation rate,releases Ce/Zn ions that restore mitochondrial metabolic homeostasis and M1/M2 balance of macrophages through swift redox reactions.This process reduces the glycolysis level of macrophages by down-regulating the NF-κB p65 signaling pathway,enhances their mitochondrial metabolic dependence,alleviates excessive early inflammatory responses,and promptly initiates osteogenesis.The FM network provided a stable platform for macrophage glycolytic transformation and simulated extracellular matrix microenvironment,continuously restoring mitochondrial homeostasis and accelerating ossification center for-mation through the release of metal ions from the internal CeZnHA for efficient bone immune cascade reactions.This strategy of bone immunity mediated by the restoration of macrophage mitochondrial metabolic function and glucose metabolic flux homeostasis opens up a new approach to treating bone defects.展开更多
Hydrogel-based patches have demonstrated their values in diabetic wounds repair,particularly those intelligent dressings with continuous repair promoting and monitoring capabilities.Here,we propose a type of dual phys...Hydrogel-based patches have demonstrated their values in diabetic wounds repair,particularly those intelligent dressings with continuous repair promoting and monitoring capabilities.Here,we propose a type of dual physiological responsive structural color particles for wound repair.The particles are composed of a hyaluronic acid methacryloyl(HAMA)-sodium alginate(Alg)inverse opal scaffold,filled with oxidized dextran(ODex)/quaternized chitosan(QCS)hydrogel.The photo-polymerized HAMA and ionically cross-linked Ca-Alg constitute to the dual-network hydrogel with stable structural color.Furthermore,the ODex/QCS hydrogel,combined with glucose oxidase(GOX),exhibits pH/glucose dual responsiveness.Moreover,antimmicrobial peptide(AMP)plus vascular endothelial growth factor(VEGF)are comprised within the GOX-doped ODex/QCS hydrogel.In the high-glucose wound environment,GOX catalyzes glucose to generate acidic products,triggering rapid release of AMP and VEGF.Importantly,this process also leads to structural color changes of the particles,offering significant potential for wound monitoring.It has been demonstrated that such particles greatly promote the healing progress of diabetic wound in vivo.These results indicate that the present dual responsive particles would find valuable applications in diabetic wounds repair and the associated areas.展开更多
Microneedles have demonstrated valuable applications in diabetic wound management.Many endeavors are devoted to developing microneedles with well-designed structures and enhanced functions.Herein,we present an elabora...Microneedles have demonstrated valuable applications in diabetic wound management.Many endeavors are devoted to developing microneedles with well-designed structures and enhanced functions.Herein,we present an elaborate microneedle patch with breathability for wound healing by a multi-step replication method.The microneedle patch consists of a breathable porous supporting substrate and core-shell tips involving poly(vinyl alcohol)shells loaded with antimicrobial peptides(PVA@AMPs shell)and crosslinked Gelma cores encapsulated with exosomes(Gelma@exo core).The PVA was crosslinked with a ROS-responsive linker,which results in degradation of the microneedle shell in the inflammatory microenvironment,thus inducing the release of loaded AMPs to inhibit bacteria.Further,the exosomes continuously release from the exposed Gelma@exo core,promoting tissue regeneration and regulating the immune response.Besides,the high porosity of the supporting substrate makes the microneedle patches more suitable for chronic wounds.Based on these features,it was demonstrated that the microneedle patch exhibits desirable performance in in vivo animal tests.Thus,we believe that the proposed microneedle patches have remarkable potential in wound healing and related fields.展开更多
Long-term exposure to ultraviolet radiation compromises skin structural integrity and results in disruption of normal physiological functions.Stem cells have gained attention in anti-photoaging,while controlling the t...Long-term exposure to ultraviolet radiation compromises skin structural integrity and results in disruption of normal physiological functions.Stem cells have gained attention in anti-photoaging,while controlling the tissue mechanical microenvironment of cell delivery sites is crucial for regulating cell fate and achieving optimal therapeutic performances.Here,we introduce a mechanically regulated human recombinant collagen(RHC)microcarrier generated through microfluidics,which is capable of modulating stem cell differentiation to treat photoaged skin.By controlling the cross-linking parameters,the mechanical properties of microcarriers could precisely tuned to optimize the stem cell differentiation.The microcarriers are surface functionalized with fibronectin(Fn)-platelet derived growth factor-BB(PDGF-BB)to facilitate adipose derived mesenchymal stem cells(Ad-MSCs)loading.In in vivo experiments,subcutaneous injection of stem cell loaded RHC microcarriers significantly reduced skin wrinkles after ultraviolet-injury,effectively promoted collagen synthesis,and increased vascular density.These encouraging results indicate that the present mechanically regulated microcarriers have great potential to deliver stem cells and regulate their differentiation for anti-photoaging treatments.展开更多
Bladder cancer is one of the concerning malignancies worldwide,which is lacking effective targeted therapy.Gene therapy is a potential approach for bladder cancer treatment.While,a safe and effective targeted gene del...Bladder cancer is one of the concerning malignancies worldwide,which is lacking effective targeted therapy.Gene therapy is a potential approach for bladder cancer treatment.While,a safe and effective targeted gene delivery system is urgently needed for prompting the bladder cancer treatment in vivo.In this study,we confirmed that the bladder cancer had CD44 overexpression and small interfering RNAs(siRNA)with high interfere to Bcl2 oncogene were designed and screened.Then hyaluronic acid dialdehyde(HAD)was prepared in an ethanol-water mixture and covalently conjugated to the chitosan nanoparticles(CS-HAD NPs)to achieve CD44 targeted siRNA delivery.The in vitro and in vivo evaluations indicated that the siRNA-loaded CS-HAD NPs(siRNA@CS-HAD NPs)were approximately 100 nm in size,with improved stability,high siRNA encapsulation efficiency and low cytotoxicity.CS-HAD NPs could target to CD44 receptor and deliver the therapeutic siRNA into T24 bladder cancer cells through a ligand-receptor-mediated targeting mechanism and had a specific accumulation capacity in vivo to interfere the targeted oncogene Bcl2 in bladder cancer.Overall,a CD44 targeted gene delivery system based on natural macromolecules was developed for effective bladder cancer treatment,which could be more conducive to clinical application due to its simple preparation and high biological safety.展开更多
Therapeutic oligonucleotides(TOs)represent one of the most promising drug candidates in the targeted cancer treatment due to their high specificity and capability of modulating cellular pathways that are not readily d...Therapeutic oligonucleotides(TOs)represent one of the most promising drug candidates in the targeted cancer treatment due to their high specificity and capability of modulating cellular pathways that are not readily druggable.However,efficiently delivering of TOs to cancer cellular targets is still the biggest challenge in promoting their clinical translations.Emerging as a significant drug delivery vector,nanoparticles(NPs)can not only protect TOs from nuclease degradation and enhance their tumor accumulation,but also can improve the cell uptake efficiency of TOs as well as the following endosomal escape to increase the therapeutic index.Furthermore,targeted and on-demand drug release of TOs can also be approached to minimize the risk of toxicity towards normal tissues using stimuli-responsive NPs.In the past decades,remarkable progresses have been made on the TOs delivery based on various NPs with specific purposes.In this review,we will first give a brief introduction on the basis of TOs as well as the action mechanisms of several typical TOs,and then describe the obstacles that prevent the clinical translation of TOs,followed by a comprehensive overview of the recent progresses on TOs delivery based on several various types of nanocarriers containing lipid-based nanoparticles,polymeric nanoparticles,gold nanoparticles,porous nanoparticles,DNA/RNA nanoassembly,extracellular vesicles,and imaging-guided drug delivery nanoparticles.展开更多
Rupture or erosion of inflammatory atherosclerotic vulnerable plaque is essential to acute coronary events,while the target intervene of vulnerable plaque is very challenging,due to the relatively small volume,high he...Rupture or erosion of inflammatory atherosclerotic vulnerable plaque is essential to acute coronary events,while the target intervene of vulnerable plaque is very challenging,due to the relatively small volume,high hemodynamic shear stress,and multifactorial nature of the lesion foci.Herein,we utilize the biological functionality of neutrophil and the versatility of microbubble in the acoustic field,to form Neu-balloon through CD11b antibody binding.The Neu-balloon inherits the advantage of neutrophils on firming the endothelium adhesion even at shear stress up to 16 dyne/cm^(2)and also maintains the acoustic enhancement property from the microbubble,to accumulate at atherosclerotic lesions under acoustic in an atherosclerotic Apo E^(-/-) mice model.Interestingly,Neo-balloon also has high and broad drug loading capacity,which enables the delivery of indocyanine green and miR-126a-5p into vulnerable plagues in vivo.Overall,the bionic Neu-balloon holds great potential to boost on-demand drug transportation into plaques in vivo.展开更多
Biofunctionalization of artificial nerve implants by incorporation of specific bioactive factors has greatly enhanced the success of grafting procedures for peripheral nerve regeneration.However,most studies on novel ...Biofunctionalization of artificial nerve implants by incorporation of specific bioactive factors has greatly enhanced the success of grafting procedures for peripheral nerve regeneration.However,most studies on novel biofunctionalized implants have emphasized the promotion of neuronal and axonal repair over vascularization,a process critical for long-term functional restoration.We constructed a dual-biofunctionalized chitosan/collagen composite scaffold with Ile-Lys-Val-Ala-Val(IKVAV)and vascular endothelial growth factor(VEGF)by combining solution blending,in situ lyophilization,and surface biomodification.Immobilization of VEGF and IKVAV on the scaffolds was confirmed both qualitatively by staining and quantitatively by ELISA.Various single-and dual-biofunctionalized scaffolds were compared for the promotion of endothelial cell(EC)and Schwann cell(SC)proliferation as well as the induction of angiogenic and neuroregeneration-associated genes by these cells in culture.The efficacy of these scaffolds for vascularization was evaluated by implantation in chicken embryos,while functional repair capacity in vivo was assessed in rats subjected to a 10mm sciatic nerve injury.Dual-biofunctionalized scaffolds supported robust EC and SC proliferation and upregulated the expression levels of multiple genes and proteins related to neuroregeneration and vascularization.Dual-biofunctionalized scaffolds demonstrated superior vascularization induction in embryos and greater promotion of vascularization,myelination,and functional recovery in rats.These findings support the clinical potential of VEGF/IKVAV dual-biofunctionalized chitosan/collagen composite scaffolds for facilitating peripheral nerve regeneration,making it an attractive candidate for repairing critical nerve defect.The study may provide a critical experimental and theoretical basis for the development and design of new artificial nerve implants with excellent biological performance.展开更多
Nanozymes are considered to represent a new era of antibacterial agents,while their antibacterial efficiency is limited by the increasing tissue depth of infection.To address this issue,here,we report a copper and sil...Nanozymes are considered to represent a new era of antibacterial agents,while their antibacterial efficiency is limited by the increasing tissue depth of infection.To address this issue,here,we report a copper and silk fibroin(Cu-SF)complex strategy to synthesize alternative copper single-atom nanozymes(SAzymes)with atomically dispersed copper sites anchored on ultrathin 2D porous N-doped carbon nanosheets(CuN_(x)-CNS)and tunable N coordination numbers in the CuN_(x) sites(x=2 or 4).The CuN_(x)-CNS SAzymes inherently possess triple peroxidase(POD)-,catalase(CAT)-,and oxidase(OXD)-like activities,facilitating the conversion of H_(2)O_(2)and O_(2)into reactive oxygen species(ROS)through parallel POD-and OXD-like or cascaded CAT-and OXD-like reactions.Compared to CuN_(2)-CNS,tailoring the N coordination number from 2 to 4 endows the SAzyme(CuN_(4)-CNS)with higher multienzyme activities due to its superior electron structure and lower energy barrier.Meanwhile,CuN_(x)-CNS display strong absorption in the second near-infrared(NIR-II)biowindow with deeper tissue penetration,offering NIR-II-responsive enhanced ROS generation and photothermal treatment in deep tissues.The in vitro and in vivo results demonstrate that the optimal CuN_(4)-CNS can effectively inhibit multidrug-resistant bacteria and eliminate stubborn biofilms,thus exhibiting high therapeutic efficacy in both superficial skin wound and deep implant-related biofilm infections.展开更多
Antibody-mediated rejection(ABMR)is a major cause of dysfunction and loss of transplanted kidney.The current treatments for ABMR involve nonspecific inhibition and clearance of T/B cells or plasma cells.However,the pr...Antibody-mediated rejection(ABMR)is a major cause of dysfunction and loss of transplanted kidney.The current treatments for ABMR involve nonspecific inhibition and clearance of T/B cells or plasma cells.However,the prognosis of patients following current treatment is poor.T follicular helper cells(Tfh)play an important role in allograft-specific antibodies secreting plasma cell(PC)development.Tfh cells are therefore considered to be important therapeutic targets for the treatment of antibody hypersecretion disorders,such as transplant rejection and autoimmune diseases.Tacrolimus(Tac),the primary immunosuppressant,prevents rejection by reducing T cell activation.However,its administration should be closely monitored to avoid serious side effects.In this study,we investigated whether Tac delivery to helper T(CD4^(+))cells using functionalized mesoporous nanoparticles can block Tfh cell differentiation after alloantigen exposure.Results showed that Tac delivery ameliorated humoral rejection injury in rodent kidney graft by suppressing Tfh cell development,PC,and donor-specific antibody(DSA)generation without causing severe side effects compared with delivery through the drug administration pathway.This study provides a promising therapeutic strategy for preventing humoral rejection in solid organ transplantation.The specific and controllable drug delivery avoids multiple disorder risks and side effects observed in currently used clinical approaches.展开更多
Platinum-based chemotherapy remains the main systemic treatment of ovarian cancer(OC).However,the inevitable development of platinum and poly(adenosine diphosphate-ribose)polymerase inhibitor(PARPi)resistance is assoc...Platinum-based chemotherapy remains the main systemic treatment of ovarian cancer(OC).However,the inevitable development of platinum and poly(adenosine diphosphate-ribose)polymerase inhibitor(PARPi)resistance is associated with poor outcomes,which becomes a major obstacle in the management of this disease.The present study developed“all-in-one”nanoparticles that contained the PARPi olaparib and gallium(Ga)(III)(olaparib-Ga)to effectively reverse PARPi resistance in platinum-resistant A2780-cis and SKOV3-cis OC cells and in SKOV3-cis tumor models.Notably,the olaparib-Ga suppressed SKOV3-cis tumor growth with negligible toxicity.Moreover,the suppression effect was more evident when combining olaparib-Ga with cisplatin or carboplatin,as evaluated in A2780-cis and SKOV3-cis cells.Mechanistically,the combined treatment induced DNA damage,which elicited the activation of ataxia telangiectasia mutated(ATM)/AMT-and Rad3-related(ATR)checkpoint kinase 1(Chk1)/Chk2 signal transduction pathways.This led to the arrest of cell cycle progression at S and G2/M phases,which eventually resulted in apoptosis and cell death due to unrepairable DNA damage.In addition,effective therapeutic responses to olaparib-Ga and cisplatin combination or olaparib-Ga and carboplatin combination were observed in SKOV3-cis tumor-bearing animal models.Altogether,the present findings demonstrate that olaparib-Ga has therapeutic implications in platinum-resistant OC cells,and the combination of olaparib-Ga with cisplatin or carboplatin may be promising for treating patients with OC who exhibit resistance to both PARPi and platinum.展开更多
Lung cancer has become one of the key life-threatening factors and is the most common type of tumor.With the improvement of equipment and the improvement of lung cancer awareness,the surgical treatment of lung cancer ...Lung cancer has become one of the key life-threatening factors and is the most common type of tumor.With the improvement of equipment and the improvement of lung cancer awareness,the surgical treatment of lung cancer is becoming more and more mature.Surgery can provide an important part of individualized treatment strategies for patients with different stages of lung cancer and different wishes.In addition,the concept of minimally invasive,precise,and intelligent has triggered a revolutionary change in the surgical treatment strategy for lung cancer.Therefore,this review focuses on the development of lung cancer surgery history,summarizing the era from traditional surgery to the era of minimally invasive thoracic surgery based on TV-assisted thoracic surgery.The operating methods and treatment effects of different surgical methods are comprehensively introduced,and the optimization and improvement of different surgical methods in the future are also discussed.Along with the concept of minimally invasive surgical techniques,there are more and more explorations of nanotechnology in the surgical treatment of lung cancer.The application of nanotechnology in lung cancer imaging,and the combination of surgery with nanomedicine is an effective solution for cancer treatment today.So,this review also summarizes the application prospects of nanotechnology before,during and after lung cancer surgery.展开更多
Bone defects caused by congenital diseases,trauma,infection,tumors,or other factors are common orthopedic diseases,which affect the normal movement of patients significantly.[1]Clinical intervention is still required ...Bone defects caused by congenital diseases,trauma,infection,tumors,or other factors are common orthopedic diseases,which affect the normal movement of patients significantly.[1]Clinical intervention is still required to achieve the complete healing and functional restoration.During that,the autologous or allogeneic bone grafts are the present gold standard treatment for large or severe bone damage,with about 2.2 million bone grafting operations being performed annually globally.展开更多
The development of tumor drug microcarriers has attracted considerable interest due to their distinctive therapeutic performances.Current attempts tend to elab-orate on the micro/nano-structure design of the microcarr...The development of tumor drug microcarriers has attracted considerable interest due to their distinctive therapeutic performances.Current attempts tend to elab-orate on the micro/nano-structure design of the microcarriers to achieve multiple drug delivery and spatiotemporal responsive features.Here,the desired hydrogel microspheres are presented with spatiotemporal responsiveness for the treatment of gastric cancer.The microspheres are generated based on inverse opals,their skele-ton is fabricated by biofriendly hyaluronic acid methacrylate(HAMA)and gelatin methacrylate(GelMA),and is thenfilled with a phase-changing hydrogel composed offish gelatin and agarose.Besides,the incorporated black phosphorus quantum dots(BPQDs)within thefilling hydrogel endow the microspheres with outstanding pho-tothermal responsiveness.Two antitumor drugs,sorafenib(SOR)and doxorubicin(DOX),are loaded in the skeleton andfilling hydrogel,respectively.It is found that the drugs show different release profiles upon near-infrared(NIR)irradiation,which exerts distinct performances in a controlled manner.Through both in vitro and in vivo experiments,it is demonstrated that such microspheres can significantly reduce tumor cell viability and enhance the efficiency in treating gastric cancer,indicating a promising stratagem in thefield of drug delivery and tumor therapy.展开更多
Oligonucleotide-based therapy has experienced remarkable development in the past 2 decades,but its broad applications are severely hampered by delivery vectors.Widely used viral vectors and lipid nanovectors are suffe...Oligonucleotide-based therapy has experienced remarkable development in the past 2 decades,but its broad applications are severely hampered by delivery vectors.Widely used viral vectors and lipid nanovectors are suffering from immune clearance after repeating usage or requiring refrigerated transportation and storage,respectively.In this work,amino-modified virus-mimetic spike silica nanoparticles(NH_(2)-SSNs)were fabricated using a 1-pot surfactant-free approach with controlled spike lengths,which were demonstrated with excellent delivery performance and biosafety in nearly all cell types and mice.It indicated that NH2-SSNs entered cells by spike-dependent cell membrane docking and dynamin-dependent endocytosis.The positively charged spikes with proper length on the surface can facilitate the efficient encapsulation of RNAs,protect the loaded RNAs from degradation,and trigger an early endosome escape during intracellular trafficking,similarly to the cellular internalization mechanism of virions.Regarding the fantastic properties of NH_(2)-SSNs in nucleic acid delivery,it revealed that nanoparticles with solid spikes on the surface would be excellent vehicles for gene therapy,presenting self-evident advantages in storage,transportation,modification,and quality control in large-scale production compared to lipid nanovectors.展开更多
基金supported by the National Natural Science Foundation of China(82073388 and 82201287)the Affiliated Hospital of Guangdong Medical University Clinical Research Program(LCYJ2020B005)+7 种基金the Natural Out-standing Youth Fund of Guangdong Province(2022B1515020090)Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases(2022B1212030003)Guangzhou Science and Technology Plan Project(Grant No.202102021238)Academy of Finland Research Fellow(353146)Project(347897)Solutions for Health Profile(336355)InFLAMES Flagship(337531)Tor,Joe och Pentti Borgs minnesfond,and Finland China Food and Health International Pilot Project funded by the Finnish Ministry of Education and Culture.
文摘Nanomaterial-based drug delivery systems are susceptible to premature drug leakage and systemic toxicity due to lack of specific targeting,and live-cell drug delivery is also prone to be restricted by drug carrier-cellinteractions.Here,a method is established to adsorb drug-loaded nanomaterials externally to the live cells,which reduces cytotoxicity caused by drug uptake and improves the bioactivity of the carrier cells and drug release at the lesion site.It was found that polyphenols act like"doublesided tape"to bridge metal-organic framework(MOF)nanoparticles with live macrophages(Mop),attaching MOFs to the Mp surface and minimizing intracellular uptake,with no negative effect on cell proliferation.On this basis,a"macrophage missile"with peroxymonosulfate(PMS)-loaded MOF nanoparticles on the cell surface was constructed.As a"propellant",the Mo,in which bioactivity is preserved,can selectively identify and target tumor cells,precisely bringing nanomedicines to the lesion.MOF nanoparticles are used to load and catalyze PMS,which acts as an exogenous source of reactive oxygen species,showing higher efficacy and lower toxicity in an oxygen-independent manner.The primary study results demonstrate that this innovative combination of biology and nanomaterials remarkably enhances tumor targeting and therapeutic efficacy while reducing systemic side effects.This approach is expected to provide a more effective and safer treatment for lung cancer and holds promise for broader applications in other cancer therapies.
基金supported by the Program of Shanghai Academic/Technology Research Leader(22XD1422600)the Research Fellow(Grant No.353146)+2 种基金Research Project(347897)Solution for Health Profile(336355)InFLAMES Flagship(337531)grants and Printed Intelligence Infrastructure"(PII-FIRI)from Research Council of Finland.
文摘The alterations in glucose metabolism flux induced by mitochondrial function changes are crucial for regulating bone immune homeostasis.The restoration of mitochondrial homeostasis,serving as a pivotal rheostat for balancing glucose metabolism in immune cells,can effectively mitigate inflammation and initiate osteogenesis.Herein,an ion-activated mitochondrial rheostat fiber-microsphere polymerization system(FM@CeZnHA)was innovatively constructed.Physical-chemical and molecular biological methods confirmed that CeZnHA,char-acterized by a rapid degradation rate,releases Ce/Zn ions that restore mitochondrial metabolic homeostasis and M1/M2 balance of macrophages through swift redox reactions.This process reduces the glycolysis level of macrophages by down-regulating the NF-κB p65 signaling pathway,enhances their mitochondrial metabolic dependence,alleviates excessive early inflammatory responses,and promptly initiates osteogenesis.The FM network provided a stable platform for macrophage glycolytic transformation and simulated extracellular matrix microenvironment,continuously restoring mitochondrial homeostasis and accelerating ossification center for-mation through the release of metal ions from the internal CeZnHA for efficient bone immune cascade reactions.This strategy of bone immunity mediated by the restoration of macrophage mitochondrial metabolic function and glucose metabolic flux homeostasis opens up a new approach to treating bone defects.
基金supported by the National Key Research and Development Program of China(2022YFA1105300)the National Natural Science Foundation of China(82372145,82102181,52403189)+5 种基金the Natural Science Foundation of Jiangsu Province(BK20210009)the Nanjing Distinguished Young Scholars Foundation(JQX22002)supported by the Research Project(347897)Solution for Health Profile(336355)InFLAMES Flagship(337531)"Printed Intelligence Infrastructure(PII-FIRI)"from Research Council of Finland.
文摘Hydrogel-based patches have demonstrated their values in diabetic wounds repair,particularly those intelligent dressings with continuous repair promoting and monitoring capabilities.Here,we propose a type of dual physiological responsive structural color particles for wound repair.The particles are composed of a hyaluronic acid methacryloyl(HAMA)-sodium alginate(Alg)inverse opal scaffold,filled with oxidized dextran(ODex)/quaternized chitosan(QCS)hydrogel.The photo-polymerized HAMA and ionically cross-linked Ca-Alg constitute to the dual-network hydrogel with stable structural color.Furthermore,the ODex/QCS hydrogel,combined with glucose oxidase(GOX),exhibits pH/glucose dual responsiveness.Moreover,antimmicrobial peptide(AMP)plus vascular endothelial growth factor(VEGF)are comprised within the GOX-doped ODex/QCS hydrogel.In the high-glucose wound environment,GOX catalyzes glucose to generate acidic products,triggering rapid release of AMP and VEGF.Importantly,this process also leads to structural color changes of the particles,offering significant potential for wound monitoring.It has been demonstrated that such particles greatly promote the healing progress of diabetic wound in vivo.These results indicate that the present dual responsive particles would find valuable applications in diabetic wounds repair and the associated areas.
基金funded by Research Project(347897)Solution for Health Profile(336355)InFLAMES Flagship(337531)Grants and Printed Intelligence Infrastructure(PII-FIRI)from Research Council of Finland.
文摘Microneedles have demonstrated valuable applications in diabetic wound management.Many endeavors are devoted to developing microneedles with well-designed structures and enhanced functions.Herein,we present an elaborate microneedle patch with breathability for wound healing by a multi-step replication method.The microneedle patch consists of a breathable porous supporting substrate and core-shell tips involving poly(vinyl alcohol)shells loaded with antimicrobial peptides(PVA@AMPs shell)and crosslinked Gelma cores encapsulated with exosomes(Gelma@exo core).The PVA was crosslinked with a ROS-responsive linker,which results in degradation of the microneedle shell in the inflammatory microenvironment,thus inducing the release of loaded AMPs to inhibit bacteria.Further,the exosomes continuously release from the exposed Gelma@exo core,promoting tissue regeneration and regulating the immune response.Besides,the high porosity of the supporting substrate makes the microneedle patches more suitable for chronic wounds.Based on these features,it was demonstrated that the microneedle patch exhibits desirable performance in in vivo animal tests.Thus,we believe that the proposed microneedle patches have remarkable potential in wound healing and related fields.
基金supported by the National Key Research and Development Program of China(2022YFA1105300)the National Natural Science Foundation of China(52073060,61927805 and 82400718)+5 种基金the Nanjing Medical Science and Technique Development Foundation(ZKX21019)the Clinical Trials from Nanjing Drum Tower Hospital(2022-LCYJ-ZD-01)supported by the Research Project(347897)Solution for Health Profile(336355)InFLAMES Flagship(337531)"Printed Intelligence Infrastructure"(PII-FIRI)"from Research Council of Finland.
文摘Long-term exposure to ultraviolet radiation compromises skin structural integrity and results in disruption of normal physiological functions.Stem cells have gained attention in anti-photoaging,while controlling the tissue mechanical microenvironment of cell delivery sites is crucial for regulating cell fate and achieving optimal therapeutic performances.Here,we introduce a mechanically regulated human recombinant collagen(RHC)microcarrier generated through microfluidics,which is capable of modulating stem cell differentiation to treat photoaged skin.By controlling the cross-linking parameters,the mechanical properties of microcarriers could precisely tuned to optimize the stem cell differentiation.The microcarriers are surface functionalized with fibronectin(Fn)-platelet derived growth factor-BB(PDGF-BB)to facilitate adipose derived mesenchymal stem cells(Ad-MSCs)loading.In in vivo experiments,subcutaneous injection of stem cell loaded RHC microcarriers significantly reduced skin wrinkles after ultraviolet-injury,effectively promoted collagen synthesis,and increased vascular density.These encouraging results indicate that the present mechanically regulated microcarriers have great potential to deliver stem cells and regulate their differentiation for anti-photoaging treatments.
基金This study was financially supported by the National Natural Science Foundation of China(81772713,81472411,81401899,81372752)Taishan Scholar Program of Shandong Province(tsqn20161077)+4 种基金Key Research and Development Program of Shandong Province(2018GSF118197)China Postdoctoral Science Foundation(2017M622144)Qingdao Postdoctoral Application Research Project.Prof.Zhang acknowledged the support from Academy of Finland(Grant no.328933)Sigrid Juselius Foundation(Grant no.28002247K1)We thank Dr.Chang Liu fromÅbo Akademi University for giving some advice to analyze the TGA data,and Ms.Qian Wen from Biomedical Center of Qingdao University for her guidance and support of in vivo fluorescence imaging.
文摘Bladder cancer is one of the concerning malignancies worldwide,which is lacking effective targeted therapy.Gene therapy is a potential approach for bladder cancer treatment.While,a safe and effective targeted gene delivery system is urgently needed for prompting the bladder cancer treatment in vivo.In this study,we confirmed that the bladder cancer had CD44 overexpression and small interfering RNAs(siRNA)with high interfere to Bcl2 oncogene were designed and screened.Then hyaluronic acid dialdehyde(HAD)was prepared in an ethanol-water mixture and covalently conjugated to the chitosan nanoparticles(CS-HAD NPs)to achieve CD44 targeted siRNA delivery.The in vitro and in vivo evaluations indicated that the siRNA-loaded CS-HAD NPs(siRNA@CS-HAD NPs)were approximately 100 nm in size,with improved stability,high siRNA encapsulation efficiency and low cytotoxicity.CS-HAD NPs could target to CD44 receptor and deliver the therapeutic siRNA into T24 bladder cancer cells through a ligand-receptor-mediated targeting mechanism and had a specific accumulation capacity in vivo to interfere the targeted oncogene Bcl2 in bladder cancer.Overall,a CD44 targeted gene delivery system based on natural macromolecules was developed for effective bladder cancer treatment,which could be more conducive to clinical application due to its simple preparation and high biological safety.
基金This work was financially supported by the Natural Science Foundation of China(81871472)Natural Science Foundation of Guangdong Province(Project No.2019A1515010696 and 2021A1515012333)+1 种基金Shenzhen Municipal Science,Technology and Innovation Commission(Project No.JCYJ20190807163003704)“100 Talents Program”of the start-up foundation from Sun Yat-sen University,Academy of Finland(328933)and Sigrid Jus´elius Foundation.
文摘Therapeutic oligonucleotides(TOs)represent one of the most promising drug candidates in the targeted cancer treatment due to their high specificity and capability of modulating cellular pathways that are not readily druggable.However,efficiently delivering of TOs to cancer cellular targets is still the biggest challenge in promoting their clinical translations.Emerging as a significant drug delivery vector,nanoparticles(NPs)can not only protect TOs from nuclease degradation and enhance their tumor accumulation,but also can improve the cell uptake efficiency of TOs as well as the following endosomal escape to increase the therapeutic index.Furthermore,targeted and on-demand drug release of TOs can also be approached to minimize the risk of toxicity towards normal tissues using stimuli-responsive NPs.In the past decades,remarkable progresses have been made on the TOs delivery based on various NPs with specific purposes.In this review,we will first give a brief introduction on the basis of TOs as well as the action mechanisms of several typical TOs,and then describe the obstacles that prevent the clinical translation of TOs,followed by a comprehensive overview of the recent progresses on TOs delivery based on several various types of nanocarriers containing lipid-based nanoparticles,polymeric nanoparticles,gold nanoparticles,porous nanoparticles,DNA/RNA nanoassembly,extracellular vesicles,and imaging-guided drug delivery nanoparticles.
基金the National Natural Science Foundation of China(nos.82071939,82030051,81571689,and 81871472)Research Fellow(grant no.328933),Solutions for Health Profile(336355)+1 种基金InFLAMES Flagship(337531)projects from Academy of Finland,as well as the Finland China Food and Health International Pilot Project funded by the Finnish Ministry of Education and Culturegrant from Shenzhen Basic Research Program(no.JCYJ20200109114825064).
文摘Rupture or erosion of inflammatory atherosclerotic vulnerable plaque is essential to acute coronary events,while the target intervene of vulnerable plaque is very challenging,due to the relatively small volume,high hemodynamic shear stress,and multifactorial nature of the lesion foci.Herein,we utilize the biological functionality of neutrophil and the versatility of microbubble in the acoustic field,to form Neu-balloon through CD11b antibody binding.The Neu-balloon inherits the advantage of neutrophils on firming the endothelium adhesion even at shear stress up to 16 dyne/cm^(2)and also maintains the acoustic enhancement property from the microbubble,to accumulate at atherosclerotic lesions under acoustic in an atherosclerotic Apo E^(-/-) mice model.Interestingly,Neo-balloon also has high and broad drug loading capacity,which enables the delivery of indocyanine green and miR-126a-5p into vulnerable plagues in vivo.Overall,the bionic Neu-balloon holds great potential to boost on-demand drug transportation into plaques in vivo.
基金the financial support of the National Natural Science Foundation of China(31771054,81871472,and 31830028)Academy of Finland Research Fellow(328933)+5 种基金Sigrid Jusélius Foundation grant(28002247k1)Natural Key Science Research Program of Jiangsu Provincial Department of Education(19KJA320006)National Key Research and Development Program of China(2016YFC1101600)Directive Project of Science and Technology Plan of Nantong City(MS12018028)226 High-Level Talent Training Project(2nd level,2018 II-182)of Nantong CityQinglan Project of Jiangsu Province(2018).
文摘Biofunctionalization of artificial nerve implants by incorporation of specific bioactive factors has greatly enhanced the success of grafting procedures for peripheral nerve regeneration.However,most studies on novel biofunctionalized implants have emphasized the promotion of neuronal and axonal repair over vascularization,a process critical for long-term functional restoration.We constructed a dual-biofunctionalized chitosan/collagen composite scaffold with Ile-Lys-Val-Ala-Val(IKVAV)and vascular endothelial growth factor(VEGF)by combining solution blending,in situ lyophilization,and surface biomodification.Immobilization of VEGF and IKVAV on the scaffolds was confirmed both qualitatively by staining and quantitatively by ELISA.Various single-and dual-biofunctionalized scaffolds were compared for the promotion of endothelial cell(EC)and Schwann cell(SC)proliferation as well as the induction of angiogenic and neuroregeneration-associated genes by these cells in culture.The efficacy of these scaffolds for vascularization was evaluated by implantation in chicken embryos,while functional repair capacity in vivo was assessed in rats subjected to a 10mm sciatic nerve injury.Dual-biofunctionalized scaffolds supported robust EC and SC proliferation and upregulated the expression levels of multiple genes and proteins related to neuroregeneration and vascularization.Dual-biofunctionalized scaffolds demonstrated superior vascularization induction in embryos and greater promotion of vascularization,myelination,and functional recovery in rats.These findings support the clinical potential of VEGF/IKVAV dual-biofunctionalized chitosan/collagen composite scaffolds for facilitating peripheral nerve regeneration,making it an attractive candidate for repairing critical nerve defect.The study may provide a critical experimental and theoretical basis for the development and design of new artificial nerve implants with excellent biological performance.
基金the National Natural Science Foundation of China(32222041,82072425,82160421,and 82072498)the Natural Science Foundation of Jiangsu Province(BE2020666,BK20211322,and BK20220059)+3 种基金Finland-China Food and Health International Pilot Project funded by the Finnish Ministry of Education and Culture,the Academy Research Fellow(328933)Solutions for Health Strategic Research Profiling Area(336355)InFLAMES Flagship(337531)Grants from Academy of Finland,the Special Project of Diagnosis and Treatment for Clinical Diseases of Suzhou(LCZX202003)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD),and the jiangsu Specially Appointed Professor"Program and Postgraduate Research&Practice Innovation Program of jiangsu Province(KYCX22_3217).
文摘Nanozymes are considered to represent a new era of antibacterial agents,while their antibacterial efficiency is limited by the increasing tissue depth of infection.To address this issue,here,we report a copper and silk fibroin(Cu-SF)complex strategy to synthesize alternative copper single-atom nanozymes(SAzymes)with atomically dispersed copper sites anchored on ultrathin 2D porous N-doped carbon nanosheets(CuN_(x)-CNS)and tunable N coordination numbers in the CuN_(x) sites(x=2 or 4).The CuN_(x)-CNS SAzymes inherently possess triple peroxidase(POD)-,catalase(CAT)-,and oxidase(OXD)-like activities,facilitating the conversion of H_(2)O_(2)and O_(2)into reactive oxygen species(ROS)through parallel POD-and OXD-like or cascaded CAT-and OXD-like reactions.Compared to CuN_(2)-CNS,tailoring the N coordination number from 2 to 4 endows the SAzyme(CuN_(4)-CNS)with higher multienzyme activities due to its superior electron structure and lower energy barrier.Meanwhile,CuN_(x)-CNS display strong absorption in the second near-infrared(NIR-II)biowindow with deeper tissue penetration,offering NIR-II-responsive enhanced ROS generation and photothermal treatment in deep tissues.The in vitro and in vivo results demonstrate that the optimal CuN_(4)-CNS can effectively inhibit multidrug-resistant bacteria and eliminate stubborn biofilms,thus exhibiting high therapeutic efficacy in both superficial skin wound and deep implant-related biofilm infections.
基金the National Natural Science Foundation of China(82070766,81770719,82070767,and 81970651)Research Fellow(Grant No.328933)+1 种基金Solutions for Health Profile(336355)InFLAMES Flagship(337531)projects from the Academy of Finland,the Science and Technology Department of Zhejiang Province(2019C03029),the Finland China Food and Health Interna tional Pilot Project funded by the Finnish Ministry of Education and Culture,and the Sigrid Jusélius Foundation.
文摘Antibody-mediated rejection(ABMR)is a major cause of dysfunction and loss of transplanted kidney.The current treatments for ABMR involve nonspecific inhibition and clearance of T/B cells or plasma cells.However,the prognosis of patients following current treatment is poor.T follicular helper cells(Tfh)play an important role in allograft-specific antibodies secreting plasma cell(PC)development.Tfh cells are therefore considered to be important therapeutic targets for the treatment of antibody hypersecretion disorders,such as transplant rejection and autoimmune diseases.Tacrolimus(Tac),the primary immunosuppressant,prevents rejection by reducing T cell activation.However,its administration should be closely monitored to avoid serious side effects.In this study,we investigated whether Tac delivery to helper T(CD4^(+))cells using functionalized mesoporous nanoparticles can block Tfh cell differentiation after alloantigen exposure.Results showed that Tac delivery ameliorated humoral rejection injury in rodent kidney graft by suppressing Tfh cell development,PC,and donor-specific antibody(DSA)generation without causing severe side effects compared with delivery through the drug administration pathway.This study provides a promising therapeutic strategy for preventing humoral rejection in solid organ transplantation.The specific and controllable drug delivery avoids multiple disorder risks and side effects observed in currently used clinical approaches.
基金the National Natural Science Foundation of China(82072855)the Fundamental Research Funds for the Central Universities(2021FZZX001-43)+6 种基金Innovative Talent Plan of Zhejiang Health Science and Technology Project(2021RC086)the Beijing Kanghua Foundation for the Development of Traditional Chinese and Western Medicine(KH-2021-LLZX-016)4+X Clinical Research Project of Women's Hospital,School of Medicine,Zhejiang University(ZDFY2022-4X202)WHZJU Global Partnership Seed Fund(G2022A003)H.Z.acknowledges financial support from the research fellow(grant no.353146),project(347897)solutions for Health Profile(336355)InFLAMES Flagship(337531)grants from Academy of Finland,and the Finland China Food and Health International Pilot Project funded by the Finnish Ministry of Education and Culture(no.280Mo052K1).
文摘Platinum-based chemotherapy remains the main systemic treatment of ovarian cancer(OC).However,the inevitable development of platinum and poly(adenosine diphosphate-ribose)polymerase inhibitor(PARPi)resistance is associated with poor outcomes,which becomes a major obstacle in the management of this disease.The present study developed“all-in-one”nanoparticles that contained the PARPi olaparib and gallium(Ga)(III)(olaparib-Ga)to effectively reverse PARPi resistance in platinum-resistant A2780-cis and SKOV3-cis OC cells and in SKOV3-cis tumor models.Notably,the olaparib-Ga suppressed SKOV3-cis tumor growth with negligible toxicity.Moreover,the suppression effect was more evident when combining olaparib-Ga with cisplatin or carboplatin,as evaluated in A2780-cis and SKOV3-cis cells.Mechanistically,the combined treatment induced DNA damage,which elicited the activation of ataxia telangiectasia mutated(ATM)/AMT-and Rad3-related(ATR)checkpoint kinase 1(Chk1)/Chk2 signal transduction pathways.This led to the arrest of cell cycle progression at S and G2/M phases,which eventually resulted in apoptosis and cell death due to unrepairable DNA damage.In addition,effective therapeutic responses to olaparib-Ga and cisplatin combination or olaparib-Ga and carboplatin combination were observed in SKOV3-cis tumor-bearing animal models.Altogether,the present findings demonstrate that olaparib-Ga has therapeutic implications in platinum-resistant OC cells,and the combination of olaparib-Ga with cisplatin or carboplatin may be promising for treating patients with OC who exhibit resistance to both PARPi and platinum.
基金supported by Application Research Center of 3D simulation engineering technology for diagnosis and treatment of chest diseases Project No.:20130604050tcappreciated that the Academy of Finland (InFLAMES Flagship Grant No.337531)+3 种基金research Fellow (Grant No.328933)project (347897)solutions for Health Pro-file (336355)the Finland China Food and Health International Pilot Project funded by the Finnish Ministry of Education and Culture,and China Scholarship Council support this work.
文摘Lung cancer has become one of the key life-threatening factors and is the most common type of tumor.With the improvement of equipment and the improvement of lung cancer awareness,the surgical treatment of lung cancer is becoming more and more mature.Surgery can provide an important part of individualized treatment strategies for patients with different stages of lung cancer and different wishes.In addition,the concept of minimally invasive,precise,and intelligent has triggered a revolutionary change in the surgical treatment strategy for lung cancer.Therefore,this review focuses on the development of lung cancer surgery history,summarizing the era from traditional surgery to the era of minimally invasive thoracic surgery based on TV-assisted thoracic surgery.The operating methods and treatment effects of different surgical methods are comprehensively introduced,and the optimization and improvement of different surgical methods in the future are also discussed.Along with the concept of minimally invasive surgical techniques,there are more and more explorations of nanotechnology in the surgical treatment of lung cancer.The application of nanotechnology in lung cancer imaging,and the combination of surgery with nanomedicine is an effective solution for cancer treatment today.So,this review also summarizes the application prospects of nanotechnology before,during and after lung cancer surgery.
基金supported by the National Key Research and Development Program of China(2020YFA0908200)National Natural Science Foundation of China(81871472)+1 种基金Academy of Finland(Grant No.328933)Finland China Food and Health International Pilot Project funded by the Finnish Ministry of Education and Culture(280M0052K1).
文摘Bone defects caused by congenital diseases,trauma,infection,tumors,or other factors are common orthopedic diseases,which affect the normal movement of patients significantly.[1]Clinical intervention is still required to achieve the complete healing and functional restoration.During that,the autologous or allogeneic bone grafts are the present gold standard treatment for large or severe bone damage,with about 2.2 million bone grafting operations being performed annually globally.
基金National Natural Science Foundation of China,Grant/Award Number:82372145Research Fellow,Grant/Award Number:353146+3 种基金Research Project,Grant/Award Number:347897Solutions for Health Profile,Grant/Award Number:336355InFLAMES Flagship,Grant/Award Number:337531Finland China Food and Health International Pilot project funded by Finnish MInistry of Education and Culture。
文摘The development of tumor drug microcarriers has attracted considerable interest due to their distinctive therapeutic performances.Current attempts tend to elab-orate on the micro/nano-structure design of the microcarriers to achieve multiple drug delivery and spatiotemporal responsive features.Here,the desired hydrogel microspheres are presented with spatiotemporal responsiveness for the treatment of gastric cancer.The microspheres are generated based on inverse opals,their skele-ton is fabricated by biofriendly hyaluronic acid methacrylate(HAMA)and gelatin methacrylate(GelMA),and is thenfilled with a phase-changing hydrogel composed offish gelatin and agarose.Besides,the incorporated black phosphorus quantum dots(BPQDs)within thefilling hydrogel endow the microspheres with outstanding pho-tothermal responsiveness.Two antitumor drugs,sorafenib(SOR)and doxorubicin(DOX),are loaded in the skeleton andfilling hydrogel,respectively.It is found that the drugs show different release profiles upon near-infrared(NIR)irradiation,which exerts distinct performances in a controlled manner.Through both in vitro and in vivo experiments,it is demonstrated that such microspheres can significantly reduce tumor cell viability and enhance the efficiency in treating gastric cancer,indicating a promising stratagem in thefield of drug delivery and tumor therapy.
基金the National Natu ral Science Foundation of China(U22A20582,X.W.,22005197,J.F.,61435010 and 61575089,Han Z.,U1803128,M.Q.,81991525,X.W.,81871472,Han Z.)the Natural Science Founda-tion of Shandong Province(ZR202110150015,ZR2021LSW013,ZR202110290057)+8 种基金the China Postdoctoral Science Foun-dation(Grant No.2021M692197,J.F.)State Key Research Development Program of China(2019YFB2203503,Han Z.)the Science and Technology Innovation Commission of Shenzhen(KQTD2015032416270385,JCYJ20150625103619275,Han Z.,JCYJ20180305124854790,M.Q.)the Natural Science Foun-dation of Guangdong Province(2018A030310500)the Taishan Scholar Project(tsqn201909054,tsqn201909170)the Fundamental Research Funds for the Central Universities to X.W.and M.Q.,and Tor,Joe and Pentti Borg Memorial Fund(R.B.).This project was funded by the Deanship of Scientific Research(DSR)at King Abdulaziz University,Jeddah,under grant no.(KEP-MSc-70-130-42).The Research Fellow(Grant No.328933)Solutions for Health Profile(336355)InFLAMES Flagship(337531)projects from Academy of Finland,as well as the Finland-China Food and Health(FCFH)International Pilot Project funded by the Finnish Ministry of Education and Culture are acknowledged.
文摘Oligonucleotide-based therapy has experienced remarkable development in the past 2 decades,but its broad applications are severely hampered by delivery vectors.Widely used viral vectors and lipid nanovectors are suffering from immune clearance after repeating usage or requiring refrigerated transportation and storage,respectively.In this work,amino-modified virus-mimetic spike silica nanoparticles(NH_(2)-SSNs)were fabricated using a 1-pot surfactant-free approach with controlled spike lengths,which were demonstrated with excellent delivery performance and biosafety in nearly all cell types and mice.It indicated that NH2-SSNs entered cells by spike-dependent cell membrane docking and dynamin-dependent endocytosis.The positively charged spikes with proper length on the surface can facilitate the efficient encapsulation of RNAs,protect the loaded RNAs from degradation,and trigger an early endosome escape during intracellular trafficking,similarly to the cellular internalization mechanism of virions.Regarding the fantastic properties of NH_(2)-SSNs in nucleic acid delivery,it revealed that nanoparticles with solid spikes on the surface would be excellent vehicles for gene therapy,presenting self-evident advantages in storage,transportation,modification,and quality control in large-scale production compared to lipid nanovectors.
