Gene therapy provides a promising approach in treating cancers with high efficacy and selectivity and few adverse effects.Currently,the development of functional vectors with safety and effectiveness is the intense fo...Gene therapy provides a promising approach in treating cancers with high efficacy and selectivity and few adverse effects.Currently,the development of functional vectors with safety and effectiveness is the intense focus for improving the delivery of nucleic acid drugs for gene therapy.For this purpose,stimuli-responsive nanocarriers displayed strong potential in improving the overall efficiencies of gene therapy and reducing adverse effects via effective protection,prolonged blood circulation,specific tumor accumulation,and controlled release profile of nucleic acid drugs.Besides,synergistic therapy could be achieved when combined with other therapeutic regimens.This review summarizes recent advances in various stimuliresponsive nanocarriers for gene delivery.Particularly,the nanocarriers responding to endogenous stimuli including pH,reactive oxygen species,glutathione,and enzyme,etc.,and exogenous stimuli including light,thermo,ultrasound,magnetic field,etc.,are introduced.Finally,the future challenges and prospects of stimuli-responsive gene delivery nanocarriers toward potential clinical translation are well discussed.The major objective of this review is to present the biomedical potential of stimuli-responsive gene delivery nanocarriers for cancer therapy and provide guidance for developing novel nanoplatforms that are clinically applicable.展开更多
Complications of the liver are amongst the world’s worst diseases.Liver fibrosis is the first stage of liver problems,while cirrhosis is the last stage,which can lead to death.The creation of effective anti-fibrotic ...Complications of the liver are amongst the world’s worst diseases.Liver fibrosis is the first stage of liver problems,while cirrhosis is the last stage,which can lead to death.The creation of effective anti-fibrotic drug delivery methods appears critical due to the liver’s metabolic capacity for drugs and the presence of insurmountable physiological impediments in the way of targeting.Recent breakthroughs in anti-fibrotic agents have substantially assisted in fibrosis;nevertheless,the working mechanism of anti-fibrotic medications is not fully understood,and there is a need to design delivery systems that are well-understood and can aid in cirrhosis.Nanotechnology-based delivery systems are regarded to be effective but they have not been adequately researched for liver delivery.As a result,the capability of nanoparticles in hepatic delivery was explored.Another approach is targeted drug delivery,which can considerably improve efficacy if delivery systems are designed to target hepatic stellate cells(HSCs).We have addressed numerous delivery strategies that target HSCs,which can eventually aid in fibrosis.Recently genetics have proved to be useful,and methods for delivering genetic material to the target place have also been investigated where different techniques are depicted.To summarize,this review paper sheds light on themost recent breakthroughs in drug and gene-based nano and targeted delivery systems that have lately shown useful for the treatment of liver fibrosis and cirrhosis.展开更多
Antisense oligodeoxynucleotide(ASODN)can directly interfere a series of biological events of the target RNA derived from tumor cells through Watson-Crick base pairing,in turn,plays antitumor therapeutic roles.In the s...Antisense oligodeoxynucleotide(ASODN)can directly interfere a series of biological events of the target RNA derived from tumor cells through Watson-Crick base pairing,in turn,plays antitumor therapeutic roles.In the study,a novel HIF-1αASODN-loaded nanocomposite was formulated to efficiently deliver gene to the target RNA.The physicochemical properties of nanocomposite were characterized using TEM,FTIR,DLS and zeta potentials.The mean diameter of resulting GEL-DGL-FA-ASODN-DCA nanocomposite was about 170–192 nm,and according to the agarose gel retardation assay,the loading amount of ASODN accounted for 166.7 mg/g.The results of cellular uptake showed that the nanocomposite could specifically target to HepG2 and Hela cells.The cytotoxicity assay demonstrated that the toxicity of vectors was greatly reduced by using DCA to reversibly block the cationic DGL.The subcellular distribution images clearly displayed the lysosomal escape ability of the DCA-modified nanocomposite.In vitro exploration of molecular mechanism indicated that the nanocomposite could inhibit m RNA expression and HIF-1αprotein translation at different levels.In vivo optical images and quantitative assay testified that the formulation accumulated preferentially in the tumor tissue.In vivo antitumor efficacy research confirmed that this nanocomposite had significant antitumor activity and the tumor inhibitory rate was 77.99%.These results manifested that the GEL-DGL-FA-ASODNDCA nanocomposite was promising in gene therapeutics for antitumor by interacting directly with target RNA.展开更多
Cationic liposome(Lipo) and polyethylenimine(PEI) are widely applied for nonviral gene transfection.In this study,in order to combine the favorable properties of Lipo and PEI systems for gene delivery,Lipo/PEI complex...Cationic liposome(Lipo) and polyethylenimine(PEI) are widely applied for nonviral gene transfection.In this study,in order to combine the favorable properties of Lipo and PEI systems for gene delivery,Lipo/PEI complexes with different contents of PEI(5%,10%,20% and 40% relative to phosphatidyl choline in reaction system) were prepared.The physicochemical properties of Lipo/PEI complexes,as well as the influences of PEI content on the storage stability,cytotoxicity and transfection efficiency were investigated.The transmission electron microscopy(TEM) images showed that Lipo/PEI complexes had smaller size compared to pure Lipo.The zeta potential values decreased with the increasing content of PEI.After storaged for 3 months at 4 ℃,obvious aggregation was observed when the addition of PEI content was up to 20%.In vitro cytotoxicity assay showed that Lipo/PEI complexes had decreased cytotoxicity over pure PEI,while the cytotoxicity was enhanced as the PEI content increased.Importantly,the luciferase activity assay and confocal microscope observation revealed that Lipo/PEI complexes prepared with the lowest amount of PEI(Lipo/PEI-5%)possessed the highest transfection efficiency.Thus,these results suggest that feeding the appropriate content of PEI in Lipo/PEI complexes allows them to be excellent vehicle for gene delivery.展开更多
Introduction Cancer is an attractive target of gene therapy and currently represents the disease in most clinical trials[1]. Strategies for cancer gene therapy include: (1) stimulation of immune responses to tumor cel...Introduction Cancer is an attractive target of gene therapy and currently represents the disease in most clinical trials[1]. Strategies for cancer gene therapy include: (1) stimulation of immune responses to tumor cells,(2) delivery of specific enzymes展开更多
Mesenchymal stem cells(MSCs)are promising seed cells for neural regeneration therapy owing to their plasticity and accessibility.They possess several inherent characteristics advantageous for the transplantation-based...Mesenchymal stem cells(MSCs)are promising seed cells for neural regeneration therapy owing to their plasticity and accessibility.They possess several inherent characteristics advantageous for the transplantation-based treatment of neurological disorders,including neural differentiation,immunosuppression,neurotrophy,and safety.However,the therapeutic efficacy of MSCs alone remains unsatisfactory in most cases.To improve some of their abilities,many studies have employed genetic engineering to transfer key genes into MSCs.Both viral and nonviral methods can be used to overexpress therapeutic proteins that complement the inherent properties.However,to date,different modes of gene transfer have specific drawbacks and advantages.In addition,MSCs can be functionalized through targeted gene modification to facilitate neural repair by promoting neural differentiation,enhancing neurotrophic and neuroprotective functions,and increasing survival and homing abilities.The methods of gene transfer and selection of delivered genes still need to be optimized for improved therapeutic and targeting efficacies while minimizing the loss of MSC function.In this review,we focus on gene transport technologies for engineering MSCs and the application of strategies for selecting optimal delivery genes.Further,we describe the prospects and challenges of their application in animal models of different neurological lesions to broaden treatment alternatives for neurological diseases.展开更多
Mesoporous silica nanoparticles(MSNs) are attracting increasing interest for potential biomedical applications. With tailored mesoporous structure, huge surface area and pore volume,selective surface functionality, as...Mesoporous silica nanoparticles(MSNs) are attracting increasing interest for potential biomedical applications. With tailored mesoporous structure, huge surface area and pore volume,selective surface functionality, as well as morphology control, MSNs exhibit high loading capacity for therapeutic agents and controlled release properties if modified with stimuli-responsive groups, polymers or proteins. In this review article, the applications of MSNs in pharmaceutics to improve drug bioavailability, reduce drug toxicity, and deliver with cellular targetability are summarized. Particularly,the exciting progress in the development of MSNs-based effective delivery systems for poorly soluble drugs, anticancer agents, and therapeutic genes are highlighted.展开更多
There have been significant advancements in the field of retinal gene therapy in the past several years.In particular,therapeutic efficacy has been achieved in three separate human clinical trials conducted to assess ...There have been significant advancements in the field of retinal gene therapy in the past several years.In particular,therapeutic efficacy has been achieved in three separate human clinical trials conducted to assess the ability of adeno-associated viruses(AAV)to treat of a type of Leber’s congenital amaurosis caused by RPE65 mutations.However,despite the success of retinal gene therapy with AAV,challenges remain for delivering large therapeutic genes or genes requiring long DNA regulatory elements for controlling their expression.For example,Stargardt’s disease,a form of juvenile macular degeneration,is caused by defects in ABCA4,a gene that is too large to be packaged in AAV.Therefore,we investigated the ability of helper dependent adenovirus(HD-Ad)to deliver genes to the retina as it has a much larger transgene capacity.Using an EGFP reporter,our results showed that HD-Ad can transduce the entire retinal epithelium of a mouse using a dose of only 1105 infectious units and maintain transgene expression for at least 4 months.The results demonstrate that HD-Ad has the potential to be an effective vector for the gene therapy of the retina.展开更多
Intramuscular expression of functional proteins is a promising strategy for therapeutic purposes.Previously,we developed an intramuscular gene delivery method by combining Pluronic L64 and optimized electropulse,which...Intramuscular expression of functional proteins is a promising strategy for therapeutic purposes.Previously,we developed an intramuscular gene delivery method by combining Pluronic L64 and optimized electropulse,which is among the most efficient methods to date.However,plasmid DNAs(pDNAs)in this method were not compressed,making them unstable and inefficient in vivo.We considered that a proper compression of pDNAs by an appropriate material should facilitate gene expression in this L64-electropulse system.Here,we reported our finding of such a material,Epigallocatechin gallate(EGCG),a natural compound in green teas,which could compress and protect pDNAs and significantly increase intramuscular gene expression in the L64-electropulse system.Meanwhile,we found that polyethylenimine(PEI)could also slightly improve exogenous gene expression in the optimal procedure.By analysing the characteristic differences between EGCG and PEI,we concluded that negatively charged materials with strong affinity to nucleic acids and/or other properties suitable for gene delivery,such as EGCG,are better alternatives than cationic materials(like PEI)for muscle-based gene delivery.The results revealed that a critical principle for material/pDNA complex benefitting intramuscular gene delivery/expression is to keep the complex negatively charged.This proof-of-concept study displays the breakthrough in compressing pDNAs and provides a principle and strategy to develop more efficient intramuscular gene delivery systems for therapeutic applications.展开更多
Currently,there is no cure for traumatic spinal co rd injury but one therapeutic approach showing promise is gene therapy.In this systematic review and meta-analysis,we aim to assess the efficacy of gene therapies in ...Currently,there is no cure for traumatic spinal co rd injury but one therapeutic approach showing promise is gene therapy.In this systematic review and meta-analysis,we aim to assess the efficacy of gene therapies in pre-clinical models of spinal cord injury and the risk of bias.In this metaanalysis,registe red at PROSPERO(Registration ID:CRD42020185008),we identified relevant controlled in vivo studies published in English by searching the PubMed,Web of Science,and Embase databases.No restrictions of the year of publication were applied and the last literature search was conducted on August 3,2020.We then conducted a random-effects meta-analysis using the restricted maximum likelihood estimator.A total of 71 studies met our inclusion crite ria and were included in the systematic review.Our results showed that overall,gene therapies were associated with improvements in locomotor score(standardized mean difference[SMD]:2.07,95%confidence interval[CI]:1.68-2.47,Tau^(2)=2.13,I^(2)=83.6%)and axonal regrowth(SMD:2.78,95%CI:1.92-3.65,Tau^(2)=4.13,I^(2)=85.5%).There was significant asymmetry in the funnel plots of both outcome measures indicating the presence of publication bias.We used a modified CAMARADES(Collaborative Approach to M eta-Analysis and Review of Animal Data in Experimental Studies)checklist to assess the risk of bias,finding that the median score was 4(IQR:3-5).In particula r,reports of allocation concealment and sample size calculations were lacking.In conclusion,gene therapies are showing promise as therapies for spinal co rd injury repair,but there is no consensus on which gene or genes should be targeted.展开更多
Hollow needle array-based tissue nanotransfection(TNT)presents an in vivo transfection approach that directly translocate exogeneous genes to target tissues by using electric pulses.In this work,the gene delivery proc...Hollow needle array-based tissue nanotransfection(TNT)presents an in vivo transfection approach that directly translocate exogeneous genes to target tissues by using electric pulses.In this work,the gene delivery process of TNT was simulated and experimentally validated.We adopted the asymptotic method and cell-array-based model to investigate the electroporation behaviors of cells within the skin structure.The distribution of nonuniform electric field across the skin results in various electroporation behavior for each cell.Cells underneath the hollow microchannels of the needle exhibited the highest total pore numbers compared to others due to the stronger localized electric field.The percentage of electroporated cells within the skin structure,with pore radius over 10 nm,increases from 25%to 82%as the applied voltage increases from 100 to 150 V/mm.Furthermore,the gene delivery behavior across the skin tissue was investigated through the multilayer-stack-based model.The delivery distance increased nonlinearly as the applied voltage and pulse number increased,which mainly depends on the diffusion characteristics and electric conductivity of each layer.It was also found that the skin is required to be exfoliated prior to the TNT procedure to enhance the delivery depth.This work provides the foundation for transition from the study of murine skin to translation use in large animals and human settings.展开更多
Gene therapy is a promising method to treat acquired and inherited diseases by introducing exogenous genes into specific recipient cells.Polymeric micelles with different nanoscopic morphologies and properties hold gr...Gene therapy is a promising method to treat acquired and inherited diseases by introducing exogenous genes into specific recipient cells.Polymeric micelles with different nanoscopic morphologies and properties hold great promise for gene delivery system.Conventional cationic polymers,poly(ethyleneimine)(PEI),poly(L-lysine)(PLL),poly(2-dimethylaminoethyl methacrylate)(PDMAEMA)and novel cationic polymers poly(2-oxazoline)s(POxs),have been incorporated into block copolymers and decorated with targeting moieties to enhance transfection efficiency.In order to minimize cytotoxicity,nonionic block copolymer micelles are utilized to load gene through hydrophilic and hydrophobic interactions or covalent conjugations,recently.From our perspective,properties(shape,size,and mechanical stiffness,etc.)of block copolymer micelles may significantly affect cytotoxicity,transfection efficiency,circulation time,and load capacity of gene vectors in vivo and in vitro.This review briefly sums up recent efforts in cationic and nonionic amphiphilic polymeric micelles for gene delivery.展开更多
Numerous nanocarriers have been currently developed for intracellular delivery.The potential cytotoxicity of these very small inorganic nanocarriers has raised great consideration.Thus,it becomes of utmost importance ...Numerous nanocarriers have been currently developed for intracellular delivery.The potential cytotoxicity of these very small inorganic nanocarriers has raised great consideration.Thus,it becomes of utmost importance to conduct the intracellular trace of nanocarriers.Among many analytical techniques,surface enhanced Raman scattering(SERS)method is one of the current state-of-the-art techniques for cell visualization and trace.In this work,a novel stellate porous silica based gene delivery system has been designed for SERS trace purpose.A stellate porous silica nanoparticle modified with many small Au nanoparticles is designed to replace common metallic SERS tags.The results show that the designed system not only could deliver si RNA into cells for therapy,but also could realize SERS trace with high sensitivity and non-invasive features.The constructed delivery system has considerable potential to trace the dynamic gene delivery in living cells.展开更多
There are several challenges to inner ear drug delivery and imaging due to the existence of tight biological barriers to the target structure and the dense bone surrounding it. Advances in imaging and nanomedicine may...There are several challenges to inner ear drug delivery and imaging due to the existence of tight biological barriers to the target structure and the dense bone surrounding it. Advances in imaging and nanomedicine may provide knowledge for overcoming the existing limitations to both the diagnosis and treatment of inner ear diseases. Novel techniques have improved the efficacy of drug delivery and targeting to the inner ear, as well as the quality and accuracy of imaging this structure. In this review, we will describe the pathways and biological barriers of the inner ear regarding drug delivery, the beneficial applications and limitations of the imaging techniques available for inner ear research, the behavior of engineered nanomaterials in inner ear applications, and future perspectives for nanomedicine-based inner ear imaging.展开更多
Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system,a hallmark in Parkinson's disease.The human cerebral dopa...Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system,a hallmark in Parkinson's disease.The human cerebral dopamine neurotrophic factor(h CDNF)has recently emerged as a strong candidate for Parkinson's disease therapy.This study shows that h CDNF expression in dopamine neurons using the neurotensinpolyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological,biochemical,and behavioral alterations.Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the h CDNF gene,ranging in size from 20 to 150 nm,enabled the expression of a secretable h CDNF in vitro.Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable h CDNF in dopamine neurons,whose levels remained constant throughout the study in the substantia nigra compacta and striatum.Compared with the lesioned group,tyrosine hydroxylase-positive(TH^(+))nigral cell population and TH+fiber density rose in the substantia nigra compacta and striatum after h CDNF transfection.An increase inβIII-tubulin and growth-associated protein 43 phospho-S41(GAP43 p)followed TH^(+)cell recovery,as well as dopamine and its catabolite levels.Partial reversal(80%)of drugactivated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved.Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects.These findings support the potential of nanoparticle-mediated h CDNF gene delivery to develop a disease-modifying treatment against Parkinson's disease.The Institutional Animal Care and Use Committee of Centro de Investigación y de Estudios Avanzados approved our experimental procedures for animal use(authorization No.162-15)on June 9,2019.展开更多
Localized delivery of drugs is an emerging field both with regards to drug delivery during disease as well as in tissue engineering.Despite significant achievements made in the last decades,the efficient delivery of p...Localized delivery of drugs is an emerging field both with regards to drug delivery during disease as well as in tissue engineering.Despite significant achievements made in the last decades,the efficient delivery of proteins and peptides remains challenging,especially in cases requiring long-term release of proteins after application.The localized delivery of nucleic acids(NA)represents an interesting alternative due to higher physicochemical stability of NA,increased efficiency by harnessing cells as bioreactors for the production of required proteins and improved versatility with regards to expression of specific proteins through plasmid DNA or repression of gene products through siRNA.However,unlike most proteins and peptides,NA must be delivered to the cytoplasm or nucleus to be efficacious,resulting in significant delivery challenges.We herein describe frequently used non-viral vectors for the delivery of NA including polyplexes,lipoplexes and lipopolyplexes and summarize recent developments in the field of nucleic acid delivery systems for local application based on hydrogels,solid scaffolds and physical delivery methods.The challenges associated with the different approaches are identified and options to address these challenges are discussed.展开更多
Enhanced stability of polyplexes in physiological condition was an important prerequisite for successful systemic gene delivery.Herein novel method was reported to develop stable gene vector by nanotechnology.Thiolate...Enhanced stability of polyplexes in physiological condition was an important prerequisite for successful systemic gene delivery.Herein novel method was reported to develop stable gene vector by nanotechnology.Thiolated polyplexes were constructed and then cross-linked with gold nanoparticles(AuNPs)by gold-thiol interactions.TEM pictures showed that AuNPs were attached to the shell of spherical polyplexes.The hybrid gene vector was stable enough in physiological condition and maintained efficient transfec...展开更多
Gene therapy offers important perspectives in current and future medicine but suffers from imperfect vectors for the delivery of the therapeutic gene. Most preclinical and clinical trials have been based on the use of...Gene therapy offers important perspectives in current and future medicine but suffers from imperfect vectors for the delivery of the therapeutic gene. Most preclinical and clinical trials have been based on the use of viral vectors, which have evident advantages but also some serious disadvantages. In the past decade the use of DNA transposon-based systems for gene delivery has emerged as a non-viral alternative. DNA transposon vector engineering remains largely in a preclinical phase but some interesting results have been obtained. This mini-review aims to provide the current state of the art on DNA transposon vectors used in a gene therapy perspective.展开更多
Gene deletion has been a valuable tool for unraveling the mysteries of molecular biology.Early approaches included gene trapping and gene targetting to disrupt or delete a gene randomly or at a specific location,respe...Gene deletion has been a valuable tool for unraveling the mysteries of molecular biology.Early approaches included gene trapping and gene targetting to disrupt or delete a gene randomly or at a specific location,respectively.Using these technologies in mouse embryos led to the generation of mouse knocko ut models and many scientific discoveries.The efficacy and specificity of these approaches have significantly increased with the advent of new technology such as cluste red regula rly inters paced short palindromic repeats for targetted gene deletion.However,several limitations including unwanted off-target gene deletion have hindered their widespread use in the field.Crerecombinase technology has provided additional capacity for cell-specific gene deletion.In this review,we provide a summary of currently available literature on the application of this system for targetted deletion of neuronal genes.This article has been constructed to provide some background info rmation for the new trainees on the mechanism and to provide necessary information for the design,and application of the Cre-recombinase system thro ugh reviewing the most f requent promoters that are currently available for genetic manipulation of neuro ns.We additionally will provide a summary of the latest technological developments that can be used for targeting neurons.This may also serve as a general guide for the selection of appropriate models for biomedical research.展开更多
The integrated lipopeptide(RVA)/gene complexes are fabricated with bi-directional regulation on tumor cells and micro-environment.After self-assembling and target coating modification,the poly(γ-glutamic acid)(γ-PGA...The integrated lipopeptide(RVA)/gene complexes are fabricated with bi-directional regulation on tumor cells and micro-environment.After self-assembling and target coating modification,the poly(γ-glutamic acid)(γ-PGA)/RVA nano-vectors can sequentially respond to pH&redox stimuli,and guarantee efficient therapeutic gene delivery and control release of all-trans retinoic acid.The design provides a facile but promising strategy to treat refractory cancers.展开更多
基金the financial support from the National Key Research and Development Program of China(2020YFA0908200)the National Natural Science Foundation of China(52103196 and 52073060)+1 种基金Guangdong Basic and Applied Basic Research Foundation(2021B1515120054)the Shenzhen Fundamental Research Program(JCYJ20190813152616459 and JCYJ20210324133214038)。
文摘Gene therapy provides a promising approach in treating cancers with high efficacy and selectivity and few adverse effects.Currently,the development of functional vectors with safety and effectiveness is the intense focus for improving the delivery of nucleic acid drugs for gene therapy.For this purpose,stimuli-responsive nanocarriers displayed strong potential in improving the overall efficiencies of gene therapy and reducing adverse effects via effective protection,prolonged blood circulation,specific tumor accumulation,and controlled release profile of nucleic acid drugs.Besides,synergistic therapy could be achieved when combined with other therapeutic regimens.This review summarizes recent advances in various stimuliresponsive nanocarriers for gene delivery.Particularly,the nanocarriers responding to endogenous stimuli including pH,reactive oxygen species,glutathione,and enzyme,etc.,and exogenous stimuli including light,thermo,ultrasound,magnetic field,etc.,are introduced.Finally,the future challenges and prospects of stimuli-responsive gene delivery nanocarriers toward potential clinical translation are well discussed.The major objective of this review is to present the biomedical potential of stimuli-responsive gene delivery nanocarriers for cancer therapy and provide guidance for developing novel nanoplatforms that are clinically applicable.
文摘Complications of the liver are amongst the world’s worst diseases.Liver fibrosis is the first stage of liver problems,while cirrhosis is the last stage,which can lead to death.The creation of effective anti-fibrotic drug delivery methods appears critical due to the liver’s metabolic capacity for drugs and the presence of insurmountable physiological impediments in the way of targeting.Recent breakthroughs in anti-fibrotic agents have substantially assisted in fibrosis;nevertheless,the working mechanism of anti-fibrotic medications is not fully understood,and there is a need to design delivery systems that are well-understood and can aid in cirrhosis.Nanotechnology-based delivery systems are regarded to be effective but they have not been adequately researched for liver delivery.As a result,the capability of nanoparticles in hepatic delivery was explored.Another approach is targeted drug delivery,which can considerably improve efficacy if delivery systems are designed to target hepatic stellate cells(HSCs).We have addressed numerous delivery strategies that target HSCs,which can eventually aid in fibrosis.Recently genetics have proved to be useful,and methods for delivering genetic material to the target place have also been investigated where different techniques are depicted.To summarize,this review paper sheds light on themost recent breakthroughs in drug and gene-based nano and targeted delivery systems that have lately shown useful for the treatment of liver fibrosis and cirrhosis.
基金supported by the National Natural Science Foundation of China Fund(No 81541060)Science and Technology Projects from the Science Technology and Innovation Committee of Shenzhen Municipality(grant no.JCJY20170818110340383 and JCJY20170307163529489)。
文摘Antisense oligodeoxynucleotide(ASODN)can directly interfere a series of biological events of the target RNA derived from tumor cells through Watson-Crick base pairing,in turn,plays antitumor therapeutic roles.In the study,a novel HIF-1αASODN-loaded nanocomposite was formulated to efficiently deliver gene to the target RNA.The physicochemical properties of nanocomposite were characterized using TEM,FTIR,DLS and zeta potentials.The mean diameter of resulting GEL-DGL-FA-ASODN-DCA nanocomposite was about 170–192 nm,and according to the agarose gel retardation assay,the loading amount of ASODN accounted for 166.7 mg/g.The results of cellular uptake showed that the nanocomposite could specifically target to HepG2 and Hela cells.The cytotoxicity assay demonstrated that the toxicity of vectors was greatly reduced by using DCA to reversibly block the cationic DGL.The subcellular distribution images clearly displayed the lysosomal escape ability of the DCA-modified nanocomposite.In vitro exploration of molecular mechanism indicated that the nanocomposite could inhibit m RNA expression and HIF-1αprotein translation at different levels.In vivo optical images and quantitative assay testified that the formulation accumulated preferentially in the tumor tissue.In vivo antitumor efficacy research confirmed that this nanocomposite had significant antitumor activity and the tumor inhibitory rate was 77.99%.These results manifested that the GEL-DGL-FA-ASODNDCA nanocomposite was promising in gene therapeutics for antitumor by interacting directly with target RNA.
基金National Natural Science Foundations of China(Nos.31271028,31570984)Innovation Program of Shanghai Municipal Education Commission,China(No.13ZZ051)+2 种基金International Cooperation Fund of the Science and Technology Commission of Shanghai Municipality,China(No.15540723400)Open Foundation of State Key Laboratory for Modification of Chemical Fibers and Polymer Materials,China(No.LK1416)“111 Project”Biomedical Textile Materials Science and Technology,China(No.B07024)
文摘Cationic liposome(Lipo) and polyethylenimine(PEI) are widely applied for nonviral gene transfection.In this study,in order to combine the favorable properties of Lipo and PEI systems for gene delivery,Lipo/PEI complexes with different contents of PEI(5%,10%,20% and 40% relative to phosphatidyl choline in reaction system) were prepared.The physicochemical properties of Lipo/PEI complexes,as well as the influences of PEI content on the storage stability,cytotoxicity and transfection efficiency were investigated.The transmission electron microscopy(TEM) images showed that Lipo/PEI complexes had smaller size compared to pure Lipo.The zeta potential values decreased with the increasing content of PEI.After storaged for 3 months at 4 ℃,obvious aggregation was observed when the addition of PEI content was up to 20%.In vitro cytotoxicity assay showed that Lipo/PEI complexes had decreased cytotoxicity over pure PEI,while the cytotoxicity was enhanced as the PEI content increased.Importantly,the luciferase activity assay and confocal microscope observation revealed that Lipo/PEI complexes prepared with the lowest amount of PEI(Lipo/PEI-5%)possessed the highest transfection efficiency.Thus,these results suggest that feeding the appropriate content of PEI in Lipo/PEI complexes allows them to be excellent vehicle for gene delivery.
基金supported by a predoctoral fellowship from the National Institutes of Health and a research grant from the National Science Foundation
文摘Introduction Cancer is an attractive target of gene therapy and currently represents the disease in most clinical trials[1]. Strategies for cancer gene therapy include: (1) stimulation of immune responses to tumor cells,(2) delivery of specific enzymes
基金This work was supported by the National Natural Science Foundation of China(81871503 from Qingsong Ye)National Key R&D Program of China(2022YFC2504200 from Qingsong Ye)Key research and development project of Hubei Province and Chutian Researcher Project(X22020024 from Yan He).
文摘Mesenchymal stem cells(MSCs)are promising seed cells for neural regeneration therapy owing to their plasticity and accessibility.They possess several inherent characteristics advantageous for the transplantation-based treatment of neurological disorders,including neural differentiation,immunosuppression,neurotrophy,and safety.However,the therapeutic efficacy of MSCs alone remains unsatisfactory in most cases.To improve some of their abilities,many studies have employed genetic engineering to transfer key genes into MSCs.Both viral and nonviral methods can be used to overexpress therapeutic proteins that complement the inherent properties.However,to date,different modes of gene transfer have specific drawbacks and advantages.In addition,MSCs can be functionalized through targeted gene modification to facilitate neural repair by promoting neural differentiation,enhancing neurotrophic and neuroprotective functions,and increasing survival and homing abilities.The methods of gene transfer and selection of delivered genes still need to be optimized for improved therapeutic and targeting efficacies while minimizing the loss of MSC function.In this review,we focus on gene transport technologies for engineering MSCs and the application of strategies for selecting optimal delivery genes.Further,we describe the prospects and challenges of their application in animal models of different neurological lesions to broaden treatment alternatives for neurological diseases.
基金financial support from the National Natural Science Foundation of China (81473155)the Natural Science Fund Project of Guangdong Province (Grant No. 2016A030312013)+1 种基金the Science and Technology Plan Projects of Guangdong Province (Grant No. 2015B020232010)the Science and Technology Foundation Guangzhou (201707010103)
文摘Mesoporous silica nanoparticles(MSNs) are attracting increasing interest for potential biomedical applications. With tailored mesoporous structure, huge surface area and pore volume,selective surface functionality, as well as morphology control, MSNs exhibit high loading capacity for therapeutic agents and controlled release properties if modified with stimuli-responsive groups, polymers or proteins. In this review article, the applications of MSNs in pharmaceutics to improve drug bioavailability, reduce drug toxicity, and deliver with cellular targetability are summarized. Particularly,the exciting progress in the development of MSNs-based effective delivery systems for poorly soluble drugs, anticancer agents, and therapeutic genes are highlighted.
文摘There have been significant advancements in the field of retinal gene therapy in the past several years.In particular,therapeutic efficacy has been achieved in three separate human clinical trials conducted to assess the ability of adeno-associated viruses(AAV)to treat of a type of Leber’s congenital amaurosis caused by RPE65 mutations.However,despite the success of retinal gene therapy with AAV,challenges remain for delivering large therapeutic genes or genes requiring long DNA regulatory elements for controlling their expression.For example,Stargardt’s disease,a form of juvenile macular degeneration,is caused by defects in ABCA4,a gene that is too large to be packaged in AAV.Therefore,we investigated the ability of helper dependent adenovirus(HD-Ad)to deliver genes to the retina as it has a much larger transgene capacity.Using an EGFP reporter,our results showed that HD-Ad can transduce the entire retinal epithelium of a mouse using a dose of only 1105 infectious units and maintain transgene expression for at least 4 months.The results demonstrate that HD-Ad has the potential to be an effective vector for the gene therapy of the retina.
基金the National Natural Science Foundation of China(no.31370972)the 111 Project(no.B16033)the National Key Research and Development Program of China(2017YFB0702600,2017YFB0702603)。
文摘Intramuscular expression of functional proteins is a promising strategy for therapeutic purposes.Previously,we developed an intramuscular gene delivery method by combining Pluronic L64 and optimized electropulse,which is among the most efficient methods to date.However,plasmid DNAs(pDNAs)in this method were not compressed,making them unstable and inefficient in vivo.We considered that a proper compression of pDNAs by an appropriate material should facilitate gene expression in this L64-electropulse system.Here,we reported our finding of such a material,Epigallocatechin gallate(EGCG),a natural compound in green teas,which could compress and protect pDNAs and significantly increase intramuscular gene expression in the L64-electropulse system.Meanwhile,we found that polyethylenimine(PEI)could also slightly improve exogenous gene expression in the optimal procedure.By analysing the characteristic differences between EGCG and PEI,we concluded that negatively charged materials with strong affinity to nucleic acids and/or other properties suitable for gene delivery,such as EGCG,are better alternatives than cationic materials(like PEI)for muscle-based gene delivery.The results revealed that a critical principle for material/pDNA complex benefitting intramuscular gene delivery/expression is to keep the complex negatively charged.This proof-of-concept study displays the breakthrough in compressing pDNAs and provides a principle and strategy to develop more efficient intramuscular gene delivery systems for therapeutic applications.
基金supported by Scottish Rugby Union,Graham and Pam Dixon,Medical Research Scotland,University of Aberdeen HOTSTART Scholarship Programme(to WH)。
文摘Currently,there is no cure for traumatic spinal co rd injury but one therapeutic approach showing promise is gene therapy.In this systematic review and meta-analysis,we aim to assess the efficacy of gene therapies in pre-clinical models of spinal cord injury and the risk of bias.In this metaanalysis,registe red at PROSPERO(Registration ID:CRD42020185008),we identified relevant controlled in vivo studies published in English by searching the PubMed,Web of Science,and Embase databases.No restrictions of the year of publication were applied and the last literature search was conducted on August 3,2020.We then conducted a random-effects meta-analysis using the restricted maximum likelihood estimator.A total of 71 studies met our inclusion crite ria and were included in the systematic review.Our results showed that overall,gene therapies were associated with improvements in locomotor score(standardized mean difference[SMD]:2.07,95%confidence interval[CI]:1.68-2.47,Tau^(2)=2.13,I^(2)=83.6%)and axonal regrowth(SMD:2.78,95%CI:1.92-3.65,Tau^(2)=4.13,I^(2)=85.5%).There was significant asymmetry in the funnel plots of both outcome measures indicating the presence of publication bias.We used a modified CAMARADES(Collaborative Approach to M eta-Analysis and Review of Animal Data in Experimental Studies)checklist to assess the risk of bias,finding that the median score was 4(IQR:3-5).In particula r,reports of allocation concealment and sample size calculations were lacking.In conclusion,gene therapies are showing promise as therapies for spinal co rd injury repair,but there is no consensus on which gene or genes should be targeted.
基金This work was supported in part by National Institutes of Health(NIH)grant(No.DK128845)Department of Defense grant(Nos.W81XWH-21-1-0097,W81XWH-21-1-0033,and W81XWH-20-1-251)to C.K.S,NIH grant(No.GM143572)to Y.X,and NIH grant(No.DK129592)to S.G.
文摘Hollow needle array-based tissue nanotransfection(TNT)presents an in vivo transfection approach that directly translocate exogeneous genes to target tissues by using electric pulses.In this work,the gene delivery process of TNT was simulated and experimentally validated.We adopted the asymptotic method and cell-array-based model to investigate the electroporation behaviors of cells within the skin structure.The distribution of nonuniform electric field across the skin results in various electroporation behavior for each cell.Cells underneath the hollow microchannels of the needle exhibited the highest total pore numbers compared to others due to the stronger localized electric field.The percentage of electroporated cells within the skin structure,with pore radius over 10 nm,increases from 25%to 82%as the applied voltage increases from 100 to 150 V/mm.Furthermore,the gene delivery behavior across the skin tissue was investigated through the multilayer-stack-based model.The delivery distance increased nonlinearly as the applied voltage and pulse number increased,which mainly depends on the diffusion characteristics and electric conductivity of each layer.It was also found that the skin is required to be exfoliated prior to the TNT procedure to enhance the delivery depth.This work provides the foundation for transition from the study of murine skin to translation use in large animals and human settings.
基金supported by the National Natural Science Foundation of China (Nos.51973019,22175024).
文摘Gene therapy is a promising method to treat acquired and inherited diseases by introducing exogenous genes into specific recipient cells.Polymeric micelles with different nanoscopic morphologies and properties hold great promise for gene delivery system.Conventional cationic polymers,poly(ethyleneimine)(PEI),poly(L-lysine)(PLL),poly(2-dimethylaminoethyl methacrylate)(PDMAEMA)and novel cationic polymers poly(2-oxazoline)s(POxs),have been incorporated into block copolymers and decorated with targeting moieties to enhance transfection efficiency.In order to minimize cytotoxicity,nonionic block copolymer micelles are utilized to load gene through hydrophilic and hydrophobic interactions or covalent conjugations,recently.From our perspective,properties(shape,size,and mechanical stiffness,etc.)of block copolymer micelles may significantly affect cytotoxicity,transfection efficiency,circulation time,and load capacity of gene vectors in vivo and in vitro.This review briefly sums up recent efforts in cationic and nonionic amphiphilic polymeric micelles for gene delivery.
基金financially supported by the Australian Research Council(ARC)Discovery Projects(Nos.DP140104062 and DP160104866)Fundamental Research Funds for the Central Universities(Nos.FRF-TP-19-017B1,2302015-06500017,FRF-BR-19-003B,FRF-BD-20-14A)National Natural Science Foundation of China(No.21501009)。
文摘Numerous nanocarriers have been currently developed for intracellular delivery.The potential cytotoxicity of these very small inorganic nanocarriers has raised great consideration.Thus,it becomes of utmost importance to conduct the intracellular trace of nanocarriers.Among many analytical techniques,surface enhanced Raman scattering(SERS)method is one of the current state-of-the-art techniques for cell visualization and trace.In this work,a novel stellate porous silica based gene delivery system has been designed for SERS trace purpose.A stellate porous silica nanoparticle modified with many small Au nanoparticles is designed to replace common metallic SERS tags.The results show that the designed system not only could deliver si RNA into cells for therapy,but also could realize SERS trace with high sensitivity and non-invasive features.The constructed delivery system has considerable potential to trace the dynamic gene delivery in living cells.
基金supported by the National Natural Science Foundation of China(grant number:81170914/H1304)
文摘There are several challenges to inner ear drug delivery and imaging due to the existence of tight biological barriers to the target structure and the dense bone surrounding it. Advances in imaging and nanomedicine may provide knowledge for overcoming the existing limitations to both the diagnosis and treatment of inner ear diseases. Novel techniques have improved the efficacy of drug delivery and targeting to the inner ear, as well as the quality and accuracy of imaging this structure. In this review, we will describe the pathways and biological barriers of the inner ear regarding drug delivery, the beneficial applications and limitations of the imaging techniques available for inner ear research, the behavior of engineered nanomaterials in inner ear applications, and future perspectives for nanomedicine-based inner ear imaging.
基金supported by the Consejo Nacional de Ciencia Tecnología(Conacyt)de México(Grant#254686,to DMF)。
文摘Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system,a hallmark in Parkinson's disease.The human cerebral dopamine neurotrophic factor(h CDNF)has recently emerged as a strong candidate for Parkinson's disease therapy.This study shows that h CDNF expression in dopamine neurons using the neurotensinpolyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological,biochemical,and behavioral alterations.Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the h CDNF gene,ranging in size from 20 to 150 nm,enabled the expression of a secretable h CDNF in vitro.Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable h CDNF in dopamine neurons,whose levels remained constant throughout the study in the substantia nigra compacta and striatum.Compared with the lesioned group,tyrosine hydroxylase-positive(TH^(+))nigral cell population and TH+fiber density rose in the substantia nigra compacta and striatum after h CDNF transfection.An increase inβIII-tubulin and growth-associated protein 43 phospho-S41(GAP43 p)followed TH^(+)cell recovery,as well as dopamine and its catabolite levels.Partial reversal(80%)of drugactivated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved.Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects.These findings support the potential of nanoparticle-mediated h CDNF gene delivery to develop a disease-modifying treatment against Parkinson's disease.The Institutional Animal Care and Use Committee of Centro de Investigación y de Estudios Avanzados approved our experimental procedures for animal use(authorization No.162-15)on June 9,2019.
文摘Localized delivery of drugs is an emerging field both with regards to drug delivery during disease as well as in tissue engineering.Despite significant achievements made in the last decades,the efficient delivery of proteins and peptides remains challenging,especially in cases requiring long-term release of proteins after application.The localized delivery of nucleic acids(NA)represents an interesting alternative due to higher physicochemical stability of NA,increased efficiency by harnessing cells as bioreactors for the production of required proteins and improved versatility with regards to expression of specific proteins through plasmid DNA or repression of gene products through siRNA.However,unlike most proteins and peptides,NA must be delivered to the cytoplasm or nucleus to be efficacious,resulting in significant delivery challenges.We herein describe frequently used non-viral vectors for the delivery of NA including polyplexes,lipoplexes and lipopolyplexes and summarize recent developments in the field of nucleic acid delivery systems for local application based on hydrogels,solid scaffolds and physical delivery methods.The challenges associated with the different approaches are identified and options to address these challenges are discussed.
基金the National Natural Science Foundation of China(No.50403021)Natural Science Foundation of Zhejiang Province(No.Y407173)the Education Department of Zhejiang Province(No.20051498)
文摘Enhanced stability of polyplexes in physiological condition was an important prerequisite for successful systemic gene delivery.Herein novel method was reported to develop stable gene vector by nanotechnology.Thiolated polyplexes were constructed and then cross-linked with gold nanoparticles(AuNPs)by gold-thiol interactions.TEM pictures showed that AuNPs were attached to the shell of spherical polyplexes.The hybrid gene vector was stable enough in physiological condition and maintained efficient transfec...
文摘Gene therapy offers important perspectives in current and future medicine but suffers from imperfect vectors for the delivery of the therapeutic gene. Most preclinical and clinical trials have been based on the use of viral vectors, which have evident advantages but also some serious disadvantages. In the past decade the use of DNA transposon-based systems for gene delivery has emerged as a non-viral alternative. DNA transposon vector engineering remains largely in a preclinical phase but some interesting results have been obtained. This mini-review aims to provide the current state of the art on DNA transposon vectors used in a gene therapy perspective.
文摘Gene deletion has been a valuable tool for unraveling the mysteries of molecular biology.Early approaches included gene trapping and gene targetting to disrupt or delete a gene randomly or at a specific location,respectively.Using these technologies in mouse embryos led to the generation of mouse knocko ut models and many scientific discoveries.The efficacy and specificity of these approaches have significantly increased with the advent of new technology such as cluste red regula rly inters paced short palindromic repeats for targetted gene deletion.However,several limitations including unwanted off-target gene deletion have hindered their widespread use in the field.Crerecombinase technology has provided additional capacity for cell-specific gene deletion.In this review,we provide a summary of currently available literature on the application of this system for targetted deletion of neuronal genes.This article has been constructed to provide some background info rmation for the new trainees on the mechanism and to provide necessary information for the design,and application of the Cre-recombinase system thro ugh reviewing the most f requent promoters that are currently available for genetic manipulation of neuro ns.We additionally will provide a summary of the latest technological developments that can be used for targeting neurons.This may also serve as a general guide for the selection of appropriate models for biomedical research.
基金financially supported by National Natural Science Foundation of China(NSFC,Nos.81873921 and 51903174)Sino-German Cooperation Group Project(No.GZ1512)+2 种基金China Postdoctoral Science Foundation(No.2021M702772)Chengdu Science and Technology Program(No.2020-GH02-00007-HZ)Sichuan University Postdoctoral Interdisciplinary Innovation Startup Foundation and the Fundamental Research Funds for Central Universities(No.2021SCU12070)。
文摘The integrated lipopeptide(RVA)/gene complexes are fabricated with bi-directional regulation on tumor cells and micro-environment.After self-assembling and target coating modification,the poly(γ-glutamic acid)(γ-PGA)/RVA nano-vectors can sequentially respond to pH&redox stimuli,and guarantee efficient therapeutic gene delivery and control release of all-trans retinoic acid.The design provides a facile but promising strategy to treat refractory cancers.