RNA interference(RNAi)using small interfering RNA(siRNA)has shown potential as a therapeutic option for the treatment of arthritis by silencing specific genes.However,siRNA delivery faces several challenges,including ...RNA interference(RNAi)using small interfering RNA(siRNA)has shown potential as a therapeutic option for the treatment of arthritis by silencing specific genes.However,siRNA delivery faces several challenges,including stability,targeting,off-target effects,endosomal escape,immune response activation,intravascular degradation,and renal clearance.A variety of nanotherapeutics like lipidic nanoparticles,liposomes,polymeric nanoparticles,and solid lipid nanoparticles have been developed to improve siRNA cellular uptake,protect it from degradation,and enhance its therapeutic efficacy.Researchers are also investigating chemical modifications and bioconjugation to reduce its immunogenicity.This review discusses the potential of siRNA nanotherapeutics as a therapeutic option for various immune-mediated diseases,including rheumatoid arthritis,osteoarthritis,etc.siRNA nanotherapeutics have shown an upsurge of interest and the future looks promising for such interdisciplinary approach-based modalities that combine the principles of molecular biology,nanotechnology,and formulation sciences.展开更多
Several crucial stromal cell populations regulate hematopoiesis and malignant diseases in bone marrow niches.Precise regulation of these cell types can remodel niches and develop new therapeutics.Multiple nanocarriers...Several crucial stromal cell populations regulate hematopoiesis and malignant diseases in bone marrow niches.Precise regulation of these cell types can remodel niches and develop new therapeutics.Multiple nanocarriers have been developed to transport drugs into the bone marrow selectively.However,the delivery efficiency of these nanotherapeutics into crucial niche cells is still unknown,and there is no method available for predicting delivery efficiency in these cell types.Here,we constructed a three-dimensional bone marrow niche composed of three crucial cell populations:endothelial cells(ECs),mesenchymal stromal cells(MSCs),and osteoblasts(OBs).Mimetic niches were used to detect the cellular uptake of three typical drug nanocarriers into ECs/MSCs/OBs in vitro.Less than 5%of nanocarriers were taken up by three stromal cell types,and most of themwere located in the extracellular matrix.Delivery efficiency in sinusoidal ECs,arteriole ECs,MSCs,and OBs in vivo was analyzed.The correlation analysis showed that the cellular uptake of three nanocarriers in crucial cell types in vitro is positively linear correlated with its delivery efficiency in vivo.The delivery efficiency into MSCs was remarkably higher than that into ECs and OBs,no matterwhat kind of nanocarrier.The overall efficiency into sinusoidal ECswas greatly lower than that into arteriole ECs.All nanocarriers were hard to be delivered into OBs(<1%).Our findings revealed that cell tropisms of nanocarriers with different compositions and ligand attachments in vivo could be predicted via detecting their cellular uptake in bone marrow niches in vitro.This study provided the methodology for niche-directed nanotherapeutics development.展开更多
Inflammatory bowel disease(IBD) is a chronic relapsing disease in gastrointestinal tract. Conventional medications lack the efficacy to offer complete remission in IBD therapy,and usually associate with serious side e...Inflammatory bowel disease(IBD) is a chronic relapsing disease in gastrointestinal tract. Conventional medications lack the efficacy to offer complete remission in IBD therapy,and usually associate with serious side effects. Recent studies indicated that nanoparticle-based nanotherapeutics may offer precise and safe alternative to conventional medications via enhanced targeting,sustained drug release,and decreased adverse effects. Here,we reviewed orally cell-specific nanotherapeutics developed in recent years. In addition,the various obstacles for oral drug delivery are also reviewed in this manuscript. Orally administrated cell-specific nanotherapeutics is expected to become a novel therapeutic approach for IBD treatment.展开更多
Acute kidney injury(AKI)is a serious kidney disease without specific medications currently except for expensive dialysis treatment.Some potential drugs are limited due to their high hydrophobicity,poor in vivo stabili...Acute kidney injury(AKI)is a serious kidney disease without specific medications currently except for expensive dialysis treatment.Some potential drugs are limited due to their high hydrophobicity,poor in vivo stability,low bioavailability and possible adverse effects.Besides,kidney-targeted drugs are not common and small molecules are cleared too quickly to achieve effective drug concentrations in injured kidneys.These problems limit the development of pharmacological therapy for AKI.Nanotherapeutics based on nanotechnology have been proved to be an emerging and promising treatment strategy for AKI,which may solve the pharmacological therapy dilemma.More and more nanotherapeutics with different physicochemical properties are developed to efficiently deliver drugs,increase accumulation and control release of drugs in injury kidneys and also directly as effective antioxidants.Here,we discuss the recent nanotherapeutics applied in the treatment and prevention of AKI with improved effectiveness and few side effects.展开更多
The clinical efficacy of current cancer therapies falls short,and there is a pressing demand to integrate new targets with conventional therapies.Autophagy,a highly conserved self-degradation process,has received cons...The clinical efficacy of current cancer therapies falls short,and there is a pressing demand to integrate new targets with conventional therapies.Autophagy,a highly conserved self-degradation process,has received considerable attention as an emerging therapeutic target for cancer.With the rapid development of nanomedicine,nanomaterials have been widely utilized in cancer therapy due to their unrivaled delivery performance.Hence,considering the potential benefits of integrating autophagy and nanotechnology in cancer therapy,we outline the latest advances in autophagy-based nanotherapeutics.Based on a brief background related to autophagy and nanotherapeutics and their impact on tumor progression,the feasibility of autophagy-based nanotherapeutics for cancer treatment is demonstrated.Further,emerging nanotherapeutics developed to modulate autophagy are reviewed from the perspective of cell signaling pathways,including modulation of the mammalian target of rapamycin(mTOR)pathway,autophagy-related(ATG)and its complex expression,reactive oxygen species(ROS)and mitophagy,interference with autophagosome-lysosome fusion,and inhibition of hypoxia-mediated autophagy.In addition,combination therapies in which nano-autophagy modulation is combined with chemotherapy,phototherapy,and immunotherapy are also described.Finally,the prospects and challenges of autophagy-based nanotherapeutics for efficient cancer treatment are envisioned.展开更多
During the development of leukemia,the overgrowth of leukemia cells in the bone marrow transforms the normal hematopoietic microenvironment into the leukemia microenvironment which favors its growth and inhibits norma...During the development of leukemia,the overgrowth of leukemia cells in the bone marrow transforms the normal hematopoietic microenvironment into the leukemia microenvironment which favors its growth and inhibits normal hematopoietic stem cells.The leukemia microenvironment exhibits abnormalities in redox substances,metabolism,immune response,mesenchymal cells,extracellular matrix,stromal cells,hypoxia,and more.These factors collectively provide a shelter for the malignant proliferation of leukemia cells.Recently,as the understanding of the leukemia microenvironment deepens,targeting or remodeling the abnormal leukemia microenvironment is becoming an effective strategy for leukemia treatment.Nanomedicine technology can effectively change pharmacokinetic profiles,thus demonstrating many advantages in modulating the leukemia microenvironment and improving therapeutic selectivity.In this review,we outline the characteristics of abnormal leukemia bone marrow microenvironment,focusing on the abnormal changes in the redox,metabolic and immune microenvironment.We also summarize emerging nanotechnology strategies in remodeling or targeting the aforementioned abnormal microenvironment.In addition,the unique advantages and bright prospects of nanotechnology in remodeling and targeting the leukemia microenvironment are discussed.展开更多
CRISPR, as an emerging gene editing technology, has been widely used in multiple fields due to its convenient operation, less cost, high efficiency and precision. This robust and effective device has revolutionized th...CRISPR, as an emerging gene editing technology, has been widely used in multiple fields due to its convenient operation, less cost, high efficiency and precision. This robust and effective device has revolutionized the development of biomedical research at an unexpected speed in recent years. The development of intelligent and precise CRISPR delivery strategies in a controllable and safe manner is the prerequisite for translational clinical medicine in gene therapy field. In this review, the therapeutic application of CRISPR delivery and the translational potential of gene editing was firstly discussed. Critical obstacles for the delivery of CRISPR system in vivo and shortcomings of CRISPR system itself were also analyzed. Given that intelligent nanoparticles have demonstrated great potential on the delivery of CRISPR system, here we mainly focused on stimuli-responsive nanocarriers. We also summarized various strategies for CIRSPR-Cas9 system delivered by intelligent nanocarriers which would respond to different endogenous and exogenous signal stimulus. Moreover, new genome editors mediated by nanotherapeutic vectors for gene therapy were also discussed. Finally, we discussed future prospects of genome editing for existing nanocarriers in clinical settings.展开更多
Liver fibrosis and hepatocellular carcinoma(HCC)have been worldwide threats nowadays.Liver fibrosis is reversible in early stages but will develop precancerosis of HCC in cirrhotic stage.In pathological liver,excessiv...Liver fibrosis and hepatocellular carcinoma(HCC)have been worldwide threats nowadays.Liver fibrosis is reversible in early stages but will develop precancerosis of HCC in cirrhotic stage.In pathological liver,excessive H_(2)O_(2) is generated and accumulated,which impacts the functionality of hepatocytes,Kupffer cells(KCs)and hepatic stellate cells(HSCs),leading to genesis of fibrosis and HCC.H_(2)O_(2) accumulation is associated with overproduction of superoxide anion(O_(2)^(·-))and abolished antioxidant enzyme systems.Plenty of therapeutics focused on H_(2)O_(2) have shown satisfactory effects against liver fibrosis or HCC in different ways.This review summarized the reasons of liver H_(2)O_(2) accumulation,and the role of H_(2)O_(2) in genesis of liver fibrosis and HCC.Additionally,nanotherapeutics targeting H_(2)O_(2) were summarized for further consideration of antifibrotic or antitumor therapy.展开更多
Inflammatory bowel disease(IBD)is a nonspecific inflammatory disease of the intestine that includes Crohn’s disease and ulcerative colitis.Because IBD is difficult to heal and easily relapses,it could worsen patient ...Inflammatory bowel disease(IBD)is a nonspecific inflammatory disease of the intestine that includes Crohn’s disease and ulcerative colitis.Because IBD is difficult to heal and easily relapses,it could worsen patient quality of life and increase economic burdens.Curcumin(CUR)is a bioactive component derived from the rhizome of turmeric(Curcuma longa).Many basic and clinical studies have shown that CUR can efficiently treat IBD by decreasing the activity of proinflammatory cytokines by communicating with transcription factors and signaling molecules.However,due to the limitations of being almost insoluble in aqueous solutions and having low oral bioavailability,it is important to select appropriate pharmaceutical preparations.展开更多
Moderate or severe burns are potentially devastating injuries that can even cause death,and many of them occur every year.Infection prevention,anti-inflammation,pain management and administration of growth factors pla...Moderate or severe burns are potentially devastating injuries that can even cause death,and many of them occur every year.Infection prevention,anti-inflammation,pain management and administration of growth factors play key roles in the treatment of burn wounds.Novel therapeutic strategies under development,such as nanotherapeutics,are promising prospects for burn wound treatment.Nanotherapeutics,including metallic and polymeric nanoformulations,have been extensively developed to manage various types of burns.Both human and animal studies have demonstrated that nanotherapeutics are biocompatible and effective in this application.Herein,we provide comprehensive knowledge of and an update on the progress of various nanoformulations for the treatment of burn wounds.展开更多
Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone ...Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.展开更多
Therapeutic options are quite limited in clinics for the successful repair of infected/degenerated tissues.Although the prevalent treatment is the complete removal of the whole infected tissue,this leads to a loss of ...Therapeutic options are quite limited in clinics for the successful repair of infected/degenerated tissues.Although the prevalent treatment is the complete removal of the whole infected tissue,this leads to a loss of tissue function and serious complications.Herein the dental pulp infection,as one of the most common dental problems,was selected as a clinically relevant case to regenerate using a multifunctional nanotherapeutic approach.For this,a mesoporous bioactive glass nano-delivery system incorporating silicate,calcium,and copper as well as loading epidermal growth factor(EGF)was designed to provide antibacterial/pro-angiogenic and osteo/odontogenic multiple therapeutic effects.Amine-functionalized Cu-doped bioactive glass nanospheres(Cu-BGn)were prepared to be 50–60 nm in size,mesoporous,positive-charged and bone-bioactive.The Cu-BGn could release bioactive ions(copper,calcium and silicate ions)with therapeutically-effective doses.The Cu-BGn treatment to human umbilical vein endothelial cells(HUVEC)led to significant enhancement of the migration,tubule formation and expression of angiogenic gene(e.g.vascular endothelial growth factor,VEGF).Furthermore,the EGF-loaded Cu-BGn(EGF@Cu-BGn)showed pro-angiogenic effects with antibacterial activity against E.faecalis,a pathogen commonly involved in the pulp infection.Of note,under the co-culture condition of HUVEC with E.faecalis,the secretion of VEGF was up-regulated.In addition,the osteo/odontogenic stimulation of the EGF@Cu-BGn was evidenced with human dental pulp stem cells.The local administration of the EGF@Cu-BGn in a rat molar tooth defect infected with E.faecalis revealed significant in vivo regenerative capacity,highlighting the nanotherapeutic uses of the multifunctional nanoparticles for regenerating infected/damaged hard tissues.展开更多
High-density lipoprotein (HDL) serves as a natural nanoparticle with compositional and functional heterogeneity and contributes to the maintenance of lipid metabolism and various biological functions. HDL also trans...High-density lipoprotein (HDL) serves as a natural nanoparticle with compositional and functional heterogeneity and contributes to the maintenance of lipid metabolism and various biological functions. HDL also transports endogenous microRNAs, vitamins, hormones, and proteins through blood and interstitial fluids to various organs. These unique and diverse features of HDL have encouraged its applications for the transport of therapeutics and diagnostic reagents in the last decade. In this review, we describe the heterogeneous characteristics and biological functions of HDL and highlight HDL mimetic approaches, including apolipoprotein mimetic peptides and reconstituted HDL nanoparticles. Given the potential of HDL as a nanocarrier delivering various therapeutic agents, we discuss the current representative studies of HDL mimetic nanotherapeutics for cardiovascular and neurodegenerative diseases and analyze the current challenges and future perspective.展开更多
There has been a lot of basic and clinical research on Alzheimer’s disease(AD)over the last 100 years,but its mechanisms and treatments have not been fully clarified.Despite some controversies,the amyloid-beta hypoth...There has been a lot of basic and clinical research on Alzheimer’s disease(AD)over the last 100 years,but its mechanisms and treatments have not been fully clarified.Despite some controversies,the amyloid-beta hypothesis is one of the most widely accepted causes of AD.In this study,we disclose a new amyloid-beta plaque disaggregating agent and an AD brain-targeted delivery system using porous silicon nanoparticles(pSiNPs)as a therapeutic nano-platform to overcome AD.We hypothesized that the negatively charged sulfonic acid functional group could disaggregate plaques and construct a chemical library.As a result of the in vitro assay of amyloid plaques and library screening,we confirmed that 6-amino-2-naphthalenesulfonic acid(ANA)showed the highest efficacy for plaque disaggregation as a hit compound.To confirm the targeted delivery of ANA to the AD brain,a nano-platform was created using porous silicon nanoparticles(pSiNPs)with ANA loaded into the pore of pSiNPs and biotin-polyethylene glycol(PEG)surface functionalization.The resulting nano-formulation,named Biotin-CaCl2-ANA-pSiNPs(BCAP),delivered a large amount of ANA to the AD brain and ameliorated memory impairment of the AD mouse model through the disaggregation of amyloid plaques in the brain.This study presents a new bioactive small molecule for amyloid plaque disaggregation and its promising therapeutic nano-platform for AD brain-targeted delivery.展开更多
Precise drug delivery to tumors with low system toxicity is one of the most important and challenging tasks for pharmaceutical researchers. Despite progress in the field of nanotherapeutics, the use of artificially sy...Precise drug delivery to tumors with low system toxicity is one of the most important and challenging tasks for pharmaceutical researchers. Despite progress in the field of nanotherapeutics, the use of artificially synthesized nanocarriers still faces several challenges, including rapid clearance from blood circulation and limited capability of overcoming multiple physiological barriers, which hamper the clinical application of nanoparticle-based therapies. Since leukocytes(including monocytes/macrophages,neutrophils, dendritic cells and lymphocytes) target tumors and can migrate across physiological barriers,leukocytes are increasing utilized as carriers to transfer nanoparticles to tumors. In this review we specifically focus on the molecular and cellular mechanisms of leukocytes that can be exploited as a vehicle to deliver nanoparticles to tumors and summarize the latest research on how leukocytes can be harnessed to improve therapeutic end-points. We also discuss the challenges and opportunities of this leukocyte-derived nanoparticle drug delivery system.展开更多
Hypoxic-ischemic encephalopathy is the leading cause of permanent brain injury in term newborns and currently has no cure. Inflammatory processes play a key role in the progression of this disease and may be amenable ...Hypoxic-ischemic encephalopathy is the leading cause of permanent brain injury in term newborns and currently has no cure. Inflammatory processes play a key role in the progression of this disease and may be amenable to a targeted pharmaceutical intervention. Curcumin is a dietary compound with potent anti-inflammatory, antioxidant, and antiapoptotic properties but is limited in therapeutic applications due to its low aqueous solubility, low bioavailability, and rapid first-pass hepatic metabolism. To address these limitations, loading curcumin into poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles may increase relevant pharmacokinetic parameters and allow for effective drug delivery to the brain. Using the Vannucci model of unilateral hypoxic-ischemic brain injury in neonatal rats, we studied the in vivo effect of curcumin-loaded PLGA-PEG nanoparticles on brain uptake and diffusion of curcumin and on neuroprotection. The curcumin-loaded nanoparticles were able to overcome the impaired blood-brain barrier, diffuse effectively through the brain parenchyma, localize in regions of injury, and deliver a protective effect in the injured neonatal brain. The application of curcumin and PLGA-PEG nanoparticle-mediated delivery to a clinically relevant model of neonatal brain injury provides greater opportunities for clinical translation of targeted therapies for hypoxic-ischemic encephalopathy.展开更多
文摘RNA interference(RNAi)using small interfering RNA(siRNA)has shown potential as a therapeutic option for the treatment of arthritis by silencing specific genes.However,siRNA delivery faces several challenges,including stability,targeting,off-target effects,endosomal escape,immune response activation,intravascular degradation,and renal clearance.A variety of nanotherapeutics like lipidic nanoparticles,liposomes,polymeric nanoparticles,and solid lipid nanoparticles have been developed to improve siRNA cellular uptake,protect it from degradation,and enhance its therapeutic efficacy.Researchers are also investigating chemical modifications and bioconjugation to reduce its immunogenicity.This review discusses the potential of siRNA nanotherapeutics as a therapeutic option for various immune-mediated diseases,including rheumatoid arthritis,osteoarthritis,etc.siRNA nanotherapeutics have shown an upsurge of interest and the future looks promising for such interdisciplinary approach-based modalities that combine the principles of molecular biology,nanotechnology,and formulation sciences.
基金support from the National Natural Science Foundation of China(81703713,82174095,82274364)Natural Science Foundation of Zhejiang Province grants(LZ23H290001,LZ22H290001)internal support from Zhejiang Chinese Medical University(2022GJYY011).
文摘Several crucial stromal cell populations regulate hematopoiesis and malignant diseases in bone marrow niches.Precise regulation of these cell types can remodel niches and develop new therapeutics.Multiple nanocarriers have been developed to transport drugs into the bone marrow selectively.However,the delivery efficiency of these nanotherapeutics into crucial niche cells is still unknown,and there is no method available for predicting delivery efficiency in these cell types.Here,we constructed a three-dimensional bone marrow niche composed of three crucial cell populations:endothelial cells(ECs),mesenchymal stromal cells(MSCs),and osteoblasts(OBs).Mimetic niches were used to detect the cellular uptake of three typical drug nanocarriers into ECs/MSCs/OBs in vitro.Less than 5%of nanocarriers were taken up by three stromal cell types,and most of themwere located in the extracellular matrix.Delivery efficiency in sinusoidal ECs,arteriole ECs,MSCs,and OBs in vivo was analyzed.The correlation analysis showed that the cellular uptake of three nanocarriers in crucial cell types in vitro is positively linear correlated with its delivery efficiency in vivo.The delivery efficiency into MSCs was remarkably higher than that into ECs and OBs,no matterwhat kind of nanocarrier.The overall efficiency into sinusoidal ECswas greatly lower than that into arteriole ECs.All nanocarriers were hard to be delivered into OBs(<1%).Our findings revealed that cell tropisms of nanocarriers with different compositions and ligand attachments in vivo could be predicted via detecting their cellular uptake in bone marrow niches in vitro.This study provided the methodology for niche-directed nanotherapeutics development.
基金Supported by the National Natural Science Foundation of China,No.51503172 and No.81571807the Fundamental Research Funds for the Central Universities,No.SWU114086 and No.XDJK2015C067+3 种基金the Scientific Research Foundation for the Returned Overseas Chinese Scholars(State Education Ministry)the Department of Veterans Affairs(Merit Award to Merlin D)the National Institutes of Health of Diabetes and Digestive and Kidney,No.RO1-DK-071594Career Scientist Award from the Department of Veterans Affairs(to Merlin D)
文摘Inflammatory bowel disease(IBD) is a chronic relapsing disease in gastrointestinal tract. Conventional medications lack the efficacy to offer complete remission in IBD therapy,and usually associate with serious side effects. Recent studies indicated that nanoparticle-based nanotherapeutics may offer precise and safe alternative to conventional medications via enhanced targeting,sustained drug release,and decreased adverse effects. Here,we reviewed orally cell-specific nanotherapeutics developed in recent years. In addition,the various obstacles for oral drug delivery are also reviewed in this manuscript. Orally administrated cell-specific nanotherapeutics is expected to become a novel therapeutic approach for IBD treatment.
基金supported by New Century 151 Talent Project of Zhejiang ProvinceJoint Institute of Lishui Hospital and Zhejiang University for nanomaterials and nanotechnology。
文摘Acute kidney injury(AKI)is a serious kidney disease without specific medications currently except for expensive dialysis treatment.Some potential drugs are limited due to their high hydrophobicity,poor in vivo stability,low bioavailability and possible adverse effects.Besides,kidney-targeted drugs are not common and small molecules are cleared too quickly to achieve effective drug concentrations in injured kidneys.These problems limit the development of pharmacological therapy for AKI.Nanotherapeutics based on nanotechnology have been proved to be an emerging and promising treatment strategy for AKI,which may solve the pharmacological therapy dilemma.More and more nanotherapeutics with different physicochemical properties are developed to efficiently deliver drugs,increase accumulation and control release of drugs in injury kidneys and also directly as effective antioxidants.Here,we discuss the recent nanotherapeutics applied in the treatment and prevention of AKI with improved effectiveness and few side effects.
基金the National Natural Science Foundation of China(No.81971729)for financial support.
文摘The clinical efficacy of current cancer therapies falls short,and there is a pressing demand to integrate new targets with conventional therapies.Autophagy,a highly conserved self-degradation process,has received considerable attention as an emerging therapeutic target for cancer.With the rapid development of nanomedicine,nanomaterials have been widely utilized in cancer therapy due to their unrivaled delivery performance.Hence,considering the potential benefits of integrating autophagy and nanotechnology in cancer therapy,we outline the latest advances in autophagy-based nanotherapeutics.Based on a brief background related to autophagy and nanotherapeutics and their impact on tumor progression,the feasibility of autophagy-based nanotherapeutics for cancer treatment is demonstrated.Further,emerging nanotherapeutics developed to modulate autophagy are reviewed from the perspective of cell signaling pathways,including modulation of the mammalian target of rapamycin(mTOR)pathway,autophagy-related(ATG)and its complex expression,reactive oxygen species(ROS)and mitophagy,interference with autophagosome-lysosome fusion,and inhibition of hypoxia-mediated autophagy.In addition,combination therapies in which nano-autophagy modulation is combined with chemotherapy,phototherapy,and immunotherapy are also described.Finally,the prospects and challenges of autophagy-based nanotherapeutics for efficient cancer treatment are envisioned.
基金the National Key R&D Program of China(No.2022YFE0111600)Liaoning Province Applied Basic Research Program(No.2022JH2/101300097)+3 种基金Liaoning Revitalization Talents Program(No.XLYC22202019)China Postdoctoral Science Foundation(No.2023MD744228)Postdoctoral Fellowship Program of CPSF(No.GZC20231731)General Program of Department of Education of Liaoning Province(No.JYTMS20231355)。
文摘During the development of leukemia,the overgrowth of leukemia cells in the bone marrow transforms the normal hematopoietic microenvironment into the leukemia microenvironment which favors its growth and inhibits normal hematopoietic stem cells.The leukemia microenvironment exhibits abnormalities in redox substances,metabolism,immune response,mesenchymal cells,extracellular matrix,stromal cells,hypoxia,and more.These factors collectively provide a shelter for the malignant proliferation of leukemia cells.Recently,as the understanding of the leukemia microenvironment deepens,targeting or remodeling the abnormal leukemia microenvironment is becoming an effective strategy for leukemia treatment.Nanomedicine technology can effectively change pharmacokinetic profiles,thus demonstrating many advantages in modulating the leukemia microenvironment and improving therapeutic selectivity.In this review,we outline the characteristics of abnormal leukemia bone marrow microenvironment,focusing on the abnormal changes in the redox,metabolic and immune microenvironment.We also summarize emerging nanotechnology strategies in remodeling or targeting the aforementioned abnormal microenvironment.In addition,the unique advantages and bright prospects of nanotechnology in remodeling and targeting the leukemia microenvironment are discussed.
基金funded by National Natural Science Foundation of China (No. 31901010)Jiangsu Specially Appointed Professorship Foundationthe Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine)。
文摘CRISPR, as an emerging gene editing technology, has been widely used in multiple fields due to its convenient operation, less cost, high efficiency and precision. This robust and effective device has revolutionized the development of biomedical research at an unexpected speed in recent years. The development of intelligent and precise CRISPR delivery strategies in a controllable and safe manner is the prerequisite for translational clinical medicine in gene therapy field. In this review, the therapeutic application of CRISPR delivery and the translational potential of gene editing was firstly discussed. Critical obstacles for the delivery of CRISPR system in vivo and shortcomings of CRISPR system itself were also analyzed. Given that intelligent nanoparticles have demonstrated great potential on the delivery of CRISPR system, here we mainly focused on stimuli-responsive nanocarriers. We also summarized various strategies for CIRSPR-Cas9 system delivered by intelligent nanocarriers which would respond to different endogenous and exogenous signal stimulus. Moreover, new genome editors mediated by nanotherapeutic vectors for gene therapy were also discussed. Finally, we discussed future prospects of genome editing for existing nanocarriers in clinical settings.
基金This work was financially supported by the National Natural Science Foundation of China(Nos.52003246,81922073 and 81973481)the Traditional Chinese Medicine Key Scientific Research Fund Project of Zhejiang Province(Nos.2018ZY004,2022ZQ032 and 2021ZZ009)the Youth Natural Science Program of Zhejiang Chinese Medical University(2021JKZKTS007A).
文摘Liver fibrosis and hepatocellular carcinoma(HCC)have been worldwide threats nowadays.Liver fibrosis is reversible in early stages but will develop precancerosis of HCC in cirrhotic stage.In pathological liver,excessive H_(2)O_(2) is generated and accumulated,which impacts the functionality of hepatocytes,Kupffer cells(KCs)and hepatic stellate cells(HSCs),leading to genesis of fibrosis and HCC.H_(2)O_(2) accumulation is associated with overproduction of superoxide anion(O_(2)^(·-))and abolished antioxidant enzyme systems.Plenty of therapeutics focused on H_(2)O_(2) have shown satisfactory effects against liver fibrosis or HCC in different ways.This review summarized the reasons of liver H_(2)O_(2) accumulation,and the role of H_(2)O_(2) in genesis of liver fibrosis and HCC.Additionally,nanotherapeutics targeting H_(2)O_(2) were summarized for further consideration of antifibrotic or antitumor therapy.
文摘Inflammatory bowel disease(IBD)is a nonspecific inflammatory disease of the intestine that includes Crohn’s disease and ulcerative colitis.Because IBD is difficult to heal and easily relapses,it could worsen patient quality of life and increase economic burdens.Curcumin(CUR)is a bioactive component derived from the rhizome of turmeric(Curcuma longa).Many basic and clinical studies have shown that CUR can efficiently treat IBD by decreasing the activity of proinflammatory cytokines by communicating with transcription factors and signaling molecules.However,due to the limitations of being almost insoluble in aqueous solutions and having low oral bioavailability,it is important to select appropriate pharmaceutical preparations.
基金supported by the Open Project Program of the State Key Laboratory of Trauma,Burn and Combined Injury,Third Military Medical University(No.SKLKF201905,SKLKF201918).
文摘Moderate or severe burns are potentially devastating injuries that can even cause death,and many of them occur every year.Infection prevention,anti-inflammation,pain management and administration of growth factors play key roles in the treatment of burn wounds.Novel therapeutic strategies under development,such as nanotherapeutics,are promising prospects for burn wound treatment.Nanotherapeutics,including metallic and polymeric nanoformulations,have been extensively developed to manage various types of burns.Both human and animal studies have demonstrated that nanotherapeutics are biocompatible and effective in this application.Herein,we provide comprehensive knowledge of and an update on the progress of various nanoformulations for the treatment of burn wounds.
基金supported by the National Natural Science Foundation of China(#81872220 and#81703437)Xinjiang Uygur Autonomous Region Science and Technology Support Project(#2020E0290)+4 种基金Basic Public Welfare Research Project of Zhejiang Province(#LGF18H160034,LGC21B050011 and#LGF20H300012),Science and Technology Bureau of Jiaxing(2020AY10021)Key Research and Development and Transformation project of Qinghai Province(2021-SF-C20)Dutch Cancer Foundation(KWF project#10666)a Zhejiang Provincial Foreign Expert Program Grant,Zhejiang Provincial Key Natural Science Foundation of China(#Z20H160031)and Jiaxing Key Laboratory of Oncological Photodynamic Therapy and Targeted Drug Research,and“Innovative Jiaxing·Excellent Talent Support Program”-Top Talents in Technological Innovation.
文摘Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.
基金a National Research Foundation of Korea(NRF)grant funded by the Ministry of Science and ICT(2019R1C1C1002490,2018R1A2B3003446)by the Global Research Development Center Program(2018K1A4A3A01064257)by the Priority Research Center Program provided by the Ministry of Education(2019R1A6A1A11034536)。
文摘Therapeutic options are quite limited in clinics for the successful repair of infected/degenerated tissues.Although the prevalent treatment is the complete removal of the whole infected tissue,this leads to a loss of tissue function and serious complications.Herein the dental pulp infection,as one of the most common dental problems,was selected as a clinically relevant case to regenerate using a multifunctional nanotherapeutic approach.For this,a mesoporous bioactive glass nano-delivery system incorporating silicate,calcium,and copper as well as loading epidermal growth factor(EGF)was designed to provide antibacterial/pro-angiogenic and osteo/odontogenic multiple therapeutic effects.Amine-functionalized Cu-doped bioactive glass nanospheres(Cu-BGn)were prepared to be 50–60 nm in size,mesoporous,positive-charged and bone-bioactive.The Cu-BGn could release bioactive ions(copper,calcium and silicate ions)with therapeutically-effective doses.The Cu-BGn treatment to human umbilical vein endothelial cells(HUVEC)led to significant enhancement of the migration,tubule formation and expression of angiogenic gene(e.g.vascular endothelial growth factor,VEGF).Furthermore,the EGF-loaded Cu-BGn(EGF@Cu-BGn)showed pro-angiogenic effects with antibacterial activity against E.faecalis,a pathogen commonly involved in the pulp infection.Of note,under the co-culture condition of HUVEC with E.faecalis,the secretion of VEGF was up-regulated.In addition,the osteo/odontogenic stimulation of the EGF@Cu-BGn was evidenced with human dental pulp stem cells.The local administration of the EGF@Cu-BGn in a rat molar tooth defect infected with E.faecalis revealed significant in vivo regenerative capacity,highlighting the nanotherapeutic uses of the multifunctional nanoparticles for regenerating infected/damaged hard tissues.
文摘High-density lipoprotein (HDL) serves as a natural nanoparticle with compositional and functional heterogeneity and contributes to the maintenance of lipid metabolism and various biological functions. HDL also transports endogenous microRNAs, vitamins, hormones, and proteins through blood and interstitial fluids to various organs. These unique and diverse features of HDL have encouraged its applications for the transport of therapeutics and diagnostic reagents in the last decade. In this review, we describe the heterogeneous characteristics and biological functions of HDL and highlight HDL mimetic approaches, including apolipoprotein mimetic peptides and reconstituted HDL nanoparticles. Given the potential of HDL as a nanocarrier delivering various therapeutic agents, we discuss the current representative studies of HDL mimetic nanotherapeutics for cardiovascular and neurodegenerative diseases and analyze the current challenges and future perspective.
基金supported by the National Key Research and Development Program of China (2022YFB3804600)the National Natural Science Foundation of China (22135005, 52073218,52273301, 51833007, and 51988102)+2 种基金Jiangsu Province Science Foundation for Youths (BK20200241)the Fundamental Research Funds for the Central Universities (2042022kf1162)the Center for Electron Microscopy at Wuhan University for their substantial supports for Transmission electron microscopy (JEM-2100)。
基金supported by Basic Science Research Program through the National Research Foundation(NRF)of Korea funded by the Ministry of Education(2018-R1A6A1A03025124D.K.)+5 种基金supported by Bio&Medical Technology Development Program of the NRF of Korea funded by the Ministry of Science&ICT(2022-M3A9H1014157,2021-M3A9I5030523D.K.)a grant from Korea Health Technology R&D Project of the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea(HI21C0239D.K.)supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(2022-R1F1A1069954D.K.).
文摘There has been a lot of basic and clinical research on Alzheimer’s disease(AD)over the last 100 years,but its mechanisms and treatments have not been fully clarified.Despite some controversies,the amyloid-beta hypothesis is one of the most widely accepted causes of AD.In this study,we disclose a new amyloid-beta plaque disaggregating agent and an AD brain-targeted delivery system using porous silicon nanoparticles(pSiNPs)as a therapeutic nano-platform to overcome AD.We hypothesized that the negatively charged sulfonic acid functional group could disaggregate plaques and construct a chemical library.As a result of the in vitro assay of amyloid plaques and library screening,we confirmed that 6-amino-2-naphthalenesulfonic acid(ANA)showed the highest efficacy for plaque disaggregation as a hit compound.To confirm the targeted delivery of ANA to the AD brain,a nano-platform was created using porous silicon nanoparticles(pSiNPs)with ANA loaded into the pore of pSiNPs and biotin-polyethylene glycol(PEG)surface functionalization.The resulting nano-formulation,named Biotin-CaCl2-ANA-pSiNPs(BCAP),delivered a large amount of ANA to the AD brain and ameliorated memory impairment of the AD mouse model through the disaggregation of amyloid plaques in the brain.This study presents a new bioactive small molecule for amyloid plaque disaggregation and its promising therapeutic nano-platform for AD brain-targeted delivery.
基金supported by National Natural Science Foundation of China (Nos. 81673019, 81690263 and 81373353)"Shu Guang" project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (15SG14)
文摘Precise drug delivery to tumors with low system toxicity is one of the most important and challenging tasks for pharmaceutical researchers. Despite progress in the field of nanotherapeutics, the use of artificially synthesized nanocarriers still faces several challenges, including rapid clearance from blood circulation and limited capability of overcoming multiple physiological barriers, which hamper the clinical application of nanoparticle-based therapies. Since leukocytes(including monocytes/macrophages,neutrophils, dendritic cells and lymphocytes) target tumors and can migrate across physiological barriers,leukocytes are increasing utilized as carriers to transfer nanoparticles to tumors. In this review we specifically focus on the molecular and cellular mechanisms of leukocytes that can be exploited as a vehicle to deliver nanoparticles to tumors and summarize the latest research on how leukocytes can be harnessed to improve therapeutic end-points. We also discuss the challenges and opportunities of this leukocyte-derived nanoparticle drug delivery system.
文摘Hypoxic-ischemic encephalopathy is the leading cause of permanent brain injury in term newborns and currently has no cure. Inflammatory processes play a key role in the progression of this disease and may be amenable to a targeted pharmaceutical intervention. Curcumin is a dietary compound with potent anti-inflammatory, antioxidant, and antiapoptotic properties but is limited in therapeutic applications due to its low aqueous solubility, low bioavailability, and rapid first-pass hepatic metabolism. To address these limitations, loading curcumin into poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles may increase relevant pharmacokinetic parameters and allow for effective drug delivery to the brain. Using the Vannucci model of unilateral hypoxic-ischemic brain injury in neonatal rats, we studied the in vivo effect of curcumin-loaded PLGA-PEG nanoparticles on brain uptake and diffusion of curcumin and on neuroprotection. The curcumin-loaded nanoparticles were able to overcome the impaired blood-brain barrier, diffuse effectively through the brain parenchyma, localize in regions of injury, and deliver a protective effect in the injured neonatal brain. The application of curcumin and PLGA-PEG nanoparticle-mediated delivery to a clinically relevant model of neonatal brain injury provides greater opportunities for clinical translation of targeted therapies for hypoxic-ischemic encephalopathy.