Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver dis-ease worldwide.NAFLD comprises a continuum of liver abnormalities from non-alcoholic fatty liver to nonalcoholic steatohepatitis,and can even...Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver dis-ease worldwide.NAFLD comprises a continuum of liver abnormalities from non-alcoholic fatty liver to nonalcoholic steatohepatitis,and can even lead to cirrhosis and liver cancer.However,a well-established treatment for NAFLD has yet to be identified.Exosomes have become an ideal drug delivery tool because of their high transmissibility,low immunogenicity,easy accessibility and targeting.Exosomes with specific modifications,known as engineered exosomes,have the potential to treat a variety of diseases.Here,we review the treatment of NAFLD with engineered exosomes and the potential use of exosomes as biomarkers and therapeutic targets for NAFLD.展开更多
Metastasis-associated processes are the predominant instigator of fatalities linked to cancer,wherein the pivotal role of circulating tumor cells lies in the resurgence of malignant growth.In recent epochs,exosomes,co...Metastasis-associated processes are the predominant instigator of fatalities linked to cancer,wherein the pivotal role of circulating tumor cells lies in the resurgence of malignant growth.In recent epochs,exosomes,constituents of the extracellular vesicle cohort,have garnered attention within the field of tumor theranostics owing to their inherent attributes encompassing biocompatibility,modifiability,payload capacity,stability,and therapeutic suitability.Nonetheless,the rudimentary functionalities and limited efficacy of unmodified exosomes curtail their prospective utility.In an effort to surmount these shortcomings,intricate methodologies amalgamating nanotechnology with genetic manipulation,chemotherapy,immunotherapy,and optical intervention present themselves as enhanced avenues to surveil and intercede in tumor metastasis and relapse.This review delves into the manifold techniques currently employed to engineer exosomes,with a specific focus on elucidating the interplay between exosomes and the metastatic cascade,alongside the implementation of tailored exosomes in abating tumor metastasis and recurrence.This review not only advances comprehension of the evolving landscape within this domain but also steers the trajectory of forthcoming investigations.展开更多
Cancer patients by immune checkpoint therapy have achieved long-term remission,with no recurrence of clinical symptoms of cancer for many years.Nevertheless,more than half of cancer patients are not responsive to this...Cancer patients by immune checkpoint therapy have achieved long-term remission,with no recurrence of clinical symptoms of cancer for many years.Nevertheless,more than half of cancer patients are not responsive to this therapy due to immune exhaustion.Here,we report a novel gene engineered exosome which is rationally designed by engineering PD1 gene and simultaneously enveloping an immune adjuvant imiquimod(PD1-Imi Exo)for boosting response of cancer immune checkpoint blockage therapy.The results showed that PD1-Imi Exo had a vesicular round shape(approximately 139 nm),revealed a significant targeting and a strong binding effect with both cancer cell and dendritic cell,and demonstrated a remarkable therapeutic efficacy in the melanomabearing mice and in the breast cancer-bearing mice.The mechanism was associated with two facts that PD1-Imi Exo blocked the binding of CD8+T cell with cancer cell,displaying a PD1/PDL1 immune checkpoint blockage effect,and that imiquimod released from PD1-Imi Exo promoted the maturation of immature dendritic cell,exhibiting a reversing effect on the immune exhaustion through activating and restoring function of CD8+T cell.In conclusion,the gene engineered exosome could be used for reversing T cell exhaustion in cancer immuno-therapy.This study also offers a promising new strategy for enhancing PD1/PDL1 therapeutic efficacy,pre-venting tumor recurrence or metastasis after surgery by rebuilding the patients’immunity,thus consolidating the overall prognosis.展开更多
Exosomes are extracellular vesicles which carry specific molecular information from donor cells and act as an intercellular communication vehicle,which have emerged as a novel cell-free strategy for the treatment of m...Exosomes are extracellular vesicles which carry specific molecular information from donor cells and act as an intercellular communication vehicle,which have emerged as a novel cell-free strategy for the treatment of many diseases including inflammatory disease.Recently,rising studies have developed exosome-based strategies for novel inflammation therapy due to their biocompatibility and bioactivity.Researchers not only use native exosomes as therapeutic agents for inflammation,but also strive to make up for the natural defects of exosomes through engineering methods to improve and update the property of exosomes for enhanced therapeutic effects.The engineered exosomes can improve cargo-loading efficiency,targeting ability,stability,etc.,to achieve combined and diverse treatment strategies in inflammation diseases.Herein,a comprehensive overview of the recent advances in application studies of native and engineered exosomes as well as the engineered methods is provided.Meanwhile,potential application prospects,possible challenges,the development of clinical researches of exosome treatment strategy are concluded from plentiful examples,which may be able to provide guidance and suggestions for the future research and application of exosomes.展开更多
Cancer patients by immune checkpoint therapy have achieved long-term remission,with no recurrence of clinical symptoms of cancer for many years.Nevertheless,more than half of cancer patients are not responsive to this...Cancer patients by immune checkpoint therapy have achieved long-term remission,with no recurrence of clinical symptoms of cancer for many years.Nevertheless,more than half of cancer patients are not responsive to this therapy due to immune exhaustion.Here,we report a novel gene engineered exosome which is rationally designed by engineering PD1 gene and simultaneously enveloping an immune adjuvant imiquimod(PD1-Imi Exo)for boosting response of cancer immune checkpoint blockage therapy.The results showed that PD1-Imi Exo had a vesicular round shape(approximately 139 nm),revealed a significant targeting and a strong binding effect with both cancer cell and dendritic cell,and demonstrated a remarkable therapeutic efficacy in the melanoma-bearing mice and in the breast cancer-bearing mice.The mechanism was associated with two facts that PD1-Imi Exo blocked the binding of CD8^(+)T cell with cancer cell,displaying a PD1/PDL1 immune checkpoint blockage effect,and that imiquimod released from PD1-Imi Exo promoted the maturation of immature dendritic cell,exhibiting a reversing effect on the immune exhaustion through activating and restoring function of CD8^(+)T cell.In conclusion,the gene engineered exosome could be used for reversing T cell exhaustion in cancer immunotherapy.This study also offers a promising new strategy for enhancing PD1/PDL1 therapeutic efficacy,preventing tumor recurrence or metastasis after surgery by rebuilding the patients’immunity,thus consolidating the overall prognosis.展开更多
Diabetic foot ulcer(DFU),characterized by high recurrence rate,amputations and mortality,poses a significant challenge in diabetes management.The complex pathology involves dysregulated glucose homeostasis leading to ...Diabetic foot ulcer(DFU),characterized by high recurrence rate,amputations and mortality,poses a significant challenge in diabetes management.The complex pathology involves dysregulated glucose homeostasis leading to systemic and local microenvironmental complications,including peripheral neuropathy,micro-and macro-angiopathy,recurrent infection,persistent inflammation and dysregulated re-epithelialization.Novel approaches to accelerate DFU healing are actively pursued,with a focus on utilizing exosomes.Exosomes are natural nanovesicles mediating cellular communication and containing diverse functional molecular cargos,including DNA,mRNA,microRNA(miRNA),lncRNA,proteins,lipids and metabolites.While some exosomes show promise in modulating cellular function and promoting ulcer healing,their efficacy is limited by low yield,impurities,low loading content and inadequate targeting.Engineering exosomes to enhance their curative activity represents a potentially more efficient approach for DFUs.This could facilitate focused repair and regeneration of nerves,blood vessels and soft tissue after ulcer development.This review provides an overview of DFU pathogenesis,strategies for exosome engineering and the targeted therapeutic application of engineered exosomes in addressing critical pathological changes associated with DFUs.展开更多
Addressing the urgent need for innovative depression treatments,this study heralds a breakthrough in major depressive disorder(MDD)therapy by intertwining clinical observations with neurobiological advancements.We ana...Addressing the urgent need for innovative depression treatments,this study heralds a breakthrough in major depressive disorder(MDD)therapy by intertwining clinical observations with neurobiological advancements.We analyzed brain-derived neurotrophic factor(BDNF)levels in serum exosomes from a diverse group of 60 individuals,including first-episode,drug-free MDD patients,medicated MDD patients,and healthy controls.Our results revealed a significant decrease in BDNF levels within MDD patients’exosomes,which notably increased post-medication,highlighting BDNF’s potential as a biomarker for both MDD diagnosis and treatment efficacy.Advancing these clinical findings,we developed RVG-modified exosomes engineered to overexpress BDNF(RVG-BDNF-Exos),designed to directly target neuronal cells.Our findings demonstrate that these engineered exosomes can successfully traverse the blood–brain barrier,targeting neurons in the hippocampus and prefrontal cortex.In our mouse model of depression induced by lipopolysaccharide,RVG-BDNF-Exos treatment led to a significant increase of BDNF in these key brain regions,crucial for mood regulation and neurogenesis.This intervention modulated the BDNF/TrkB/AKT signaling pathway,central to neural plasticity and implicated in depression’s pathogenesis.Behavioral assessments exhibited substantial improvements in depressive-like behaviors in mice treated with RVG-BDNF-Exos,including reduced immobility in Tail Suspension and Forced Swim Tests.Additionally,our treatment effectively decreased neuroinflammation,as evidenced by the reduction in microglia and astrocyte numbers.Moreover,RVG-BDNF-Exos treatment enhanced neurogenesis and regulated synaptic plasticity,as indicated by the increased expression of neuronal markers MAP2 and DCX,and synaptic proteins PSD95 and Syn-1.In conclusion,this study not only underscores the clinical potential of serum exosomal BDNF as a diagnostic and therapeutic marker for MDD but also demonstrates the efficacy of RVG-BDNF-Exos in alleviating depressive symptoms.Our findings pave the way for future targeted,personalized psychiatric treatments,offering a promising direction in MDD therapy.展开更多
The periosteum,a fibrous tissue membrane covering bone surfaces,is critical to osteogenesis and angiogenesis in bone reconstruction.Artificial periostea have been widely developed for bone defect repair,but most of th...The periosteum,a fibrous tissue membrane covering bone surfaces,is critical to osteogenesis and angiogenesis in bone reconstruction.Artificial periostea have been widely developed for bone defect repair,but most of these are lacking of periosteal bioactivity.Herein,a biomimetic periosteum(termed PEC-Apt-NP-Exo)is prepared based on an electrospun membrane combined with engineered exosomes(Exos).The electrospun membrane is fabricated using poly(ε-caprolactone)(core)-periosteal decellularized extracellular matrix(shell)fibers via coaxial elec-trospinning,to mimic the fibrous structure,mechanical property,and tissue microenvironment of natural periosteum.The engineered Exos derived from M2 macrophages are functionalized by surface modification of bone marrow mesenchymal stem cell(BMSC)-specific aptamers to further enhance cell recruitment,immuno-regulation,and angiogenesis in bone healing.The engineered Exos are covalently bonded to the electrospun membrane,to achieve rich loading and long-term effects of Exos.In vitro experiments demonstrate that the biomimetic periosteum promotes BMSC migration and osteogenic differentiation via Rap1/PI3K/AKT signaling pathway,and enhances vascular endothelial growth factor secretion from BMSCs to facilitate angiogenesis.In vivo studies reveal that the biomimetic periosteum promotes new bone formation in large bone defect repair by inducing M2 macrophage polarization,endogenous BMSC recruitment,osteogenic differentiation,and vascu-larization.This research provides valuable insights into the development of a multifunctional biomimetic peri-osteum for bone regeneration.展开更多
Low back pain,mainly caused by intervertebral disc degeneration(IVDD),is a common health problem;however,current surgical treatments are less than satisfactory.Thus,it is essential to develop novel non-invasive surgic...Low back pain,mainly caused by intervertebral disc degeneration(IVDD),is a common health problem;however,current surgical treatments are less than satisfactory.Thus,it is essential to develop novel non-invasive surgical methods for IVDD treatment.Here,we describe a therapeutic strategy to inhibit IVDD by injecting hydrogels modified with the extracellular matrix of costal cartilage(ECM-Gels)that are loaded with cartilage endplate stem cells(CESCs).After loaded with CESCs overexpressing Sphk2(Lenti-Sphk2-CESCs)and injected near the cartilage endplate(CEP)of rats in vivo,ECM-Gels produced Sphk2-engineered exosomes(Lenti-Sphk2-Exos).These exosomes penetrated the annulus fibrosus(AF)and transported Sphk2 into the nucleus pulposus cells(NPCs).Sphk2 activated the phosphatidylinositol 3-kinase(PI3K)/p-AKT pathway as well as the intracellular autophagy of NPCs,ultimately ameliorating IVDD.This study provides a novel and efficient non-invasive combinational strategy for IVDD treatment using injectable ECM-Gels loaded with CESCs that express Sphk2 with sustained release of functional exosomes.展开更多
Rationale:Chronic wounds associated with diabetes exact a heavy burden on individuals and society and do not have a specific treatment.Exosome therapy is an extension of stem cell therapy,and RNA interference(RNAi)-ba...Rationale:Chronic wounds associated with diabetes exact a heavy burden on individuals and society and do not have a specific treatment.Exosome therapy is an extension of stem cell therapy,and RNA interference(RNAi)-based therapy is a type of advanced precision therapy.Based on the discovery of chronic wound-related genes in diabetes,we combined exosome therapy and RNAi therapy through an engineering approach for the treatment of diabetic chronic wounds.Methods:We combined exosome therapy and RNAi therapy to establish a precision therapy for diabetes-associated wounds via an engineered exosome approach.Results:First,chronic diabetic wounds express low levels of miR-31-5p compared with nondiabetic wounds,and an miR-31-5p mimic was shown to be effective in promoting the proliferation and migration of three wound-related cell types in vitro.Second,bioinformatics analysis,luciferase reporter assays and western blotting suggested that miR-31-5p promoted angiogenesis,fibrogenesis and reepithelization by inhibiting factor-inhibiting HIF-1(HIF1AN,also named FIH)and epithelial membrane protein-1(EMP-1).Third,engineered miR-31 exosomes were generated as a miR-31-5p RNAi therapeutic agent.In vivo,the engineered miR-31 exosomes promoted diabetic wound healing by enhancing angiogenesis,fibrogenesis and reepithelization.Conclusion:Engineered miR-31 exosomes are an ideal disease pathophysiology-initiated RNAi therapeutic agent for diabetic wounds.展开更多
Rheumatoid arthritis(RA)is a chronic inflammatory disease characterized by synovitis and destruction of cartilage,promoted by sustained inflammation.However,current treatments remain unsatisfactory due to lacking of s...Rheumatoid arthritis(RA)is a chronic inflammatory disease characterized by synovitis and destruction of cartilage,promoted by sustained inflammation.However,current treatments remain unsatisfactory due to lacking of selective and effective strategies for alleviating inflammatory environments in RA joint.Inspired by neutrophil chemotaxis for inflammatory region,we therefore developed neutrophil-derived exosomes functionalized with sub-5 nm ultrasmall Prussian blue nanoparticles(uPB-Exo)via click chemistry,inheriting neutrophil-targeted biological molecules and owning excellent anti-inflammatory properties.uPB-Exo can selectively accumulate in activated fibroblast-like synoviocytes,subsequently neutralizing pro-inflammatory factors,scavenging reactive oxygen species,and alleviating inflammatory stress.In addition,uPB-Exo effectively targeted to inflammatory synovitis,penetrated deeply into the cartilage and real-time visualized inflamed joint through MRI system,leading to precise diagnosis of RA in vivo with high sensitivity and specificity.Particularly,uPB-Exo induced a cascade of anti-inflammatory events via Th17/Treg cell balance regulation,thereby significantly ameliorating joint damage.Therefore,nanoenzyme functionalized exosomes hold the great potential for enhanced treatment of RA in clinic.展开更多
The versatile multi-territory perforator flap remains a cornerstone of reconstructive surgery for diabetic ulcerations,yet its clinical efficacy faces significant challenges in hyperglycemic conditions.The diabetic mi...The versatile multi-territory perforator flap remains a cornerstone of reconstructive surgery for diabetic ulcerations,yet its clinical efficacy faces significant challenges in hyperglycemic conditions.The diabetic milieu significantly exacerbates tissue ischemia through augmented chronic inflammation and impaired angiogenesis,which collectively harm flap perfusion and compromise its overall viability.A major postoperative complication is distal flap necrosis,which is closely associated with the critical“Choke zone,”a hypoperfused transitional area that exhibits delayed vascular recruitment and suboptimal angiogenesis.This vascular bottleneck creates a precarious balance between tissue oxygen demand and supply,ultimately compromising flap viability.To address this issue,we have developed the engineering stem cell exosomes by encapsulating metformin-loaded Mesoporous silica nanoparticles into BMSC exosomes(M-MS@EXO NPs),enabling the release of metformin.Compared to traditional oral medication,delivering metformin through engineered exosomes allows for precise administration in diabetic wounds.The multifunctional M-MS@EXO NPs exhibit dual pharmacological activity by reducing the secretion of inflammatory cytokines while effectively remodeling the vascular niche within the diabetic microenvironment.Additionally,the M-MS@EXO NPs show anti-inflammatory and angiogenesis effects by inhibiting TNF/apoptosis and enhancing VEGF signaling pathways in vitro.In the dorsal multi-territory perforator flap model of type 2 diabetes,the M-MS@EXO NPs demonstrate the ability to alleviate inflammation and promote neovascularization of the Choke zone,reducing distal necrosis,which holds great promise for improving flap survival in diabetes.展开更多
Exosome is an excellent vesicle for in vivo delivery of therapeutics,including RNAi and chemical drugs.The extremely high efficiency in cancer regression can partly be attributed to its fusion mechanism in delivering ...Exosome is an excellent vesicle for in vivo delivery of therapeutics,including RNAi and chemical drugs.The extremely high efficiency in cancer regression can partly be attributed to its fusion mechanism in delivering therapeutics to cytosol without endosome trapping.However,being composed of a lipidbilayer membrane without specific recognition capacity for aimed-cells,the entry into nonspecific cells can lead to potential side-effects and toxicity.Applying engineering approaches for targeting-capacity to deliver therapeutics to specific cells is desirable.Techniques with chemical modification in vitro and genetic engineering in cells have been reported to decorate exosomes with targeting ligands.RNA nanoparticles have been used to harbor tumor-specific ligands displayed on exosome surface.The negative charge reduces nonspecific binding to vital cells with negatively charged lipid-membrane due to the electrostatic repulsion,thus lowering the side-effect and toxicity.In this review,we focus on the uniqueness of RNA nanoparticles for exosome surface display of chemical ligands,small peptides or RNA aptamers,for specific cancer targeting to deliver anticancer therapeutics,highlighting recent advances in targeted delivery of siRNA and miRNA that overcomes the previous RNAi delivery roadblocks.Proper understanding of exosome engineering with RNA nanotechnology promises efficient therapies for a wide range of cancer subtypes.展开更多
基金National Natural Science Foundation of China,No.81970535。
文摘Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver dis-ease worldwide.NAFLD comprises a continuum of liver abnormalities from non-alcoholic fatty liver to nonalcoholic steatohepatitis,and can even lead to cirrhosis and liver cancer.However,a well-established treatment for NAFLD has yet to be identified.Exosomes have become an ideal drug delivery tool because of their high transmissibility,low immunogenicity,easy accessibility and targeting.Exosomes with specific modifications,known as engineered exosomes,have the potential to treat a variety of diseases.Here,we review the treatment of NAFLD with engineered exosomes and the potential use of exosomes as biomarkers and therapeutic targets for NAFLD.
基金supported by the Top young and middleaged medical talent of Chongqing,Top young and middleaged medical studio of Chongqing,Chongqing Science and Health Joint fund for top young and middle-aged talent(2023GDRC007)the Key project for clinical innovation of Army Medical University(CX2019LC107)the project for Chongqing University Innovation Research Group,Chongqing Education Committee(CXQT20006).
文摘Metastasis-associated processes are the predominant instigator of fatalities linked to cancer,wherein the pivotal role of circulating tumor cells lies in the resurgence of malignant growth.In recent epochs,exosomes,constituents of the extracellular vesicle cohort,have garnered attention within the field of tumor theranostics owing to their inherent attributes encompassing biocompatibility,modifiability,payload capacity,stability,and therapeutic suitability.Nonetheless,the rudimentary functionalities and limited efficacy of unmodified exosomes curtail their prospective utility.In an effort to surmount these shortcomings,intricate methodologies amalgamating nanotechnology with genetic manipulation,chemotherapy,immunotherapy,and optical intervention present themselves as enhanced avenues to surveil and intercede in tumor metastasis and relapse.This review delves into the manifold techniques currently employed to engineer exosomes,with a specific focus on elucidating the interplay between exosomes and the metastatic cascade,alongside the implementation of tailored exosomes in abating tumor metastasis and recurrence.This review not only advances comprehension of the evolving landscape within this domain but also steers the trajectory of forthcoming investigations.
文摘Cancer patients by immune checkpoint therapy have achieved long-term remission,with no recurrence of clinical symptoms of cancer for many years.Nevertheless,more than half of cancer patients are not responsive to this therapy due to immune exhaustion.Here,we report a novel gene engineered exosome which is rationally designed by engineering PD1 gene and simultaneously enveloping an immune adjuvant imiquimod(PD1-Imi Exo)for boosting response of cancer immune checkpoint blockage therapy.The results showed that PD1-Imi Exo had a vesicular round shape(approximately 139 nm),revealed a significant targeting and a strong binding effect with both cancer cell and dendritic cell,and demonstrated a remarkable therapeutic efficacy in the melanomabearing mice and in the breast cancer-bearing mice.The mechanism was associated with two facts that PD1-Imi Exo blocked the binding of CD8+T cell with cancer cell,displaying a PD1/PDL1 immune checkpoint blockage effect,and that imiquimod released from PD1-Imi Exo promoted the maturation of immature dendritic cell,exhibiting a reversing effect on the immune exhaustion through activating and restoring function of CD8+T cell.In conclusion,the gene engineered exosome could be used for reversing T cell exhaustion in cancer immuno-therapy.This study also offers a promising new strategy for enhancing PD1/PDL1 therapeutic efficacy,pre-venting tumor recurrence or metastasis after surgery by rebuilding the patients’immunity,thus consolidating the overall prognosis.
基金the National Natural Science Foundation of China(Nos.51773154,31771090,31971323,and 81871315)Shanghai Science and Technology Innovation(No.18JC1414500)Young Hundred-Talent Program of Tongji University.
文摘Exosomes are extracellular vesicles which carry specific molecular information from donor cells and act as an intercellular communication vehicle,which have emerged as a novel cell-free strategy for the treatment of many diseases including inflammatory disease.Recently,rising studies have developed exosome-based strategies for novel inflammation therapy due to their biocompatibility and bioactivity.Researchers not only use native exosomes as therapeutic agents for inflammation,but also strive to make up for the natural defects of exosomes through engineering methods to improve and update the property of exosomes for enhanced therapeutic effects.The engineered exosomes can improve cargo-loading efficiency,targeting ability,stability,etc.,to achieve combined and diverse treatment strategies in inflammation diseases.Herein,a comprehensive overview of the recent advances in application studies of native and engineered exosomes as well as the engineered methods is provided.Meanwhile,potential application prospects,possible challenges,the development of clinical researches of exosome treatment strategy are concluded from plentiful examples,which may be able to provide guidance and suggestions for the future research and application of exosomes.
基金supported by the National Natural Science Foundation of China(No.82173752 and No.81874303).
文摘Cancer patients by immune checkpoint therapy have achieved long-term remission,with no recurrence of clinical symptoms of cancer for many years.Nevertheless,more than half of cancer patients are not responsive to this therapy due to immune exhaustion.Here,we report a novel gene engineered exosome which is rationally designed by engineering PD1 gene and simultaneously enveloping an immune adjuvant imiquimod(PD1-Imi Exo)for boosting response of cancer immune checkpoint blockage therapy.The results showed that PD1-Imi Exo had a vesicular round shape(approximately 139 nm),revealed a significant targeting and a strong binding effect with both cancer cell and dendritic cell,and demonstrated a remarkable therapeutic efficacy in the melanoma-bearing mice and in the breast cancer-bearing mice.The mechanism was associated with two facts that PD1-Imi Exo blocked the binding of CD8^(+)T cell with cancer cell,displaying a PD1/PDL1 immune checkpoint blockage effect,and that imiquimod released from PD1-Imi Exo promoted the maturation of immature dendritic cell,exhibiting a reversing effect on the immune exhaustion through activating and restoring function of CD8^(+)T cell.In conclusion,the gene engineered exosome could be used for reversing T cell exhaustion in cancer immunotherapy.This study also offers a promising new strategy for enhancing PD1/PDL1 therapeutic efficacy,preventing tumor recurrence or metastasis after surgery by rebuilding the patients’immunity,thus consolidating the overall prognosis.
基金supported by grants from the National Natural Science Foundation of China(No.82272261)Shanxi Province Foundation of China(No.2022JC-58,No.2021ZDLSF03-13,No.2021SF-341)+1 种基金R&D Program of Beijing Municipal Education Commission(KM202010025013)Beijing Municipal Natural Science Foundation(BJNSF7222078)to HX。
文摘Diabetic foot ulcer(DFU),characterized by high recurrence rate,amputations and mortality,poses a significant challenge in diabetes management.The complex pathology involves dysregulated glucose homeostasis leading to systemic and local microenvironmental complications,including peripheral neuropathy,micro-and macro-angiopathy,recurrent infection,persistent inflammation and dysregulated re-epithelialization.Novel approaches to accelerate DFU healing are actively pursued,with a focus on utilizing exosomes.Exosomes are natural nanovesicles mediating cellular communication and containing diverse functional molecular cargos,including DNA,mRNA,microRNA(miRNA),lncRNA,proteins,lipids and metabolites.While some exosomes show promise in modulating cellular function and promoting ulcer healing,their efficacy is limited by low yield,impurities,low loading content and inadequate targeting.Engineering exosomes to enhance their curative activity represents a potentially more efficient approach for DFUs.This could facilitate focused repair and regeneration of nerves,blood vessels and soft tissue after ulcer development.This review provides an overview of DFU pathogenesis,strategies for exosome engineering and the targeted therapeutic application of engineered exosomes in addressing critical pathological changes associated with DFUs.
基金supported by the National Natural Science Foundation of China(no.82071676).
文摘Addressing the urgent need for innovative depression treatments,this study heralds a breakthrough in major depressive disorder(MDD)therapy by intertwining clinical observations with neurobiological advancements.We analyzed brain-derived neurotrophic factor(BDNF)levels in serum exosomes from a diverse group of 60 individuals,including first-episode,drug-free MDD patients,medicated MDD patients,and healthy controls.Our results revealed a significant decrease in BDNF levels within MDD patients’exosomes,which notably increased post-medication,highlighting BDNF’s potential as a biomarker for both MDD diagnosis and treatment efficacy.Advancing these clinical findings,we developed RVG-modified exosomes engineered to overexpress BDNF(RVG-BDNF-Exos),designed to directly target neuronal cells.Our findings demonstrate that these engineered exosomes can successfully traverse the blood–brain barrier,targeting neurons in the hippocampus and prefrontal cortex.In our mouse model of depression induced by lipopolysaccharide,RVG-BDNF-Exos treatment led to a significant increase of BDNF in these key brain regions,crucial for mood regulation and neurogenesis.This intervention modulated the BDNF/TrkB/AKT signaling pathway,central to neural plasticity and implicated in depression’s pathogenesis.Behavioral assessments exhibited substantial improvements in depressive-like behaviors in mice treated with RVG-BDNF-Exos,including reduced immobility in Tail Suspension and Forced Swim Tests.Additionally,our treatment effectively decreased neuroinflammation,as evidenced by the reduction in microglia and astrocyte numbers.Moreover,RVG-BDNF-Exos treatment enhanced neurogenesis and regulated synaptic plasticity,as indicated by the increased expression of neuronal markers MAP2 and DCX,and synaptic proteins PSD95 and Syn-1.In conclusion,this study not only underscores the clinical potential of serum exosomal BDNF as a diagnostic and therapeutic marker for MDD but also demonstrates the efficacy of RVG-BDNF-Exos in alleviating depressive symptoms.Our findings pave the way for future targeted,personalized psychiatric treatments,offering a promising direction in MDD therapy.
基金the National Natural Science Foundation of China(Grant No.82301025)the Talents Introduction of Guangdong Provincial People’s Hospital(Grant Nos.KY0120220255,3227100558,8237030185)+4 种基金Guangzhou Municipal Science and Technology Bureau(Grant No.2024A04J4888)the National Key Research and Development Program of China(Grant No.2023YFC2413600)the Natural Science Foundation of Guangdong Province(Grant No.2022A1515110916)the GJYC pro-gram of Guangzhou(Grant No.2024D03J0004)the National Nat-ural Science Foundation of China(Grant No.52433010).
文摘The periosteum,a fibrous tissue membrane covering bone surfaces,is critical to osteogenesis and angiogenesis in bone reconstruction.Artificial periostea have been widely developed for bone defect repair,but most of these are lacking of periosteal bioactivity.Herein,a biomimetic periosteum(termed PEC-Apt-NP-Exo)is prepared based on an electrospun membrane combined with engineered exosomes(Exos).The electrospun membrane is fabricated using poly(ε-caprolactone)(core)-periosteal decellularized extracellular matrix(shell)fibers via coaxial elec-trospinning,to mimic the fibrous structure,mechanical property,and tissue microenvironment of natural periosteum.The engineered Exos derived from M2 macrophages are functionalized by surface modification of bone marrow mesenchymal stem cell(BMSC)-specific aptamers to further enhance cell recruitment,immuno-regulation,and angiogenesis in bone healing.The engineered Exos are covalently bonded to the electrospun membrane,to achieve rich loading and long-term effects of Exos.In vitro experiments demonstrate that the biomimetic periosteum promotes BMSC migration and osteogenic differentiation via Rap1/PI3K/AKT signaling pathway,and enhances vascular endothelial growth factor secretion from BMSCs to facilitate angiogenesis.In vivo studies reveal that the biomimetic periosteum promotes new bone formation in large bone defect repair by inducing M2 macrophage polarization,endogenous BMSC recruitment,osteogenic differentiation,and vascu-larization.This research provides valuable insights into the development of a multifunctional biomimetic peri-osteum for bone regeneration.
基金supported by the National Natural Science Foundation of China(Grant Number:81874028,81702182)the Research Program of Foundation Science and Application Technology of Chongqing(Grant Number:cstc2018jcyjAX0598)Basic Medical College Foundation of Army Medical University(2019JCZX10).
文摘Low back pain,mainly caused by intervertebral disc degeneration(IVDD),is a common health problem;however,current surgical treatments are less than satisfactory.Thus,it is essential to develop novel non-invasive surgical methods for IVDD treatment.Here,we describe a therapeutic strategy to inhibit IVDD by injecting hydrogels modified with the extracellular matrix of costal cartilage(ECM-Gels)that are loaded with cartilage endplate stem cells(CESCs).After loaded with CESCs overexpressing Sphk2(Lenti-Sphk2-CESCs)and injected near the cartilage endplate(CEP)of rats in vivo,ECM-Gels produced Sphk2-engineered exosomes(Lenti-Sphk2-Exos).These exosomes penetrated the annulus fibrosus(AF)and transported Sphk2 into the nucleus pulposus cells(NPCs).Sphk2 activated the phosphatidylinositol 3-kinase(PI3K)/p-AKT pathway as well as the intracellular autophagy of NPCs,ultimately ameliorating IVDD.This study provides a novel and efficient non-invasive combinational strategy for IVDD treatment using injectable ECM-Gels loaded with CESCs that express Sphk2 with sustained release of functional exosomes.
基金The authors acknowledge the support of the National Natural Science Foundation of China(81572178,81270397,81702317,81871752 and 81770802)the National Key R&D Program of China(2017YFC1309601 to Fang Liu)+1 种基金Shanghai Municipal Commission of Health and Family Planning under the fund(20124356)a Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant(20152232).
文摘Rationale:Chronic wounds associated with diabetes exact a heavy burden on individuals and society and do not have a specific treatment.Exosome therapy is an extension of stem cell therapy,and RNA interference(RNAi)-based therapy is a type of advanced precision therapy.Based on the discovery of chronic wound-related genes in diabetes,we combined exosome therapy and RNAi therapy through an engineering approach for the treatment of diabetic chronic wounds.Methods:We combined exosome therapy and RNAi therapy to establish a precision therapy for diabetes-associated wounds via an engineered exosome approach.Results:First,chronic diabetic wounds express low levels of miR-31-5p compared with nondiabetic wounds,and an miR-31-5p mimic was shown to be effective in promoting the proliferation and migration of three wound-related cell types in vitro.Second,bioinformatics analysis,luciferase reporter assays and western blotting suggested that miR-31-5p promoted angiogenesis,fibrogenesis and reepithelization by inhibiting factor-inhibiting HIF-1(HIF1AN,also named FIH)and epithelial membrane protein-1(EMP-1).Third,engineered miR-31 exosomes were generated as a miR-31-5p RNAi therapeutic agent.In vivo,the engineered miR-31 exosomes promoted diabetic wound healing by enhancing angiogenesis,fibrogenesis and reepithelization.Conclusion:Engineered miR-31 exosomes are an ideal disease pathophysiology-initiated RNAi therapeutic agent for diabetic wounds.
基金Key Program of NSFC(81730067)Major Project of NSFC(81991514)+5 种基金Fundamental Research Funds for the Central Universities(14380493,14380494)National Science Foundation of China(Grant No 82002370,31800806,82000069)China Postdoctoral Science Foundation(Grant No 2019M661806)Natural science foundation of Jiangsu province(Grant No BK20200117,BK20200314),Jiangsu postdoctoral research support project(Grant No 2021K059A)Nanjing University Innovation Program for PhD candidates(CXYJ21-62)Jiangsu Provincial Key Medical Center Foundation,Jiangsu Provincial Medical Outstanding Talent Foundation,Jiangsu Provincial Medical Youth Talent Foundation,Jiangsu Provincial Key Medical Talent Foundation,Program of Innovation and Entrepreneurship of Jiangsu Province.
文摘Rheumatoid arthritis(RA)is a chronic inflammatory disease characterized by synovitis and destruction of cartilage,promoted by sustained inflammation.However,current treatments remain unsatisfactory due to lacking of selective and effective strategies for alleviating inflammatory environments in RA joint.Inspired by neutrophil chemotaxis for inflammatory region,we therefore developed neutrophil-derived exosomes functionalized with sub-5 nm ultrasmall Prussian blue nanoparticles(uPB-Exo)via click chemistry,inheriting neutrophil-targeted biological molecules and owning excellent anti-inflammatory properties.uPB-Exo can selectively accumulate in activated fibroblast-like synoviocytes,subsequently neutralizing pro-inflammatory factors,scavenging reactive oxygen species,and alleviating inflammatory stress.In addition,uPB-Exo effectively targeted to inflammatory synovitis,penetrated deeply into the cartilage and real-time visualized inflamed joint through MRI system,leading to precise diagnosis of RA in vivo with high sensitivity and specificity.Particularly,uPB-Exo induced a cascade of anti-inflammatory events via Th17/Treg cell balance regulation,thereby significantly ameliorating joint damage.Therefore,nanoenzyme functionalized exosomes hold the great potential for enhanced treatment of RA in clinic.
基金supported by the supported by the National Natural Science Foundation of China(No.82072440)the Science and Technology Innovation Cultivation Fund of Zhongnan Hospital of Wuhan University(No.CXPY2023028)+2 种基金Excellent Doctor Fund Project of Zhongnan Hospital of Wuhan University(No.ZNYB2022015)Natural Science Foundation of Hubei Province(No.2024AFD167)the China Postdoctoral Science Foundation(No.2023M742701).
文摘The versatile multi-territory perforator flap remains a cornerstone of reconstructive surgery for diabetic ulcerations,yet its clinical efficacy faces significant challenges in hyperglycemic conditions.The diabetic milieu significantly exacerbates tissue ischemia through augmented chronic inflammation and impaired angiogenesis,which collectively harm flap perfusion and compromise its overall viability.A major postoperative complication is distal flap necrosis,which is closely associated with the critical“Choke zone,”a hypoperfused transitional area that exhibits delayed vascular recruitment and suboptimal angiogenesis.This vascular bottleneck creates a precarious balance between tissue oxygen demand and supply,ultimately compromising flap viability.To address this issue,we have developed the engineering stem cell exosomes by encapsulating metformin-loaded Mesoporous silica nanoparticles into BMSC exosomes(M-MS@EXO NPs),enabling the release of metformin.Compared to traditional oral medication,delivering metformin through engineered exosomes allows for precise administration in diabetic wounds.The multifunctional M-MS@EXO NPs exhibit dual pharmacological activity by reducing the secretion of inflammatory cytokines while effectively remodeling the vascular niche within the diabetic microenvironment.Additionally,the M-MS@EXO NPs show anti-inflammatory and angiogenesis effects by inhibiting TNF/apoptosis and enhancing VEGF signaling pathways in vitro.In the dorsal multi-territory perforator flap model of type 2 diabetes,the M-MS@EXO NPs demonstrate the ability to alleviate inflammation and promote neovascularization of the Choke zone,reducing distal necrosis,which holds great promise for improving flap survival in diabetes.
基金supported in part by NIH grants U01CA207946 and R01EB019036 to Peixuan Guo and NIH grant R01CA257961 to Dan Shu and Daniel W.Binzelfunded by the CM Chen Foundationsupported in part by Grant P30CA016058,National Cancer Institute,Bethesda,MD。
文摘Exosome is an excellent vesicle for in vivo delivery of therapeutics,including RNAi and chemical drugs.The extremely high efficiency in cancer regression can partly be attributed to its fusion mechanism in delivering therapeutics to cytosol without endosome trapping.However,being composed of a lipidbilayer membrane without specific recognition capacity for aimed-cells,the entry into nonspecific cells can lead to potential side-effects and toxicity.Applying engineering approaches for targeting-capacity to deliver therapeutics to specific cells is desirable.Techniques with chemical modification in vitro and genetic engineering in cells have been reported to decorate exosomes with targeting ligands.RNA nanoparticles have been used to harbor tumor-specific ligands displayed on exosome surface.The negative charge reduces nonspecific binding to vital cells with negatively charged lipid-membrane due to the electrostatic repulsion,thus lowering the side-effect and toxicity.In this review,we focus on the uniqueness of RNA nanoparticles for exosome surface display of chemical ligands,small peptides or RNA aptamers,for specific cancer targeting to deliver anticancer therapeutics,highlighting recent advances in targeted delivery of siRNA and miRNA that overcomes the previous RNAi delivery roadblocks.Proper understanding of exosome engineering with RNA nanotechnology promises efficient therapies for a wide range of cancer subtypes.
