Myelosuppression is a common and severe side effect of cancer chemotherapy,with current treatments hindered by limitations such as depletion of hematopoietic reserves,poor patient compliance,delayed therapeutic onset,...Myelosuppression is a common and severe side effect of cancer chemotherapy,with current treatments hindered by limitations such as depletion of hematopoietic reserves,poor patient compliance,delayed therapeutic onset,and high cost.To overcome these challenges,we developed Epimedium-derived nanovesicles(ENVs)from the traditional Chinese medicinal herb Epimedium,addressing the solubility and bioavailability issues associated with conventional extracts.ENVs encapsulate bioactive constituents,including icariin and hematopoiesis-promoting ceramides.In a cyclophosphamide(CTX)-induced myelosuppression mouse model,prophylactic and therapeutic oral administration of ENVs effectively alleviated hematopoietic suppression,significantly outperforming the Epimedium-based herbal extract“Joungal”(Shengbai Formula)despite equivalent icariin content.Notably,ENVs promoted hematopoietic stem cell(HSC)proliferation—an outcome rarely achieved with existing therapies.Mechanistically,ENVs modulated the gut microbiota,enriching lactobacillus species and enhancing lactate production.This microbiota-driven lactate signaling stimulated LepR+mesenchymal stem cells(MSCs)in the bone marrow niche to secrete stromal cellderived factor-1(SDF-1)and stem cell factor(SCF),thereby supporting HSC expansion and restoring hematopoietic function.In vivo safety evaluations confirmed the excellent biocompatibility of ENVs.Our findings uncover a gut-lactate-bone marrow axis through which ENVs enhance hematopoiesis and promote HSC regeneration.This work introduces a cost-effective,scalable,and orally administrable biomaterial platform with strong translational potential for the prevention and treatment of chemotherapy-induced myelosuppression.展开更多
Established evidence has unveiled two strategies for treating cancer:depleting tumor-associated macrophages(TAMs)and reprogramming M2-like TAMs into an antitumor M1 phenotype.Here,we designed novel p H-sensitive biomi...Established evidence has unveiled two strategies for treating cancer:depleting tumor-associated macrophages(TAMs)and reprogramming M2-like TAMs into an antitumor M1 phenotype.Here,we designed novel p H-sensitive biomimetic hybrid nanovesicles(EDHPA)loaded with doxorubicin(DOX).DOX@EDHPA can specifically target TAMs by activating macrophage-derived exosomes(M1-Exos)and anisamide(AA)as cancer-specific targeting ligands.In vitro and in vivo studies demonstrated that DOX@EDHPA could efficiently be delivered to the tumor site and taken up by cells.Meanwhile,it synergistically enhanced immunogenic cell death(ICD)and induced a subsequent antigen-specific T cell immune response.The tumor inhibitory rate of the DOX@EDHPA group was 1.42 times that of the free DOX group.Further analysis showed that the excellent antitumor effects of DOX@EDHPA should ascribe to the homing effect of M1-Exos on macrophages and the repolarization to antitumor M1 TAMs,which induced the elevated secretion of pro-infiammatory factors.Therefore,the hybrid EDHPA targeting TAMs to reshape the tumor microenvironment constituted a novel immunochemotherapy strategy to inhibit tumor growth.展开更多
Pancreatic cancer,characterized by dense tissue and a significant infiltration of myeloid-derived suppressor cells(MDSCs),leads to an almost complete absence of T cells infiltration and a poor response to immunotherap...Pancreatic cancer,characterized by dense tissue and a significant infiltration of myeloid-derived suppressor cells(MDSCs),leads to an almost complete absence of T cells infiltration and a poor response to immunotherapy.A strategy involving external defense of MDSCs recruitment and internal attack on tumor cells may enhance the effectiveness of chemo-immunotherapy for pancreatic cancer.Herein,a MDSCs-derived nanovesicle encapsulating the CD11b agonist leukadherin-1(LA)and the polyamide-oxaliplatin(PAMAM-OXA)nanoparticles(P),named MLR/LA@P,was constructed for pancreatic cancer treatment.The activation of CD11b by LA enhanced the binding of MLR/LA@P to ICAM-1,thereby improving tumor targeting ability and competitively inhibiting MDSCs recruitment for“external defense”.In response to matrix metalloproteinase-2(MMP2)in the tumor microenvironment,MLR/LA@P degraded and released small-sized P for deep penetration.Subsequently,OXA was released in response to glutathione within tumor cells,triggering immunogenic cell death for“internal attack”.MLR/LA@P not only inhibited the growth of orthotopic pancreatic tumors,but also prevented the formation of pre-metastatic niches(PMNs),which is promising for pancreatic cancer treatment.展开更多
Metabolic dysfunction-associated fatty liver disease(MASLD)and alcohol-associated liver disease(ALD)are prevalent chronic liver diseases that can progress to steatohepatitis,fibrosis,cirrhosis,and ultimately liver fai...Metabolic dysfunction-associated fatty liver disease(MASLD)and alcohol-associated liver disease(ALD)are prevalent chronic liver diseases that can progress to steatohepatitis,fibrosis,cirrhosis,and ultimately liver failure.Here,we demonstrated that oral administration of GNVs provided substantial protection against liver injury and fibrosis in MASLD and ALD mouse models.In a Western-style high-fat diet-induced MASLD model and a chronic binge alcohol-induced ALD model,GNVs treatment significantly reduced gut leakiness by restoring intestinal junctional complex proteins and rebalancing the gut microbiome.GNVs attenuated hepatic lipid accumulation,oxidative stress and fibrogenicmarkers.GNV treatment downregulated the fibrosis-associated tissue inhibitor of metalloproteinase-2(TIMP2)pathway in hepatic stellate cells,which is linked to enhanced matrix degradation and reduced fibrogenesis.GNVs prevent MASLD-and ALD-associated gut barrier dysfunction and liver fibrosis through modulation of the gut-liver axis and the TIMP2 pathway.Edible GNVs represent a novel,multifaceted therapeutic strategy for managing chronic liver diseases.展开更多
Metabolic-associated fatty liver disease(MAFLD),a global health burden with limited therapeutic options beyond lifestyle changes,urgently needs novel strategies.We engineered exosome-like nanovesicles(HNVs)from dried ...Metabolic-associated fatty liver disease(MAFLD),a global health burden with limited therapeutic options beyond lifestyle changes,urgently needs novel strategies.We engineered exosome-like nanovesicles(HNVs)from dried honeysuckle(Lonicera japonica),exhibiting significantly more uniform size distribution than conventional herbal extracts and characteristic nanovesicle morphology.Orally delivered HNVs,enriched with bioactive metabolites,dramatically inhibited increased fat vacuoles,lipid droplet deposition,and collagen fibrosis in the livers of mice with MAFLD induced by high-fat diet(HFD).Mechanistically,HNVs orchestrate a dual gut-liver intervention:(1)restoring gut barrier integrity,slashing serum LPS by 1.58-fold and quelling hepatic inflammation;(2)remodeling gut microbiota to suppress bile salt hydrolase(BSH),elevating taurochenodeoxycholic acid(TCDCA)2.07-fold.This microbial shift reprograms enterohepatic signaling by inhibiting the FXR-FGF15-FGFR4 axis,thereby boosting hepatic cholesterol catabolism via bile acid synthases.Critically,efficacy is strictly microbiotadependent:abolished by antibiotics and fully transferable via fecal microbiota transplantation(FMT)from HNV-treated donors.Presenting the first natural nanovesicle platform that concurrently targets gut barrier repair and metabolic reprogramming,HNVs establish a pioneering,multi-targeted therapeutic paradigm for MAFLD,directly linking gut microbial ecology to hepatic pathophysiology with high translational potential.展开更多
Plant-derived nanovesicles have gained attention given their similarity to mammalian exosomes and advantages such as low cost,sustainability,and tissue targeting.Thus,they hold promise for disease treatment and drug d...Plant-derived nanovesicles have gained attention given their similarity to mammalian exosomes and advantages such as low cost,sustainability,and tissue targeting.Thus,they hold promise for disease treatment and drug delivery.In this study,we proposed a time-efficient method,PEG 8000 combined with sucrose density gradient centrifugation to prepare ginger-derived nanovesicles(GDNVs).Subsequently,curcumin(CUR)was loaded onto GDNV by ultrasonic incubation.The optimum conditions for ginger-derived nanovesicles loaded with curcumin(CG)were ultrasound time of 3 min,a carrier-to-drug ratio(GDNV:CUR)of 1:1.The study achieved a high loading capacity(94.027%±0.094%)and encapsulation efficiency(89.300%±0.344%).Finally,the drugs'in vivo distribution and anti-colitis activity were investigated in mice.CG was primarily distributed in the colon after oral administration.Compared to CUR and GDNV,CG was superior in improving disease activity,colon length,liver and spleen coefficients,myeloperoxidase activity,and biochemical factor levels in ulcerative colitis(UC)mice.In addition,CG plays a protective role against UC by modulating serum metabolite levels and gut flora.In summary,our study demonstrated that GDNV can be used for CUR delivery with enhanced therapeutic potential.展开更多
AIM:To investigate the preparation,physicochemical characterization and cytotoxicity in vitro of Gemcitabine-loaded poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-PDLLA) nanovesicles. METHODS:The nanovesicle carri...AIM:To investigate the preparation,physicochemical characterization and cytotoxicity in vitro of Gemcitabine-loaded poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-PDLLA) nanovesicles. METHODS:The nanovesicle carriers were prepared from the amphiphilic block copolymer of PEG-PDLLA by a double emulsion technique,and gemcitabine was used as the model drug. The morphology of the nanovesicles was determined by scanning and transmission electron microscopy,and the drug content,drug entrapment and drug-release curve in vitro were detected by UV-Vis-NIR spectrophotometry. Cytotoxicity in the human pancreatic cancer cell line SW1990 was tested by 3-(4,5-dimethyl) ethiazole (MTT) assay.RESULTS:The gemcitabine-loaded nanovesicles were hollow nanospheres with a mean size of 200.6 nm,drugloading of 4.14% and drug embedding ratio of 20.54%. The nanovesicles showed excellent controlled release that was characterized by a fast initial release during the first 72 h,followed by a slower and continuous release. The MTT assay demonstrated that gemcitabine-loaded nanovesicles exhibited dose-dependent and time-delayed cytotoxicity in the human pancreatic cancer cell line SW1990.CONCLUSION:Gemcitabine-loaded PEG-PDLLA nanovesicles prepared by a double emulsion technique exhibited good performance for controlled drug release,and had similar cytotoxic activity to free gem-citabine.展开更多
Gold nanovesicles(GVs) with unique plasmonic property and large cavity hold great potential as a stimuli-responsive nanocarrier to deliver drugs for efficient tumor chemotherapy and other therapies synergistically.Her...Gold nanovesicles(GVs) with unique plasmonic property and large cavity hold great potential as a stimuli-responsive nanocarrier to deliver drugs for efficient tumor chemotherapy and other therapies synergistically.Herein,we developed doxorubicin-loaded gold nanovesicles(DGVs),offering infrared thermal(IRT) and photoacoustic(PA) dual-modal imaging guided mild hype rthermia-enhanced chemophotothermal cancer synergistic therapy.The DGVs are self-assembled by gold nanoparticles modified with amphiphilic copolymer in a predetermined concentration of doxorubicin through film rehydration method.Under the influence of laser excitation,the as-prepared DGVs exhibited good photothermal effect,which triggered the structural disruption of GVs and thus,allowed the efficient release of encapsulated DOX to enhance cell uptake for fluorescence imaging and tumor chemotherapy,respectively.In addition,DGVs also showed a strong PA and IRT signals in vivo.Our study demonstrated the potential of DGVs as stimuli-responsive drug delivery systems and cancer theranostics.展开更多
Squamous cell carcinoma (SCC) and melanoma are malignant human cancers of the skin with an annual mortality that exceeds 10,000 cases every year in the USA alone. In this study, the lysosomal protein saposin C (SapC) ...Squamous cell carcinoma (SCC) and melanoma are malignant human cancers of the skin with an annual mortality that exceeds 10,000 cases every year in the USA alone. In this study, the lysosomal protein saposin C (SapC) and the phospholipid dioloylphosphatidylserine (DOPS) were assembled into cancer-selective nanovesicles (SapC-DOPS) and successfully tested using several in vitro and in vivo skin cancer models. Using MTT assay that measures the percentage of cell death, SapC-DOPS cytotoxic effect on three skin tumor cell lines (squamous cell carcinoma, SK-MEL-28, and MeWo) was compared to two normal nontumorigenic skin cells lines, normal immortalized keratinocyte (NIK) and human fibroblast cell (HFC). We observed that the nanovesicles selectively killed the skin cancer cells by inducing apoptotic cell death whereas untransformed skin cancer cells remained unaffected. Using subcutaneous skin tumor xenografts, animals treated with SapC-DOPS by subcutaneous injection showed a 79.4% by volume tumor reduced compared to the control after 4 days of treatment. We observed that the nanovesicles killed skin cancer cells by inducing apoptotic cell death compared to the control as revealed by TUNEL staining of xenograft tumor sections.展开更多
Herbal medicine(HM)has been extensively researched and widely used since ancient times.Currently,as one of the emerging directions in HM modernization research,herbal medicine-derived nanovesicles(HMDNV),a type of nan...Herbal medicine(HM)has been extensively researched and widely used since ancient times.Currently,as one of the emerging directions in HM modernization research,herbal medicine-derived nanovesicles(HMDNV),a type of nanoparticle obtained from destructed plant tissues,hold considerable promise for disease treatment and drug delivery.The recent studies related to HMDNV and miRNAs are summarized in this review,with a special emphasis on their basic characteristics and biological activities,to provide ideas for future scientific research on HMDNV and enrich the content of active components of Traditional Chinese Medicine(TCM).展开更多
Oligonucleotide therapeutics have great potential to target the currently undruggable genes and to generate entirely new therapeutic paradigms in multiple types of disease,thus having attracted much attention in recen...Oligonucleotide therapeutics have great potential to target the currently undruggable genes and to generate entirely new therapeutic paradigms in multiple types of disease,thus having attracted much attention in recent years.However,their applications are greatly hindered by a lack of safe and efficient oligonucleotide-delivery vectors.Polyplex nanovesicles formed from oligonucleotides and the cationic block have shown exceptional features for the delivery of therapeutic oligonucleotides and other biopharmaceuticals.Nevertheless,these polyplex nanovesicles are deeply fraught with difficulty in tolerating physiological ionic strength.Inspired by the high binding ability between the dipicolylamine(DPA)/zinc(Ⅱ)complex and the phosphodiester moieties of oligonucleotides,herein,we designed a coordinative cationic block to solve the intrinsic stability dilemma.Moreover,we found the stability of the resulted polyplex nanovesicles could be easily tuned by the content of coordinated zinc ions.In vitro cellular studies implied that the prepared zinc(Ⅱ)-coordinative polyplex nanovesicles preferred to retain in the lysosomes upon internalization,making them ideal delivery candidates for the lysosome-targeting oligonucleotide therapeutics.展开更多
Lipidic nanovesicles (so called liposomes) were one the earliest forms of nanovectors. One of their limits was our lack of knowledge on the delivery pathway of their content to the target cell cytoplasm. The present c...Lipidic nanovesicles (so called liposomes) were one the earliest forms of nanovectors. One of their limits was our lack of knowledge on the delivery pathway of their content to the target cell cytoplasm. The present communication describes an efficient way to enhance the delivery. Pulsed electric fields (PEF) are known since the early 80’s to mediate a fusogenic state of plasma membranes when applied to a cell suspension or a tissue. Polykaryons are detected when PEF are applied on cells in contact during or after the pulses. Heterofusion can be obtained when a cell mixture is pulsed. When lipidic nanovesicles, either small unilamellar vesicles (SUVs) or large unilamellar vesicles (LUVs), are electrostatically brought in contact with electropermeabilized cells by a salt bridge, their content is delivered into the cytoplasm in electropermeabilized cells. The PEF parameters are selected to affect specifically the cells leaving the vesicles unaffected. It is the electropermeabilized state of the cell membrane that is the trigger of the merging between the plasma membrane and the lipid bilayer. The present investigation shows that the transfer of macromolecules can be obtained;i.e. 20 kD dextrans can be easily transferred while a direct transfer does not take place under the same electrical parameters. Cell viability was not affected by the treatment. As delivery is present only on electropermeabilized cells, a targeting of the effect is obtained in the volume where the PEF parameters are over the critical value for electropermeabilization. A homogeneous cytoplasm labeling is observed under digitised videomicroscopy. The process is a content and “membrane” mixing, following neither a kiss and run or an endocytotic pathway.展开更多
Stroke remains one of the leading causes of adult disability worldwide,with neovascularization is crucial for brain repair after stroke.However,neutrophil infiltration hinders effective neovascularization,necessitatin...Stroke remains one of the leading causes of adult disability worldwide,with neovascularization is crucial for brain repair after stroke.However,neutrophil infiltration hinders effective neovascularization,necessitating timely clearance by microglia through phagocytosis.Unfortunately,microglial phagocytic function is often impaired by metabolic defects,hindering post-stroke recovery.Ginsenoside Rg1,derived from Panax ginseng,exhibits neuroprotective properties and regulates cellular metabolism in vitro but its therapeutic application is limited by poor brain penetration.Here,we present a targeted delivery system utilizing neutrophil-like cell membrane vesicles(NCM),prepared via nitrogen cavitation,to enhance Rg1 delivery to the brain.These bio-mimetic vesicles exploit the inherent targeting ability of neutrophil membranes to reach brain injury sites and are subsequently taken up by microglia.Our findings demonstrate that Rg1-loaded vesicles enhance microglial clearance of neutrophils,reduce neutrophil extracellular traps release,and mitigate tissue damage.These effects improve the post-stroke microenvironment,promote vascular remodeling,and ultimately contribute to func-tional recovery.This strategy highlights the potential of targeted reprogramming microglial cells to enhance their endogenous repair capabilities,offering a promising therapeutic avenue for ischemic stroke management.展开更多
Exosomes are natural nano-size particles secreted by human cells,containing numerous bioactive cargos.Serving as crucial mediators of intercellular communication,exosomes are involved in many physiological and patholo...Exosomes are natural nano-size particles secreted by human cells,containing numerous bioactive cargos.Serving as crucial mediators of intercellular communication,exosomes are involved in many physiological and pathological processes,such as inflammation,tissue injury,cardiovascular diseases,tumorigenesis and tumor development.Exosomes have exhibited promising results in the diagnosis and treatment of cancer,cardiovascular diseases and others.They are a rapidly growing class of drug delivery vehicles with many advantages over conventional synthetic carriers.Exosomes used in therapeutic applications encounter several challenges,such as the lack of tissue targeting capabilities and short residence time.In this review,we discuss recent advances in exosome engineering to improve tissue targeting and describe the current types of engineered exosome-like nanovesicles,and summarize their preclinical applications in the treatment of diseases.Further,we also highlight the latest engineering strategies developed to extend exosomes retention time in vivo and exosome-like nanovesicles.展开更多
Plant-derived nanovesicles(PDNVs),including plant extracellular vesicles(EVs)and plant exosome-like nanovesicles(ELNs),are natural nano-sized membranous vesicles containing bioactive molecules.PDNVs consist of a bilay...Plant-derived nanovesicles(PDNVs),including plant extracellular vesicles(EVs)and plant exosome-like nanovesicles(ELNs),are natural nano-sized membranous vesicles containing bioactive molecules.PDNVs consist of a bilayer of lipids that can effectively encapsulate hydrophilic and lipophilic drugs,improving drug stability and solubility as well as providing increased bioavailability,reduced systemic toxicity,and enhanced target accumulation.Bioengineering strategies can also be exploited to modify the PDNVs to achieve precise targeting,controlled drug release,and massive production.Meanwhile,they are capable of crossing the blood-brain barrier(BBB)to transport the cargo to the lesion sites without harboring human pathogens,making them excellent therapeutic agents and drug delivery nanoplatform candidates for brain diseases.Herein,this article provides an initial exposition on the fundamental characteristics of PDNVs,including biogenesis,uptake process,isolation,purification,characterization methods,and source.Additionally,it sheds light on the investigation of PDNVs’utilization in brain diseases while also presenting novel perspectives on the obstacles and clinical advancements associated with PDNVs.展开更多
Clinical management of atopic dermatitis(AD)is challenged by its susceptibility to recur-rence,side effects,and high costs.We found that Portulaca oleracea L.-derived nanovesicles(PDNV)exert anti-inflammatory effects ...Clinical management of atopic dermatitis(AD)is challenged by its susceptibility to recur-rence,side effects,and high costs.We found that Portulaca oleracea L.-derived nanovesicles(PDNV)exert anti-inflammatory effects by modulating macrophage M1/M2 polarization.These effects were achieved through pathways including inhibition of nuclear factor-κB(NF-κB)and stimulator of interferon genes(STING)protein expression in diseased tissues,demonstrating their potential to ameliorate AD symptoms.To increase the transdermal permeation of PDNV,dissolvable microneedles composed primar-ily of hyaluronic acid(HA)were developed as an adjunctive means of delivery.Meanwhile,polysaccha-rides of Portulaca oleracea L.,which were synergistic with PDNV,were used as microneedle constituent materials to enhance the mechanical properties and physical stability of HA.This new means of delivery significantly improves the treatment of AD and also provides new options for the efficient utilization of plant extracellular vesicles and the treatment of AD.In addition,transcriptomic analysis of PDNV showed that the mRNAs of Portulaca oleracea L.are closest to those of ferns,which may shed light on related evolutionary and plant species identification studies.展开更多
Mesenchymal stem cells(MSCs)and MSC-derived extracellular vesicles(MSC EVs)have gained significant attention in biomedical and therapeutic applications.Nevertheless,their translation in clinical practice remains limit...Mesenchymal stem cells(MSCs)and MSC-derived extracellular vesicles(MSC EVs)have gained significant attention in biomedical and therapeutic applications.Nevertheless,their translation in clinical practice remains limited due to the lack of scalable manufacturing techniques and the prevailing safety concerns.Cell-derived extruded nanovesicles(eNVs)with high production efficiency are regarded as promising substitutes of EVs.However,like MSC EVs,their potential for tumorigenicity has yet to be exhaustively investigated.In this work,we investigated the tumorigenicity of umbilical cord mesenchymal stem cell-derived eNVs(UMSC eNVs).A549 cancer cell-derived eNVs(A549 eNVs)with potential tumorigenicity were also prepared for comparative anal-ysis.Our characterization findings revealed that,although UMSC eNVs and A549 eNVs exhibited similar mor-phologies,they differed in their molecular composition.Subsequent animal experiments demonstrated the low tumorigenicity risk of UMSC eNVs in inducing tumor pathogenesis and development.Furthermore,microRNAs(miRNAs)profiling analyses suggested that the reduced tumorigenicity of UMSC eNVs might be due to the downregulation of hsa-miR-21-5p_R+1 and hsa-miR-192-5p,and upregulation of hsa-miR-143-3p and hsa-miR-146a-5p compared to A549 eNVs.The present study provided direct experimental confirmation and underlying miRNA profiling evidence of the biosafety of UMSC eNVs in terms of tumorigenicity,which will promote the future advancement and translation of UMSC eNVs.展开更多
It remains a significant challenge to reactivate the cell cycle activity of adult mammalian cardiomyocytes(CMs).This study created a hypo-immunogenic human induced pluripotent stem cell(hiPSC)line using clustered regu...It remains a significant challenge to reactivate the cell cycle activity of adult mammalian cardiomyocytes(CMs).This study created a hypo-immunogenic human induced pluripotent stem cell(hiPSC)line using clustered regularly interspaced palindromic repeats(CRISPR)/Cas9 gene editing to knockoutβ2-microglobulin in hiPSCs(^(B2MKO)hiPSCs)for manufacturing nanovesicles(^(B2MKO)hiPSC-NVs).Approximately 9500^(B2MKO)hiPSC-NVs were produced from a single^(B2MKO)hiPSC.Proteomic analyses indicated that,compared to^(B2MKO)hiPSCs,the cargos of B2MKOhiPSC-NVs were enriched in spindle and chromosomal proteins,as well as proteins that regulate the cell cycle and scavenge reactive oxygen species(ROS).When administrated to hiPSCs derived CMs(hiPSC-CMs),^(B2MKO)hiPSC-NVs reduced lactate dehydrogenase leakage and apoptosis in hypoxia-cultured hiPSC-CMs through activating the AKT pathway,protected hiPSC-CMs from H_(2)O_(2)-induced damage by ROS scavengers in the NV cargo,increased hiPSC-CM proliferation via the YAP pathway,and were hypoimmunogenic when co-cultured with human CD8+T cells or delivered to mice.Furthermore,when^(B2MKO)hiPSC-NVs or 0.9%NaCl were intra-myocardially injected into mice after cardiac ischemia/reperfusion injury,cardiac function and infarct size,assessed 4 weeks later,were significantly improved in the^(B2MKO)hiPSC-NV group,with increased mouse CM survival and cell cycle activity.Thus,the proteins in the^(B2MKO)hiPSC-NV cargos convergently activated the AKT pathway,scavenged ROS to protect CMs,and upregulated YAP signaling to induce CM cell cycle activity.Thus,^(B2MKO)hiPSC-NVs hold great potential for cardiac protection and regeneration.展开更多
Acute lung injury(ALI)is a devastating inflammatory disease.MicroRNA155(miR155)in alveolar macrophages and lung epithelial cells enhances inflammatory reactions by inhibiting the suppressor of cytokine signaling 1(SOC...Acute lung injury(ALI)is a devastating inflammatory disease.MicroRNA155(miR155)in alveolar macrophages and lung epithelial cells enhances inflammatory reactions by inhibiting the suppressor of cytokine signaling 1(SOCS1)in ALI.Anti-miR155 oligonucleotide(AMO155)have been suggested as a potential therapeutic reagent for ALI.However,a safe and efficient carrier is required for delivery of AMO155 into the lungs for ALI therapy.In this study,cell membrane-derived nanovesicles(CMNVs)were produced from cell membranes of LA4 mouse lung epithelial cells and evaluated as a carrier of AMO155 into the lungs.For preparation of CMNVs,cell membranes were isolated from LA4 cells and CMNVs were produced by extrusion.Cholesterol-conjugated AMO155(AMO155c)was loaded into CMNVs and extracellular vesicles(EVs)by sonication.The physical characterization indicated that CMNVs with AMO155c(AMO155c/CMNV)were membrane-structured vesicles with a size of�120nm.The delivery efficiency and therapeutic efficacy of CMNVs were compared with those of EVs or polyethylenimine(25kDa,PEI25k).The delivery efficiency of AMO155c by CMNVs was similar to that by EVs.As a result,the miR155 levels were reduced by AMO155c/CMNV and AMO155c/EV.AMO155c/CMNV were administered intratracheally into the ALI models.The SOCS1 levels were increased more efficiently by AMO155c/CMNV than by the others,suggesting that miR155 effectively was inhibited by AMO155c/CMNV.In addition,the inflammatory cytokines were reduced more effectively by AMO155c/CMNV than they were by AMO155c/EV and AMO155c/PEI25k,reducing inflammation reactions.The results suggest that CMNVs are a useful carrier of AMO155c in the treatment of ALI.展开更多
Epilepsy is a complex neurological disorder aggravated by chronic neuroinflammation largely driven by reactive astrocytes.These cells promote epileptogenesis through persistent cytokine secretion and glial scar format...Epilepsy is a complex neurological disorder aggravated by chronic neuroinflammation largely driven by reactive astrocytes.These cells promote epileptogenesis through persistent cytokine secretion and glial scar formation.Current antiepileptic drugs remain ineffective in targeting these mechanisms due to limited blood-brain barrier(BBB)permeability and poor astrocytic specificity.A transferrin-functionalized biomimetic nanotherapeutic loaded with resveratrol(RN@RTA)was developed to regulate astrocyte-mediated inflammation by activating sirtuin 1(SIRT1)and suppressing the mitogen-activated protein kinase/nuclear factor Kappalight-chain-enhancer of activated B cells(MAPK/NF-κB)axis.Using in vitro BBB models,primary astrocytes,and a pilocarpine-induced chronic epilepsy mouse model,we evaluated the capacity of RN@RTA to cross the BBB,inhibit inflammatory signaling,and reduce seizure activity.Mechanistic assays included immunoprecipitation of NF-κB complexes,cytokine quantification,RNA sequencing,and histopathological assessments of glial and synaptic markers.RN@RTA achieved 82%uptake by hippocampal astrocytes and significantly reduced Il6,Tnf-α,and Nlrp3 expression.SIRT1 activation disrupted the NF-κB p65/p300 complex,leading to transcriptional repression of inflammatory genes and enhancement of autophagy.In vivo,seizure frequency decreased by 67%,synaptic structure was preserved,and astrogliosis was markedly alleviated.The findings demonstrate a dual regulatory mechanism in which RN@RTA suppresses neuroinflammatory signaling and restores neural homeostasis,offering a promising molecularly targeted approach for refractory epilepsy.展开更多
基金supported by National Natural Science Foundation of China(Nos.82104445 and 82470182]Basic Scientific Research Funds of Department of Education of Zhejiang Province(No.KYZD2024013)+2 种基金The Startup Foundation of Zhejiang Provincial People’s Hospital(Nos.C-2023-QDJJ12 and C-2024-ZZJJ05)Science and Technology Plan Project of Traditional Chinese Medicine in Zhejiang Province(No.2025ZR007)The National Administration of Traditional Chinese Medicine(No.GZY-ZJ-KJ-24044).
文摘Myelosuppression is a common and severe side effect of cancer chemotherapy,with current treatments hindered by limitations such as depletion of hematopoietic reserves,poor patient compliance,delayed therapeutic onset,and high cost.To overcome these challenges,we developed Epimedium-derived nanovesicles(ENVs)from the traditional Chinese medicinal herb Epimedium,addressing the solubility and bioavailability issues associated with conventional extracts.ENVs encapsulate bioactive constituents,including icariin and hematopoiesis-promoting ceramides.In a cyclophosphamide(CTX)-induced myelosuppression mouse model,prophylactic and therapeutic oral administration of ENVs effectively alleviated hematopoietic suppression,significantly outperforming the Epimedium-based herbal extract“Joungal”(Shengbai Formula)despite equivalent icariin content.Notably,ENVs promoted hematopoietic stem cell(HSC)proliferation—an outcome rarely achieved with existing therapies.Mechanistically,ENVs modulated the gut microbiota,enriching lactobacillus species and enhancing lactate production.This microbiota-driven lactate signaling stimulated LepR+mesenchymal stem cells(MSCs)in the bone marrow niche to secrete stromal cellderived factor-1(SDF-1)and stem cell factor(SCF),thereby supporting HSC expansion and restoring hematopoietic function.In vivo safety evaluations confirmed the excellent biocompatibility of ENVs.Our findings uncover a gut-lactate-bone marrow axis through which ENVs enhance hematopoiesis and promote HSC regeneration.This work introduces a cost-effective,scalable,and orally administrable biomaterial platform with strong translational potential for the prevention and treatment of chemotherapy-induced myelosuppression.
基金supported by the National Natural Science Foundation of China(No.NSFC31872754)。
文摘Established evidence has unveiled two strategies for treating cancer:depleting tumor-associated macrophages(TAMs)and reprogramming M2-like TAMs into an antitumor M1 phenotype.Here,we designed novel p H-sensitive biomimetic hybrid nanovesicles(EDHPA)loaded with doxorubicin(DOX).DOX@EDHPA can specifically target TAMs by activating macrophage-derived exosomes(M1-Exos)and anisamide(AA)as cancer-specific targeting ligands.In vitro and in vivo studies demonstrated that DOX@EDHPA could efficiently be delivered to the tumor site and taken up by cells.Meanwhile,it synergistically enhanced immunogenic cell death(ICD)and induced a subsequent antigen-specific T cell immune response.The tumor inhibitory rate of the DOX@EDHPA group was 1.42 times that of the free DOX group.Further analysis showed that the excellent antitumor effects of DOX@EDHPA should ascribe to the homing effect of M1-Exos on macrophages and the repolarization to antitumor M1 TAMs,which induced the elevated secretion of pro-infiammatory factors.Therefore,the hybrid EDHPA targeting TAMs to reshape the tumor microenvironment constituted a novel immunochemotherapy strategy to inhibit tumor growth.
基金supported by the Sichuan Science and Technology program(No.2022NSFSC0045)the Fundamental Research Funds for the Central Universities,and the National Natural Science Foundation of China(No.82404566).
文摘Pancreatic cancer,characterized by dense tissue and a significant infiltration of myeloid-derived suppressor cells(MDSCs),leads to an almost complete absence of T cells infiltration and a poor response to immunotherapy.A strategy involving external defense of MDSCs recruitment and internal attack on tumor cells may enhance the effectiveness of chemo-immunotherapy for pancreatic cancer.Herein,a MDSCs-derived nanovesicle encapsulating the CD11b agonist leukadherin-1(LA)and the polyamide-oxaliplatin(PAMAM-OXA)nanoparticles(P),named MLR/LA@P,was constructed for pancreatic cancer treatment.The activation of CD11b by LA enhanced the binding of MLR/LA@P to ICAM-1,thereby improving tumor targeting ability and competitively inhibiting MDSCs recruitment for“external defense”.In response to matrix metalloproteinase-2(MMP2)in the tumor microenvironment,MLR/LA@P degraded and released small-sized P for deep penetration.Subsequently,OXA was released in response to glutathione within tumor cells,triggering immunogenic cell death for“internal attack”.MLR/LA@P not only inhibited the growth of orthotopic pancreatic tumors,but also prevented the formation of pre-metastatic niches(PMNs),which is promising for pancreatic cancer treatment.
基金supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (project number RS-2024-00340542)supported in part (to B.J.S.) by the Intramural Fund of National Institute of Alcohol Abuse and Alcoholismsupported by the 2022 research grant from the Korean Society of Ginseng
文摘Metabolic dysfunction-associated fatty liver disease(MASLD)and alcohol-associated liver disease(ALD)are prevalent chronic liver diseases that can progress to steatohepatitis,fibrosis,cirrhosis,and ultimately liver failure.Here,we demonstrated that oral administration of GNVs provided substantial protection against liver injury and fibrosis in MASLD and ALD mouse models.In a Western-style high-fat diet-induced MASLD model and a chronic binge alcohol-induced ALD model,GNVs treatment significantly reduced gut leakiness by restoring intestinal junctional complex proteins and rebalancing the gut microbiome.GNVs attenuated hepatic lipid accumulation,oxidative stress and fibrogenicmarkers.GNV treatment downregulated the fibrosis-associated tissue inhibitor of metalloproteinase-2(TIMP2)pathway in hepatic stellate cells,which is linked to enhanced matrix degradation and reduced fibrogenesis.GNVs prevent MASLD-and ALD-associated gut barrier dysfunction and liver fibrosis through modulation of the gut-liver axis and the TIMP2 pathway.Edible GNVs represent a novel,multifaceted therapeutic strategy for managing chronic liver diseases.
基金supported by the Zhejiang Provincial Natural Science Foundation of China(No.KLZ25H280004 to X.Z.M.).
文摘Metabolic-associated fatty liver disease(MAFLD),a global health burden with limited therapeutic options beyond lifestyle changes,urgently needs novel strategies.We engineered exosome-like nanovesicles(HNVs)from dried honeysuckle(Lonicera japonica),exhibiting significantly more uniform size distribution than conventional herbal extracts and characteristic nanovesicle morphology.Orally delivered HNVs,enriched with bioactive metabolites,dramatically inhibited increased fat vacuoles,lipid droplet deposition,and collagen fibrosis in the livers of mice with MAFLD induced by high-fat diet(HFD).Mechanistically,HNVs orchestrate a dual gut-liver intervention:(1)restoring gut barrier integrity,slashing serum LPS by 1.58-fold and quelling hepatic inflammation;(2)remodeling gut microbiota to suppress bile salt hydrolase(BSH),elevating taurochenodeoxycholic acid(TCDCA)2.07-fold.This microbial shift reprograms enterohepatic signaling by inhibiting the FXR-FGF15-FGFR4 axis,thereby boosting hepatic cholesterol catabolism via bile acid synthases.Critically,efficacy is strictly microbiotadependent:abolished by antibiotics and fully transferable via fecal microbiota transplantation(FMT)from HNV-treated donors.Presenting the first natural nanovesicle platform that concurrently targets gut barrier repair and metabolic reprogramming,HNVs establish a pioneering,multi-targeted therapeutic paradigm for MAFLD,directly linking gut microbial ecology to hepatic pathophysiology with high translational potential.
基金supported by the Science and Technology Program of Tianjin in China(Grant No.:23ZYJDSS00030).
文摘Plant-derived nanovesicles have gained attention given their similarity to mammalian exosomes and advantages such as low cost,sustainability,and tissue targeting.Thus,they hold promise for disease treatment and drug delivery.In this study,we proposed a time-efficient method,PEG 8000 combined with sucrose density gradient centrifugation to prepare ginger-derived nanovesicles(GDNVs).Subsequently,curcumin(CUR)was loaded onto GDNV by ultrasonic incubation.The optimum conditions for ginger-derived nanovesicles loaded with curcumin(CG)were ultrasound time of 3 min,a carrier-to-drug ratio(GDNV:CUR)of 1:1.The study achieved a high loading capacity(94.027%±0.094%)and encapsulation efficiency(89.300%±0.344%).Finally,the drugs'in vivo distribution and anti-colitis activity were investigated in mice.CG was primarily distributed in the colon after oral administration.Compared to CUR and GDNV,CG was superior in improving disease activity,colon length,liver and spleen coefficients,myeloperoxidase activity,and biochemical factor levels in ulcerative colitis(UC)mice.In addition,CG plays a protective role against UC by modulating serum metabolite levels and gut flora.In summary,our study demonstrated that GDNV can be used for CUR delivery with enhanced therapeutic potential.
文摘AIM:To investigate the preparation,physicochemical characterization and cytotoxicity in vitro of Gemcitabine-loaded poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-PDLLA) nanovesicles. METHODS:The nanovesicle carriers were prepared from the amphiphilic block copolymer of PEG-PDLLA by a double emulsion technique,and gemcitabine was used as the model drug. The morphology of the nanovesicles was determined by scanning and transmission electron microscopy,and the drug content,drug entrapment and drug-release curve in vitro were detected by UV-Vis-NIR spectrophotometry. Cytotoxicity in the human pancreatic cancer cell line SW1990 was tested by 3-(4,5-dimethyl) ethiazole (MTT) assay.RESULTS:The gemcitabine-loaded nanovesicles were hollow nanospheres with a mean size of 200.6 nm,drugloading of 4.14% and drug embedding ratio of 20.54%. The nanovesicles showed excellent controlled release that was characterized by a fast initial release during the first 72 h,followed by a slower and continuous release. The MTT assay demonstrated that gemcitabine-loaded nanovesicles exhibited dose-dependent and time-delayed cytotoxicity in the human pancreatic cancer cell line SW1990.CONCLUSION:Gemcitabine-loaded PEG-PDLLA nanovesicles prepared by a double emulsion technique exhibited good performance for controlled drug release,and had similar cytotoxic activity to free gem-citabine.
基金financially supported by the National Natural Science Foundation of China (Nos.31771036,51703132)the Basic Research Program of Shenzhen (Nos.JCYJ20180507182413022,JCYJ20170412111100742)the Guangdong Province Natural Science Foundation of Major Basic Research and Cultivation Project (No.2018B030308003)。
文摘Gold nanovesicles(GVs) with unique plasmonic property and large cavity hold great potential as a stimuli-responsive nanocarrier to deliver drugs for efficient tumor chemotherapy and other therapies synergistically.Herein,we developed doxorubicin-loaded gold nanovesicles(DGVs),offering infrared thermal(IRT) and photoacoustic(PA) dual-modal imaging guided mild hype rthermia-enhanced chemophotothermal cancer synergistic therapy.The DGVs are self-assembled by gold nanoparticles modified with amphiphilic copolymer in a predetermined concentration of doxorubicin through film rehydration method.Under the influence of laser excitation,the as-prepared DGVs exhibited good photothermal effect,which triggered the structural disruption of GVs and thus,allowed the efficient release of encapsulated DOX to enhance cell uptake for fluorescence imaging and tumor chemotherapy,respectively.In addition,DGVs also showed a strong PA and IRT signals in vivo.Our study demonstrated the potential of DGVs as stimuli-responsive drug delivery systems and cancer theranostics.
文摘Squamous cell carcinoma (SCC) and melanoma are malignant human cancers of the skin with an annual mortality that exceeds 10,000 cases every year in the USA alone. In this study, the lysosomal protein saposin C (SapC) and the phospholipid dioloylphosphatidylserine (DOPS) were assembled into cancer-selective nanovesicles (SapC-DOPS) and successfully tested using several in vitro and in vivo skin cancer models. Using MTT assay that measures the percentage of cell death, SapC-DOPS cytotoxic effect on three skin tumor cell lines (squamous cell carcinoma, SK-MEL-28, and MeWo) was compared to two normal nontumorigenic skin cells lines, normal immortalized keratinocyte (NIK) and human fibroblast cell (HFC). We observed that the nanovesicles selectively killed the skin cancer cells by inducing apoptotic cell death whereas untransformed skin cancer cells remained unaffected. Using subcutaneous skin tumor xenografts, animals treated with SapC-DOPS by subcutaneous injection showed a 79.4% by volume tumor reduced compared to the control after 4 days of treatment. We observed that the nanovesicles killed skin cancer cells by inducing apoptotic cell death compared to the control as revealed by TUNEL staining of xenograft tumor sections.
基金supported by the Tianjin Committee of Science and Technology of China(No.21ZYJDJC00080 and No.22ZYJDSS00040).
文摘Herbal medicine(HM)has been extensively researched and widely used since ancient times.Currently,as one of the emerging directions in HM modernization research,herbal medicine-derived nanovesicles(HMDNV),a type of nanoparticle obtained from destructed plant tissues,hold considerable promise for disease treatment and drug delivery.The recent studies related to HMDNV and miRNAs are summarized in this review,with a special emphasis on their basic characteristics and biological activities,to provide ideas for future scientific research on HMDNV and enrich the content of active components of Traditional Chinese Medicine(TCM).
基金financially supported by the National Key Research and Development Program of China (No.2021YFA1201200)the National Natural Science Foundation of China (Nos. 51833008, 52173141 and 82102192)+1 种基金Zhejiang Provincial Key Research and Development Program (No.2020C01123)China Postdoctoral Science Foundation (No.2019M662059)
文摘Oligonucleotide therapeutics have great potential to target the currently undruggable genes and to generate entirely new therapeutic paradigms in multiple types of disease,thus having attracted much attention in recent years.However,their applications are greatly hindered by a lack of safe and efficient oligonucleotide-delivery vectors.Polyplex nanovesicles formed from oligonucleotides and the cationic block have shown exceptional features for the delivery of therapeutic oligonucleotides and other biopharmaceuticals.Nevertheless,these polyplex nanovesicles are deeply fraught with difficulty in tolerating physiological ionic strength.Inspired by the high binding ability between the dipicolylamine(DPA)/zinc(Ⅱ)complex and the phosphodiester moieties of oligonucleotides,herein,we designed a coordinative cationic block to solve the intrinsic stability dilemma.Moreover,we found the stability of the resulted polyplex nanovesicles could be easily tuned by the content of coordinated zinc ions.In vitro cellular studies implied that the prepared zinc(Ⅱ)-coordinative polyplex nanovesicles preferred to retain in the lysosomes upon internalization,making them ideal delivery candidates for the lysosome-targeting oligonucleotide therapeutics.
文摘Lipidic nanovesicles (so called liposomes) were one the earliest forms of nanovectors. One of their limits was our lack of knowledge on the delivery pathway of their content to the target cell cytoplasm. The present communication describes an efficient way to enhance the delivery. Pulsed electric fields (PEF) are known since the early 80’s to mediate a fusogenic state of plasma membranes when applied to a cell suspension or a tissue. Polykaryons are detected when PEF are applied on cells in contact during or after the pulses. Heterofusion can be obtained when a cell mixture is pulsed. When lipidic nanovesicles, either small unilamellar vesicles (SUVs) or large unilamellar vesicles (LUVs), are electrostatically brought in contact with electropermeabilized cells by a salt bridge, their content is delivered into the cytoplasm in electropermeabilized cells. The PEF parameters are selected to affect specifically the cells leaving the vesicles unaffected. It is the electropermeabilized state of the cell membrane that is the trigger of the merging between the plasma membrane and the lipid bilayer. The present investigation shows that the transfer of macromolecules can be obtained;i.e. 20 kD dextrans can be easily transferred while a direct transfer does not take place under the same electrical parameters. Cell viability was not affected by the treatment. As delivery is present only on electropermeabilized cells, a targeting of the effect is obtained in the volume where the PEF parameters are over the critical value for electropermeabilization. A homogeneous cytoplasm labeling is observed under digitised videomicroscopy. The process is a content and “membrane” mixing, following neither a kiss and run or an endocytotic pathway.
基金supported by the National Natural Science Founda-tion of China(U2202214,82074044,82374060,U21A20410)the Na-tional Key R&D Program of China(2022YFC3500300)the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-020).
文摘Stroke remains one of the leading causes of adult disability worldwide,with neovascularization is crucial for brain repair after stroke.However,neutrophil infiltration hinders effective neovascularization,necessitating timely clearance by microglia through phagocytosis.Unfortunately,microglial phagocytic function is often impaired by metabolic defects,hindering post-stroke recovery.Ginsenoside Rg1,derived from Panax ginseng,exhibits neuroprotective properties and regulates cellular metabolism in vitro but its therapeutic application is limited by poor brain penetration.Here,we present a targeted delivery system utilizing neutrophil-like cell membrane vesicles(NCM),prepared via nitrogen cavitation,to enhance Rg1 delivery to the brain.These bio-mimetic vesicles exploit the inherent targeting ability of neutrophil membranes to reach brain injury sites and are subsequently taken up by microglia.Our findings demonstrate that Rg1-loaded vesicles enhance microglial clearance of neutrophils,reduce neutrophil extracellular traps release,and mitigate tissue damage.These effects improve the post-stroke microenvironment,promote vascular remodeling,and ultimately contribute to func-tional recovery.This strategy highlights the potential of targeted reprogramming microglial cells to enhance their endogenous repair capabilities,offering a promising therapeutic avenue for ischemic stroke management.
基金supported by grants from the National Natural Science Foundation of China(32322045 to Z.Li,22207050 to L.Li,32301162 to F.Wang)Dongguan Science and Technology of Social Development Program(20231800925372 to Z.Li,20231800912372 to F.Wang).
文摘Exosomes are natural nano-size particles secreted by human cells,containing numerous bioactive cargos.Serving as crucial mediators of intercellular communication,exosomes are involved in many physiological and pathological processes,such as inflammation,tissue injury,cardiovascular diseases,tumorigenesis and tumor development.Exosomes have exhibited promising results in the diagnosis and treatment of cancer,cardiovascular diseases and others.They are a rapidly growing class of drug delivery vehicles with many advantages over conventional synthetic carriers.Exosomes used in therapeutic applications encounter several challenges,such as the lack of tissue targeting capabilities and short residence time.In this review,we discuss recent advances in exosome engineering to improve tissue targeting and describe the current types of engineered exosome-like nanovesicles,and summarize their preclinical applications in the treatment of diseases.Further,we also highlight the latest engineering strategies developed to extend exosomes retention time in vivo and exosome-like nanovesicles.
基金the National Natural Science Foundation of China(82125037,82274104,82074024,82374042)National Key R&D Program of China(2023YFC2308200)+3 种基金Jiangsu Provincial Medical Innovation Center(CXZX202225)the Natural Science Foundation of Jiangsu Province(BK20240144)the Innovation Projects of State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture(NZYSKL240103)Nanjing University of Chinese Medicine’s Project(RC202407).
文摘Plant-derived nanovesicles(PDNVs),including plant extracellular vesicles(EVs)and plant exosome-like nanovesicles(ELNs),are natural nano-sized membranous vesicles containing bioactive molecules.PDNVs consist of a bilayer of lipids that can effectively encapsulate hydrophilic and lipophilic drugs,improving drug stability and solubility as well as providing increased bioavailability,reduced systemic toxicity,and enhanced target accumulation.Bioengineering strategies can also be exploited to modify the PDNVs to achieve precise targeting,controlled drug release,and massive production.Meanwhile,they are capable of crossing the blood-brain barrier(BBB)to transport the cargo to the lesion sites without harboring human pathogens,making them excellent therapeutic agents and drug delivery nanoplatform candidates for brain diseases.Herein,this article provides an initial exposition on the fundamental characteristics of PDNVs,including biogenesis,uptake process,isolation,purification,characterization methods,and source.Additionally,it sheds light on the investigation of PDNVs’utilization in brain diseases while also presenting novel perspectives on the obstacles and clinical advancements associated with PDNVs.
基金supported by the National Natural Science Foundation of China(No.82474197)the Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning(No.TP2020054,China)+1 种基金Shanghai Seventh People’s Hospital Medical Institution Preparation and Innovative Chinese Medicine R&D(Open Bidding for Selecting the Best Candidates)Project(No.QYCXZY250204,China)the Program for Shanghai High-Level Local University Innovation Team(No.SZY20220315,China).
文摘Clinical management of atopic dermatitis(AD)is challenged by its susceptibility to recur-rence,side effects,and high costs.We found that Portulaca oleracea L.-derived nanovesicles(PDNV)exert anti-inflammatory effects by modulating macrophage M1/M2 polarization.These effects were achieved through pathways including inhibition of nuclear factor-κB(NF-κB)and stimulator of interferon genes(STING)protein expression in diseased tissues,demonstrating their potential to ameliorate AD symptoms.To increase the transdermal permeation of PDNV,dissolvable microneedles composed primar-ily of hyaluronic acid(HA)were developed as an adjunctive means of delivery.Meanwhile,polysaccha-rides of Portulaca oleracea L.,which were synergistic with PDNV,were used as microneedle constituent materials to enhance the mechanical properties and physical stability of HA.This new means of delivery significantly improves the treatment of AD and also provides new options for the efficient utilization of plant extracellular vesicles and the treatment of AD.In addition,transcriptomic analysis of PDNV showed that the mRNAs of Portulaca oleracea L.are closest to those of ferns,which may shed light on related evolutionary and plant species identification studies.
基金supported by the National Natural Science Foundation of China(32322045 to Z.Li,32301162 to F.Wang,and 22207050 to L.Li)Dongguan Science and Technology of Social Development Pro-gram(20231800925372 to Z.Li and 20231800912372 to F.Wang)。
文摘Mesenchymal stem cells(MSCs)and MSC-derived extracellular vesicles(MSC EVs)have gained significant attention in biomedical and therapeutic applications.Nevertheless,their translation in clinical practice remains limited due to the lack of scalable manufacturing techniques and the prevailing safety concerns.Cell-derived extruded nanovesicles(eNVs)with high production efficiency are regarded as promising substitutes of EVs.However,like MSC EVs,their potential for tumorigenicity has yet to be exhaustively investigated.In this work,we investigated the tumorigenicity of umbilical cord mesenchymal stem cell-derived eNVs(UMSC eNVs).A549 cancer cell-derived eNVs(A549 eNVs)with potential tumorigenicity were also prepared for comparative anal-ysis.Our characterization findings revealed that,although UMSC eNVs and A549 eNVs exhibited similar mor-phologies,they differed in their molecular composition.Subsequent animal experiments demonstrated the low tumorigenicity risk of UMSC eNVs in inducing tumor pathogenesis and development.Furthermore,microRNAs(miRNAs)profiling analyses suggested that the reduced tumorigenicity of UMSC eNVs might be due to the downregulation of hsa-miR-21-5p_R+1 and hsa-miR-192-5p,and upregulation of hsa-miR-143-3p and hsa-miR-146a-5p compared to A549 eNVs.The present study provided direct experimental confirmation and underlying miRNA profiling evidence of the biosafety of UMSC eNVs in terms of tumorigenicity,which will promote the future advancement and translation of UMSC eNVs.
基金the National Heart, Lung, and Blood Institute Grant Numbers: U01HL134764, NIH P01 HL160476 , R01HL131017, R01HL149137.
文摘It remains a significant challenge to reactivate the cell cycle activity of adult mammalian cardiomyocytes(CMs).This study created a hypo-immunogenic human induced pluripotent stem cell(hiPSC)line using clustered regularly interspaced palindromic repeats(CRISPR)/Cas9 gene editing to knockoutβ2-microglobulin in hiPSCs(^(B2MKO)hiPSCs)for manufacturing nanovesicles(^(B2MKO)hiPSC-NVs).Approximately 9500^(B2MKO)hiPSC-NVs were produced from a single^(B2MKO)hiPSC.Proteomic analyses indicated that,compared to^(B2MKO)hiPSCs,the cargos of B2MKOhiPSC-NVs were enriched in spindle and chromosomal proteins,as well as proteins that regulate the cell cycle and scavenge reactive oxygen species(ROS).When administrated to hiPSCs derived CMs(hiPSC-CMs),^(B2MKO)hiPSC-NVs reduced lactate dehydrogenase leakage and apoptosis in hypoxia-cultured hiPSC-CMs through activating the AKT pathway,protected hiPSC-CMs from H_(2)O_(2)-induced damage by ROS scavengers in the NV cargo,increased hiPSC-CM proliferation via the YAP pathway,and were hypoimmunogenic when co-cultured with human CD8+T cells or delivered to mice.Furthermore,when^(B2MKO)hiPSC-NVs or 0.9%NaCl were intra-myocardially injected into mice after cardiac ischemia/reperfusion injury,cardiac function and infarct size,assessed 4 weeks later,were significantly improved in the^(B2MKO)hiPSC-NV group,with increased mouse CM survival and cell cycle activity.Thus,the proteins in the^(B2MKO)hiPSC-NV cargos convergently activated the AKT pathway,scavenged ROS to protect CMs,and upregulated YAP signaling to induce CM cell cycle activity.Thus,^(B2MKO)hiPSC-NVs hold great potential for cardiac protection and regeneration.
基金supported by the Basic Science&Engineering Research Program(NRF-2022R1A2B5B01001920)the National Research Foundation,funded by the Ministry of Science and ICT in Korea.
文摘Acute lung injury(ALI)is a devastating inflammatory disease.MicroRNA155(miR155)in alveolar macrophages and lung epithelial cells enhances inflammatory reactions by inhibiting the suppressor of cytokine signaling 1(SOCS1)in ALI.Anti-miR155 oligonucleotide(AMO155)have been suggested as a potential therapeutic reagent for ALI.However,a safe and efficient carrier is required for delivery of AMO155 into the lungs for ALI therapy.In this study,cell membrane-derived nanovesicles(CMNVs)were produced from cell membranes of LA4 mouse lung epithelial cells and evaluated as a carrier of AMO155 into the lungs.For preparation of CMNVs,cell membranes were isolated from LA4 cells and CMNVs were produced by extrusion.Cholesterol-conjugated AMO155(AMO155c)was loaded into CMNVs and extracellular vesicles(EVs)by sonication.The physical characterization indicated that CMNVs with AMO155c(AMO155c/CMNV)were membrane-structured vesicles with a size of�120nm.The delivery efficiency and therapeutic efficacy of CMNVs were compared with those of EVs or polyethylenimine(25kDa,PEI25k).The delivery efficiency of AMO155c by CMNVs was similar to that by EVs.As a result,the miR155 levels were reduced by AMO155c/CMNV and AMO155c/EV.AMO155c/CMNV were administered intratracheally into the ALI models.The SOCS1 levels were increased more efficiently by AMO155c/CMNV than by the others,suggesting that miR155 effectively was inhibited by AMO155c/CMNV.In addition,the inflammatory cytokines were reduced more effectively by AMO155c/CMNV than they were by AMO155c/EV and AMO155c/PEI25k,reducing inflammation reactions.The results suggest that CMNVs are a useful carrier of AMO155c in the treatment of ALI.
基金supported by the Health Commission of Hubei Province scientific research project(No.WJ2021M143)the Fundamental Research Funds for the Central Universities(No.413000714)+2 种基金the Research Fund of Anhui Institute of translational medicine(No.2023zhyx-C61)the Research Fund Project of Anhui Medical University(No.2022xkj148)Hubei Society of Pathology General Project(No.2025HBAP013).
文摘Epilepsy is a complex neurological disorder aggravated by chronic neuroinflammation largely driven by reactive astrocytes.These cells promote epileptogenesis through persistent cytokine secretion and glial scar formation.Current antiepileptic drugs remain ineffective in targeting these mechanisms due to limited blood-brain barrier(BBB)permeability and poor astrocytic specificity.A transferrin-functionalized biomimetic nanotherapeutic loaded with resveratrol(RN@RTA)was developed to regulate astrocyte-mediated inflammation by activating sirtuin 1(SIRT1)and suppressing the mitogen-activated protein kinase/nuclear factor Kappalight-chain-enhancer of activated B cells(MAPK/NF-κB)axis.Using in vitro BBB models,primary astrocytes,and a pilocarpine-induced chronic epilepsy mouse model,we evaluated the capacity of RN@RTA to cross the BBB,inhibit inflammatory signaling,and reduce seizure activity.Mechanistic assays included immunoprecipitation of NF-κB complexes,cytokine quantification,RNA sequencing,and histopathological assessments of glial and synaptic markers.RN@RTA achieved 82%uptake by hippocampal astrocytes and significantly reduced Il6,Tnf-α,and Nlrp3 expression.SIRT1 activation disrupted the NF-κB p65/p300 complex,leading to transcriptional repression of inflammatory genes and enhancement of autophagy.In vivo,seizure frequency decreased by 67%,synaptic structure was preserved,and astrogliosis was markedly alleviated.The findings demonstrate a dual regulatory mechanism in which RN@RTA suppresses neuroinflammatory signaling and restores neural homeostasis,offering a promising molecularly targeted approach for refractory epilepsy.
