Diabetic kidney disease(DKD)is recognized as a severe complication in the development of diabetes mellitus(DM),posing a significant burden for global health.Major characteristics of DKD kidneys include tubulointerstit...Diabetic kidney disease(DKD)is recognized as a severe complication in the development of diabetes mellitus(DM),posing a significant burden for global health.Major characteristics of DKD kidneys include tubulointerstitial oxidative stress,inflammation,excessive extracellular matrix deposition,and progressing renal fibrosis.However,current treatment options are limited and cannot offer enough efficacy,thus urgently requiring novel therapeutic approaches.Tetrahedral framework nucleic acids(tFNAs)are a novel type of self-assembled DNA nanomaterial with excellent structural stability,biocompatibility,tailorable functionality,and regulatory effects on cellular behaviors.In this study,we established an in vitro high glucose(HG)-induced human renal tubular epithelial cells(HK-2 cells)pro-fibrogenic model and explored the antioxidative,anti-inflammatory,and antifibrotic capacity of tFNAs and the potential molecular mechanisms.tFNAs not only effectively alleviated oxidative stress through reactive oxygen species(ROS)-scavenging and activating the serine and threonine kinase(Akt)/nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)signaling pathway but also inhibited the production of proinflammatory factors such as tumor necrosis factor(TNF-α),interleukin-1β(IL-1β),and interleukin-6(IL-6)in diabetic HK-2 cells.Additionally,tFNAs significantly downregulated the expression of Collagen I andα-smooth muscle actin(α-SMA),two representative biomarkers of pro-fibrogenic myofibroblasts in the renal tubular epithelial-mesenchymal transition(EMT).Furthermore,we found that tFNAs exerted this function by inhibiting the Wnt/β-catenin signaling pathway,preventing the occurrence of EMT and fibrosis.The findings of this study demonstrated that tFNAs are naturally endowed with great potential to prevent fibrosis progress in DKD kidneys and can be further combined with emerging pharmacotherapies,providing a secure and efficient drug delivery strategy for future DKD therapy.展开更多
Hyperglycemia resulting from diabetes mellitus(DM)exacerbates osteoporosis and fractures,damaging bone regeneration due to impaired healing capacity.Stem cell therapy offers the potential for bone repair,accelerating ...Hyperglycemia resulting from diabetes mellitus(DM)exacerbates osteoporosis and fractures,damaging bone regeneration due to impaired healing capacity.Stem cell therapy offers the potential for bone repair,accelerating the healing of bone defects by introducing stem cells with osteogenic differentiation ability.Dental follicle stem cells(DFSCs)are a newly emerging type of dental stem cells that not only have the potential for multipotent differentiation but also hold easy accessibility and can stand longterm storage.However,DM-associated oxidative stress and inflammation elevate the risk of DFSCs dysfunction and apoptosis,diminishing stem cell therapy efficacy.Recent nanomaterial advances,particularly in DNA nanostructures like tetrahedral framework nucleic acids(tFNAs),have been promising candidates for modulating cellular behaviors.Accumulating experiments have shown that tFNAs’cell proliferation and migration-promoting ability and induce osteogenic differentiation of stem cells.Meanwhile,tFNAs can scavenge reactive oxygen species(ROS)and downregulate the secretion of inflammatory factors by inhibiting various inflammation-related signaling pathways.Here,we applied tFNAs to modify DFSCs and observed enhanced osteogenic differentiation alongside ROS scavenging and anti-inflammatory effects mediated by suppressing the ROS/mitogen-activated protein kinases(MAPKs)/nuclear factor kappa-B(NF-κB)signaling pathway.This intervention reduced stem cell apoptosis,bolstering stem cell therapy efficacy in DM.Our study establishes a simple yet potent tFNAs-DFSCs system,offering potential as a bone repair agent for future DM treatment.展开更多
Diabetes mellitus considerably affects bone marrow mesenchymal stem cells(BMSCs),for example,by inhibiting their proliferation and differentiation potential,which enhances the difficulty in endogenous bone regeneratio...Diabetes mellitus considerably affects bone marrow mesenchymal stem cells(BMSCs),for example,by inhibiting their proliferation and differentiation potential,which enhances the difficulty in endogenous bone regeneration.Hence,effective strategies for enhancing the functions of BMSCs in diabetes have farreaching consequences for bone healing and regeneration in diabetes patients.Tetrahedral framework nucleic acids(tFNAs)are nucleic acid nanomaterials that can autonomously enter cells and regulate their behaviors.In this study,we evaluated the effects of tFNAs on BMSCs from diabetic rats.We found that tFNAs could promote the proliferation,migration,and osteogenic differentiation of BMSCs from rats with type 2 diabetes mellitus,and inhibited cell senescence and apoptosis.Furthermore,tFNAs effectively scavenged the accumulated reactive oxygen species and activated the suppressed protein kinase B(Akt)signaling pathway.Overall,we show that tFNAs can recover the proliferation and osteogenic potential of diabetic BMSCs by alleviating oxidative stress and activating Akt signaling.The study provides a strategy for endogenous bone regeneration in diabetes and also paves the way for exploiting DNA-based nanomaterials in regenerative medicine.展开更多
The hyperplasia and destruction of synovial tissue have an important impact on the development of rheumatoid arthritis(RA), the abnormal proliferation and migration of synovial fibroblast in synovial tissue is similar...The hyperplasia and destruction of synovial tissue have an important impact on the development of rheumatoid arthritis(RA), the abnormal proliferation and migration of synovial fibroblast in synovial tissue is similar to tumor cells. Targeting anomalous synovial fibroblast and designing a high bioavailability nano drug delivery system can reduce the dosage for the treatment of rheumatoid arthritis and it is of great significance to reduce toxic and side effects and improve curative effect. In this experiment, the nobiletin-loaded tetrahedral framework nucleic acids cargo tank was established, carrying antiinflammatory small molecule monomer drug nobiletin with minimal bioavailability. Both in vitro cell experiments and in vivo animal studies proved the nano cargo tank enhance the role of nobiletin in reducing the invasiveness of pathological synovial fibroblast and promote their apoptosis, effectively alleviate the disease development of rheumatoid arthritis.展开更多
Cognitive impairment often occurs after post traumatic brain injury. In addition, recovery of cognitive impairment is largely dependent on spontaneous repair and the severity of secondary insult. The tetrahedral frame...Cognitive impairment often occurs after post traumatic brain injury. In addition, recovery of cognitive impairment is largely dependent on spontaneous repair and the severity of secondary insult. The tetrahedral framework nucleic acid is a novel nanostructure has been shown to have a positive biological effect in promoting regeneration and anti-inflammation. To explore the treatment effect of tetrahedral framework nucleic acids for cognitive impairment recovery post traumatic brain injury, we established a mouse model of traumatic brain injury and verified the efficacy of tetrahedral framework nucleic acids in promoting cognitive impairment recovery post traumatic brain injury. The results show that the tetrahedral framework nucleic acids promoted the recovery of post-traumatic cognitive function by enhancing the proliferation of endogenous neural stem cells. Besides, tetrahedral framework nucleic acids modulated the neuroinflammatory response in the acute phase by inhibiting excessive astrocyte and microglial activation. Taken together, the results of the study indicate tetrahedral framework nucleic acids for treatment of cognitive impairment post traumatic brain injury.展开更多
Osteoporosis(OP)is a noncommunicable bone disease caused by a shift in the balance between os-teoblasts and osteoclasts,and can severely affect the health of elderly persons.Autologous stem-cell transplantation can im...Osteoporosis(OP)is a noncommunicable bone disease caused by a shift in the balance between os-teoblasts and osteoclasts,and can severely affect the health of elderly persons.Autologous stem-cell transplantation can improve reduced bone density and weakened fracture healing abilities in patients with OP.However,OP can adversely affect the osteogenesis and proliferation abilities of autologous adipose-derived stem cells(ASCs).Therefore,an effective drug is required to facilitate autologous ASCs to recover their osteogenic and proliferative potential.Tetrahedral framework nucleic acid(tFNA)is a new type of nanomaterial that has ability to regulate the biological behavior of cells effectively and en-hance the bioactivity of stem cells.In this study,we examine the effects of tFNAs on the osteogenic differentiation and proliferation abilities of ASCs in rats with OP.The results indicate that the 250 nmol/L tFNAs can considerably increase the expression of osteogenesis-related markers,effectively promote the proliferation and osteogenic differentiation of osteoporotic ASCs(OP-ASCs),and help them to regain their osteogenic and proliferative potential.In short,tFNAs can enable OP-ACSs to recover their osteogenic po-tential and promote their proliferation and,therefore,can play a key regulatory role in autologous ASC transplantation.展开更多
Articular cartilage injury(ACI)remains one of the key challenges in regenerative medicine,as current treatment strategies do not result in ideal regeneration of hyaline-like cartilage.Enhancing endogenous repair via m...Articular cartilage injury(ACI)remains one of the key challenges in regenerative medicine,as current treatment strategies do not result in ideal regeneration of hyaline-like cartilage.Enhancing endogenous repair via micro-RNAs(miRNAs)shows promise as a regenerative therapy.miRNA-140 and miRNA-455 are two key and promising candidates for regulating the chondrogenic differentiation of mesenchymal stem cells(MSCs).In this study,we innovatively synthesized a multifunctional tetrahedral framework in which a nucleic acid(tFNA)-based targeting miRNA codelivery system,named A-T-M,was used.With tFNAs as vehicles,miR-140 and miR-455 were connected to and modified on tFNAs,while Apt19S(a DNA aptamer targeting MSCs)was directly integrated into the nanocomplex.The relevant results showed that A-T-M efficiently delivered miR-140 and miR-455 into MSCs and subsequently regulated MSC chondrogenic differentiation through corresponding mechanisms.Interestingly,a synergistic effect between miR-140 and miR-455 was revealed.Furthermore,A-T-M successfully enhanced the endogenous repair capacity of articular cartilage in vivo and effectively inhibited hypertrophic chondrocyte formation.A-T-M provides a new perspective and strategy for the regeneration of articular cartilage,showing strong clinical application value in the future treatment of ACI.展开更多
Erythromycin is a commonly used broad-spectrum antibiotic,but resistance to this antibiotic makes its use less effective.Considerable efforts,beside finding alternatives,are needed to enhance its antimicrobial effect ...Erythromycin is a commonly used broad-spectrum antibiotic,but resistance to this antibiotic makes its use less effective.Considerable efforts,beside finding alternatives,are needed to enhance its antimicrobial effect and stability against bacteria.Tetrahedral framework nucleic acids(tFNAs),a novel delivery vehicle with a three-dimensional nanostructure,have been studied as a carrying platform of antineoplastic drugs.In this study,the use of tFNAs in delivering erythromycin into Escherichia coli(E.coli)was investigated for the first time.The tFNAs vehicle increased the bacterial uptake of erythromycin and promoted membrane destabilization.Moreover,it increased the permeability of the bacterial cell wall,and reduced drug resistance by improving the movement of the drug across the membrane.The tFNAs-based delivery system enhanced the effects of erythromycin against E.coli.It may therefore provide an effective delivery vehicle for erythromycin in targeting antibiotic-resistant bacteria with thick cell wall.展开更多
DNA is a biological polymer that encodes and stores genetic information in all living organism. Particularly, the precise nucleobase pairing inside DNA is exploited for the self-assembling of nanostructures with defin...DNA is a biological polymer that encodes and stores genetic information in all living organism. Particularly, the precise nucleobase pairing inside DNA is exploited for the self-assembling of nanostructures with defined size, shape and functionality. These DNA nanostructures are known as framework nucleic acids(FNAs) for their skeleton-like features. Recently, FNAs have been explored in various fields ranging from physics, chemistry to biology. In this review, we mainly focus on the recent progress of FNAs in a pharmaceutical perspective. We summarize the advantages and applications of FNAs for drug discovery, drug delivery and drug analysis. We further discuss the drawbacks of FNAs and provide an outlook on the pharmaceutical research direction of FNAs in the future.展开更多
Many recent studies have shown that joint-resident mesenchymal stem cells(MSCs)play a vital role in articular cartilage(AC)in situ regeneration.Specifically,synovium-derived MSCs(SMSCs),which have strong chondrogenic ...Many recent studies have shown that joint-resident mesenchymal stem cells(MSCs)play a vital role in articular cartilage(AC)in situ regeneration.Specifically,synovium-derived MSCs(SMSCs),which have strong chondrogenic differentiation potential,may be the main driver of cartilage repair.However,both the insufficient number of MSCs and the lack of an ideal regenerative microenvironment in the defect area will seriously affect the regeneration of AC.Tetrahedral framework nucleic acids(tFNAs),notable novel nanomaterials,are considered prospective biological regulators in biomedical engineering.Here,we aimed to explore whether tFNAs have positive effects on AC in situ regeneration and to investigate the related mechanism.The results of in vitro experiments showed that the proliferation and migration of SMSCs were significantly enhanced by tFNAs.In addition,tFNAs,which were added to chondrogenic induction medium,were shown to promote the chondrogenic capacity of SMSCs by increasing the phosphorylation of Smad2/3.In animal models,the injection of tFNAs improved the therapeutic outcome of cartilage defects compared with that of the control treatments without tFNAs.In conclusion,this is the first report to demonstrate that tFNAs can promote the chondrogenic differentiation of SMSCs in vitro and enhance AC regeneration in vivo,indicating that tFNAs may become a promising therapeutic for AC regeneration.展开更多
Choroidal neovascularization(CNV)is a common pathological feature of various eye diseases and an important cause of visual impairment in middle-aged and elderly patients.In previous studies,tetrahedral framework nucle...Choroidal neovascularization(CNV)is a common pathological feature of various eye diseases and an important cause of visual impairment in middle-aged and elderly patients.In previous studies,tetrahedral framework nucleic acids(tFNAs)showed good carrier performance.In this experiment,we developed microRNA-155-equipped tFNAs(T-155)and explored its biological effects on CNV.Based on the results of in-vitro experiments,T-155 could regulate macrophages into the antiangiogenic M1 type.Then,we injected T-155 into the vitreous of laser-induced CNV model mice and found that T-155 significantly reduced the size and area of CNV,inhibited blood vessel leakage.In summary,we prove that T-155 could regulate the inflammatory process of CNV by polarizing macrophages,thereby improving the symptoms of CNV.Thus,T-155 might become a new DNA-based drug with great potential for treating CNV.展开更多
This article reviews the latest research advances of tetrahedral framework nucleic acid(t FNA)-based systems in their fabrication,modification,and the potential applications in biomedicine.TFNA arises from the synthes...This article reviews the latest research advances of tetrahedral framework nucleic acid(t FNA)-based systems in their fabrication,modification,and the potential applications in biomedicine.TFNA arises from the synthesis of four single-stranded DNA chains.Each chain contains brief sequences that complement those found in the other three,culminating in the creation of a pyramid-shaped nanostructure of approximately 10 nanometers in size.The first generation of t FNA demonstrates inherent compatibility with biological systems and the ability to permeate cell membrane effectively.These attributes translate into remarkable capabilities for regulating various cellular biological processes,fostering tissue regeneration,and modulating immune responses.The subsequent evolution of t FNA introduces enhanced adaptability and a relatively higher degree of biological stability.This advancement encompasses structural modifications,such as the addition of functional domains at the vertices or side arms,integration of low molecular weight pharmaceuticals,and the implementation of diverse strategies aimed at reversing multi-drug resistance in tumor cells or microorganisms.These augmentations empower t FNA-based systems to be utilized in different scenarios,thus broadening their potential applications in various biomedical fields.展开更多
Obesity-induced insulin resistance is the hallmark of metabolic syndrome,and chronic,low-grade tissue inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune cells.Current...Obesity-induced insulin resistance is the hallmark of metabolic syndrome,and chronic,low-grade tissue inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune cells.Current therapeutic approaches lack efficacy and immunomodulatory capacity.Thus,a new therapeutic approach is needed to prevent chronic inflammation and alleviate insulin resistance.Here,we synthesized a tetrahedral framework nucleic acid(tFNA)nanoparticle that carried resveratrol(RSV)to inhibit tissue inflammation and improve insulin sensitivity in obese mice.The prepared nanoparticles,namely tFNAs-RSV,possessed the characteristics of simple synthesis,stable properties,good water solubility,and superior biocompatibility.The tFNA-based delivery ameliorated the lability of RSV and enhanced its therapeutic efficacy.In high-fat diet(HFD)-fed mice,the administration of tFNAs-RSV ameliorated insulin resistance by alleviating inflammation status.tFNAs-RSV could reverse M1 phenotype macrophages in tissues to M2 phenotype macrophages.As for adaptive immunity,the prepared nanoparticles could repress the activation of Th1 and Th17 and promote Th2 and Treg,leading to the alleviation of insulin resistance.Furthermore,this study is the first to demonstrate that tFNAs,a nucleic acid material,possess immunomodulatory capacity.Collectively,our findings demonstrate that tFNAs-RSV alleviate insulin resistance and ameliorate inflammation in HFD mice,suggesting that nucleic acid materials or nucleic acid-based delivery systems may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.展开更多
Synthetic antigen-encoding mRNA plays an increasingly significant role in tumor vaccine technology owing to its antigen-specific immune-activation. However, its immune efficacy is challenged by inferior delivery effic...Synthetic antigen-encoding mRNA plays an increasingly significant role in tumor vaccine technology owing to its antigen-specific immune-activation. However, its immune efficacy is challenged by inferior delivery efficiency and demand for suitable adjuvants. Here, we develop a novel mRNA nanovaccine based on a multifunctional nanocapsule, which is a dual-adjuvant formulation composed of cytosine-phosphateguanine motifs loaded tetrahedral framework nucleic acid(CpG-tFNA) and an immunopeptide murine β-defensin 2(mDF2β). This m RNA nanovaccine successfully achieves intracellular delivery, antigen expression and presentation of dendritic cells, and proliferation of antigen-specific T cells. In a tumor prophylactic vaccination model, it exerts an excellent inhibitory effect on lymphoma occurrence through cellular immunity. This mRNA nanovaccine has promising prophylactic applications in tumors and many other diseases.展开更多
The increasing prevalence of methicillin-resistant Staphylococcus aureus(MRSA)due to antibiotic misuse necessitates novel therapeutic strategies to counter multidrug-resistant infections.Here,we introduce a self-assem...The increasing prevalence of methicillin-resistant Staphylococcus aureus(MRSA)due to antibiotic misuse necessitates novel therapeutic strategies to counter multidrug-resistant infections.Here,we introduce a self-assembling,aggregation-enhanced tetrahedralDNAnanostructure(tFNA)platform that achieves targeted drug delivery through controlled aggregation and sustained release,effectively restoring MRSA susceptibility toβ-lactam antibiotics.These tetrahedral frameworks,termed tFNAs-ASOsceftriaxone sodium(TACs),serve as a dual-functional system that co-encapsulates antisense oligonucleotides(ASOs)targeting the mecA gene and the β-lactam antibiotic ceftriaxone sodium(Cef).Aggregation of TACs plays a pivotal role in maximizing drug retention and stability,prolonging the localized release of both ASOs and antibiotics while maintaining high bioavailability at the infection site.Characterization studies,including size distribution,zeta potential,and fluorescence quenching assays,confirm their robust aggregation stability and encapsulation efficiency,ensuring controlled drug kinetics and prolonged therapeutic effects.Upon interaction with bacterial cells,the locally concentrated TACs facilitate efficient ASO-mediated mecA silencing,thereby disrupting PBP2a expression and re-sensitizing MRSA to β-lactams.Simultaneously,the aggregated ceftriaxone sodium reservoir ensures sustained inhibition of bacterial cell wall synthesis,leading to effective bacterial clearance.In addition,TACs display potent antibiofilm activity by penetrating the biofilm matrix and delivering therapeutics directly to the embedded bacterial population,thereby overcoming the diffusion barriers.In vivo,TACs exhibit superior therapeutic efficacy in an MRSA-induced pneumonia mouse model,significantly improving survival rates,reducing bacterial burden,and mitigating lung tissue damage.These findings highlight the transformative potential of tFNAs as an intelligent drug aggregation and release system,offering a novel paradigm for optimizing antibiotic therapy against multidrug-resistant pathogens.展开更多
The specific induction of hepatic differentiation presents a significant challenge in developing alternative liver cell sources and viable strategies for clinical therapy of acute liver failure (ALF). The past decade ...The specific induction of hepatic differentiation presents a significant challenge in developing alternative liver cell sources and viable strategies for clinical therapy of acute liver failure (ALF). The past decade has witnessed the blossom of microRNAs in regenerative medicine. Herein, microRNA 122-functionalized tetrahedral framework nucleic acid (FNA-miR-122) has emerged as an unprecedented and potential platform for directing the hepatic differentiation of adipose-derived mesenchymal stem cells (ADMSCs), which offers a straightforward and cost-effective method for generating functional hepatocyte-like cells (FNA-miR-122-iHep). Additionally, we have successfully established a liver organoid synthesis strategy by optimizing the co-culture of FNA-miR-122-iHep with endothelial cells (HUVECs), resulting in functional Hep:HUE-liver spheroids. Transcriptome analysis not only uncovered the potential molecular mechanisms through which miR-122 influences hepatic differentiation in ADMSCs, but also clarified that Hep:HUE-liver spheroids could further facilitate hepatocyte maturation and improved tissue-specific functions, which may provide new hints to be used to develop a hepatic organoid platform. Notably, compared to transplanted ADMSCs and Hep-liver spheroid, respectively, both FNA-miR-122-iHep-based single cell therapy and Hep:HUE-liver spheroid-based therapy showed high efficacy in treating ALF in vivo. Collectively, this research establishes a robust system using microRNA to induce ADMSCs into functional hepatocyte-like cells and to generate hepatic organoids in vitro, promising a highly efficient therapeutic approach for ALF.展开更多
Chemotherapeutic drugs,such as cisplatin and phenanthriplatin(PhenPt),as STING agonists to induce DNA damage and activate the cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)signaling pathway provide...Chemotherapeutic drugs,such as cisplatin and phenanthriplatin(PhenPt),as STING agonists to induce DNA damage and activate the cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)signaling pathway provides a potential strategy for clinical chemo-immunotherapy.However,treatment with Pt-based drugs leads to irreversible ectopia of phosphatidylserine(PS),a major component of the intracellular membrane,to the surface of the cancer cells by enzymes(Xkr8).Exposed PS can bind to immune cell receptors and inhibit the presentation of tumor antigens,leading to immunosuppression and attenuation of chemotherapy.Herein,we report a novel approach to enhance chemo-immunotherapy by constructing siRNA targeted Xkr8(siXkr8)-mediated tetrahedral framework nucleic acid nanogel structure concurrently loaded with PhenPt(siXkr8-FNG/PhenPt)for co-delivery of siRNA and Pt-based drugs.The results showed that siXkr8-FNG/PhenPt can not only be used as an efficient delivery carrier to deliver siXkr8,block the expression of Xkr8,reduce the exposure of PS on the cancer cells surface,but also act as an immune stimulant to activate cGAS-STING pathway,effectively improve the immunosuppressive microenvironment,produce antitumor immune response,and inhibit tumor growth and metastasis.Overall,this new delivery system is important for improving the effect of Pt-based drug chemotherapy,inducing immune enhancement and nucleic acid drug delivery.展开更多
Parkinson’s disease(PD)is one of the most prevalent neurodegenerative diseases.It is usually accompanied by motor and non-motor symptoms that seriously threaten the health and the quality of life.Novel medications ar...Parkinson’s disease(PD)is one of the most prevalent neurodegenerative diseases.It is usually accompanied by motor and non-motor symptoms that seriously threaten the health and the quality of life.Novel medications are urgently needed because current pharmaceuticals can relieve symptoms but cannot stop disease progression.The microbiota-gut-brain axis(MGBA)is closely associated with the occurrence and development of PD and is an effective therapeutic target.Tetrahedral framework nucleic acids(tFNAs)can modulate the microbiome and immune regulation.However,such nucleic acid nanostructures are very sensitive to acids which hinder this promising approach.Therefore,we prepared exosome-like nanovesicles(Exo@tac)from ginger that are acid resistant and equipped with tFNAs modified by antimicrobial peptides(AMP).We verified that Exo@tac regulates intestinal bacteria associated with the microbial-gut-brain axis in vitro and significantly improves PD symptoms in vivo when administered orally.Microbiota profiling confirmed that Exo@tac normalizes the intestinal flora composition of mouse models of PD.Our findings present a novel strategy for the development of PD drugs and the innovative delivery of nucleic acid nanomedicines.展开更多
Framework nucleic acids(FNAs)have emerged as intelligent sensing systems for the detection of tumor-related biomarkers in living cells.However,orthogonally controlled manipulation of FNAs-based nanodevices for on-site...Framework nucleic acids(FNAs)have emerged as intelligent sensing systems for the detection of tumor-related biomarkers in living cells.However,orthogonally controlled manipulation of FNAs-based nanodevices for on-site imaging of microRNAs(miRNAs)remains an intractable challenge.Herein,we report a dual endogenous stimuli-responsive FNA nanodevice that can perform miRNA sensing and imaging in a tumor-specificmanner.The sensing function of the nanodevice is silent(OFF)by rationally incorporating adenosine 5′-triphosphate(ATP)aptamer and an abasic site,which can also be activated(ON)with ATP and human apurinic/apyrimidinic endonuclease 1(APE1)in tumor cells,enabling on-site and efficient miRNA imaging with improved tumor specificity.Furthermore,we demonstrate the capability of the nanodevice for specificmiRNAimagingboth in living cells and in vivo based on the“dual keys”(overexpressed ATP and APE1 in tumors)priming mode.Therefore,this work illustrates a simple biosensing methodology with great potential for precise imaging of tumor biomarkers in clinical diagnosis and therapeutic evaluation.展开更多
Main observation and conclusion DNA circuits have been designed for implementation of various functions based on DNA strand displacement in cell-free settings,but their capabilities in biological environments remain l...Main observation and conclusion DNA circuits have been designed for implementation of various functions based on DNA strand displacement in cell-free settings,but their capabilities in biological environments remain limited.In this work,we report framework nucleic acid(FNA)-based circuits enabling intracellular logic computation for mRNA imaging.FNAs as rigid scaffolds enable to deliver our built DNA circuits into cells without aid of transfection reagents,evading a time-consuming and tedious process prior to analysis,and the pendant duplex DNA designed at one vertex of FNA as gate is suitable for four-way strand exchange,minimizing crosstalk with other nucleic acids in the cellular milieu.We demonstrated that such FNA-based circuits can operate both in vitro and in vivo logic computation,including OR and AND logic gates.Moreover,in situ mRNA imaging was also realized by exploiting native mRNA as scaffolds to bind multiple FNA-based gates for the enhanced signal-to-background ratio.We hope that this FNA-based circuit can be applied for disease diagnosis,facilitating the development of biomedicine.展开更多
基金supported by the National Natural Science Foundation of China(No.82101077)Sichuan Science and Technology Program(No.2023NSFSC1516)+2 种基金Postdoctoral Science Foundation of China(Nos.2021M692271,2023T160455)West China School/Hospital of Stomatology Sichuan University,No.RCDWJS2023-5,Fundamental Research Funds for the Central UniversitiesResearch and Develop Program,West China Hospital of Stomatology Sichuan University.
文摘Diabetic kidney disease(DKD)is recognized as a severe complication in the development of diabetes mellitus(DM),posing a significant burden for global health.Major characteristics of DKD kidneys include tubulointerstitial oxidative stress,inflammation,excessive extracellular matrix deposition,and progressing renal fibrosis.However,current treatment options are limited and cannot offer enough efficacy,thus urgently requiring novel therapeutic approaches.Tetrahedral framework nucleic acids(tFNAs)are a novel type of self-assembled DNA nanomaterial with excellent structural stability,biocompatibility,tailorable functionality,and regulatory effects on cellular behaviors.In this study,we established an in vitro high glucose(HG)-induced human renal tubular epithelial cells(HK-2 cells)pro-fibrogenic model and explored the antioxidative,anti-inflammatory,and antifibrotic capacity of tFNAs and the potential molecular mechanisms.tFNAs not only effectively alleviated oxidative stress through reactive oxygen species(ROS)-scavenging and activating the serine and threonine kinase(Akt)/nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)signaling pathway but also inhibited the production of proinflammatory factors such as tumor necrosis factor(TNF-α),interleukin-1β(IL-1β),and interleukin-6(IL-6)in diabetic HK-2 cells.Additionally,tFNAs significantly downregulated the expression of Collagen I andα-smooth muscle actin(α-SMA),two representative biomarkers of pro-fibrogenic myofibroblasts in the renal tubular epithelial-mesenchymal transition(EMT).Furthermore,we found that tFNAs exerted this function by inhibiting the Wnt/β-catenin signaling pathway,preventing the occurrence of EMT and fibrosis.The findings of this study demonstrated that tFNAs are naturally endowed with great potential to prevent fibrosis progress in DKD kidneys and can be further combined with emerging pharmacotherapies,providing a secure and efficient drug delivery strategy for future DKD therapy.
基金supported by the National Natural Science Foundation of China (Nos. 82101077, 82370929)Sichuan Science and Technology Program (Nos. 2023NSFSC1516, 2023NSFSC1706)+3 种基金Postdoctoral Science Foundation of China (Nos. 2021M692271, 2023T160455, BX20220220, 2022M722251)West China School/Hospital of Stomatology Sichuan University (No. RCDWJS2023–5)Fundamental Research Funds for the Central UniversitiesResearch and Develop Program, West China Hospital of Stomatology Sichuan University
文摘Hyperglycemia resulting from diabetes mellitus(DM)exacerbates osteoporosis and fractures,damaging bone regeneration due to impaired healing capacity.Stem cell therapy offers the potential for bone repair,accelerating the healing of bone defects by introducing stem cells with osteogenic differentiation ability.Dental follicle stem cells(DFSCs)are a newly emerging type of dental stem cells that not only have the potential for multipotent differentiation but also hold easy accessibility and can stand longterm storage.However,DM-associated oxidative stress and inflammation elevate the risk of DFSCs dysfunction and apoptosis,diminishing stem cell therapy efficacy.Recent nanomaterial advances,particularly in DNA nanostructures like tetrahedral framework nucleic acids(tFNAs),have been promising candidates for modulating cellular behaviors.Accumulating experiments have shown that tFNAs’cell proliferation and migration-promoting ability and induce osteogenic differentiation of stem cells.Meanwhile,tFNAs can scavenge reactive oxygen species(ROS)and downregulate the secretion of inflammatory factors by inhibiting various inflammation-related signaling pathways.Here,we applied tFNAs to modify DFSCs and observed enhanced osteogenic differentiation alongside ROS scavenging and anti-inflammatory effects mediated by suppressing the ROS/mitogen-activated protein kinases(MAPKs)/nuclear factor kappa-B(NF-κB)signaling pathway.This intervention reduced stem cell apoptosis,bolstering stem cell therapy efficacy in DM.Our study establishes a simple yet potent tFNAs-DFSCs system,offering potential as a bone repair agent for future DM treatment.
基金supported by National Natural Science Foundation of China(No.82301030)China Postdoctoral Science Foundation(No.2022M712384)+2 种基金Tianjin Education Commission Research Project(No.2021KJ244)Tianjin Health Science and Technology Project(No.TJWJ2021QN038)Tianjin Key Medical Discipline(Specialty)Construction Project(No.TJYXZDXK-038A).
文摘Diabetes mellitus considerably affects bone marrow mesenchymal stem cells(BMSCs),for example,by inhibiting their proliferation and differentiation potential,which enhances the difficulty in endogenous bone regeneration.Hence,effective strategies for enhancing the functions of BMSCs in diabetes have farreaching consequences for bone healing and regeneration in diabetes patients.Tetrahedral framework nucleic acids(tFNAs)are nucleic acid nanomaterials that can autonomously enter cells and regulate their behaviors.In this study,we evaluated the effects of tFNAs on BMSCs from diabetic rats.We found that tFNAs could promote the proliferation,migration,and osteogenic differentiation of BMSCs from rats with type 2 diabetes mellitus,and inhibited cell senescence and apoptosis.Furthermore,tFNAs effectively scavenged the accumulated reactive oxygen species and activated the suppressed protein kinase B(Akt)signaling pathway.Overall,we show that tFNAs can recover the proliferation and osteogenic potential of diabetic BMSCs by alleviating oxidative stress and activating Akt signaling.The study provides a strategy for endogenous bone regeneration in diabetes and also paves the way for exploiting DNA-based nanomaterials in regenerative medicine.
基金supported by the National Key R&D Program of China (No. 2019YFA0110600)National Natural Science Foundation of China (Nos. 82171006, 81970986)Sichuan Province Youth Science and Technology Innovation Team (No. 2022JDTD0021)。
文摘The hyperplasia and destruction of synovial tissue have an important impact on the development of rheumatoid arthritis(RA), the abnormal proliferation and migration of synovial fibroblast in synovial tissue is similar to tumor cells. Targeting anomalous synovial fibroblast and designing a high bioavailability nano drug delivery system can reduce the dosage for the treatment of rheumatoid arthritis and it is of great significance to reduce toxic and side effects and improve curative effect. In this experiment, the nobiletin-loaded tetrahedral framework nucleic acids cargo tank was established, carrying antiinflammatory small molecule monomer drug nobiletin with minimal bioavailability. Both in vitro cell experiments and in vivo animal studies proved the nano cargo tank enhance the role of nobiletin in reducing the invasiveness of pathological synovial fibroblast and promote their apoptosis, effectively alleviate the disease development of rheumatoid arthritis.
基金supported by the National Key R&D Program of China (No. 2019YFA0110600)the National Natural Science Foundation of China (Nos. 81970916, 81971295, 92001216, 82171355)+2 种基金the China Postdoctoral Science Foundation (No. 2021M700699)Sichuan Province Youth Science and Technology Innovation Team (No. 2022JDTD0021)Research Funding from West China School/Hospital of Stomatology Sichuan University (No.RCDWJS2021–20)。
文摘Cognitive impairment often occurs after post traumatic brain injury. In addition, recovery of cognitive impairment is largely dependent on spontaneous repair and the severity of secondary insult. The tetrahedral framework nucleic acid is a novel nanostructure has been shown to have a positive biological effect in promoting regeneration and anti-inflammation. To explore the treatment effect of tetrahedral framework nucleic acids for cognitive impairment recovery post traumatic brain injury, we established a mouse model of traumatic brain injury and verified the efficacy of tetrahedral framework nucleic acids in promoting cognitive impairment recovery post traumatic brain injury. The results show that the tetrahedral framework nucleic acids promoted the recovery of post-traumatic cognitive function by enhancing the proliferation of endogenous neural stem cells. Besides, tetrahedral framework nucleic acids modulated the neuroinflammatory response in the acute phase by inhibiting excessive astrocyte and microglial activation. Taken together, the results of the study indicate tetrahedral framework nucleic acids for treatment of cognitive impairment post traumatic brain injury.
基金supported by the National Key R&D Program of China(No.2019YFA0110600)National Natural Science Founda-tion of China(Nos.82171006,81970986,81771125,82001432)+1 种基金China Postdoctoral Science Foundation(Nos.2020TQ0213,2020M683319)West China Hospital Postdoctoral Science Foundation(No.2020HXBH104).
文摘Osteoporosis(OP)is a noncommunicable bone disease caused by a shift in the balance between os-teoblasts and osteoclasts,and can severely affect the health of elderly persons.Autologous stem-cell transplantation can improve reduced bone density and weakened fracture healing abilities in patients with OP.However,OP can adversely affect the osteogenesis and proliferation abilities of autologous adipose-derived stem cells(ASCs).Therefore,an effective drug is required to facilitate autologous ASCs to recover their osteogenic and proliferative potential.Tetrahedral framework nucleic acid(tFNA)is a new type of nanomaterial that has ability to regulate the biological behavior of cells effectively and en-hance the bioactivity of stem cells.In this study,we examine the effects of tFNAs on the osteogenic differentiation and proliferation abilities of ASCs in rats with OP.The results indicate that the 250 nmol/L tFNAs can considerably increase the expression of osteogenesis-related markers,effectively promote the proliferation and osteogenic differentiation of osteoporotic ASCs(OP-ASCs),and help them to regain their osteogenic and proliferative potential.In short,tFNAs can enable OP-ACSs to recover their osteogenic po-tential and promote their proliferation and,therefore,can play a key regulatory role in autologous ASC transplantation.
基金supported by the Natural Science Foundation of Beijing Municipality(L234024)。
文摘Articular cartilage injury(ACI)remains one of the key challenges in regenerative medicine,as current treatment strategies do not result in ideal regeneration of hyaline-like cartilage.Enhancing endogenous repair via micro-RNAs(miRNAs)shows promise as a regenerative therapy.miRNA-140 and miRNA-455 are two key and promising candidates for regulating the chondrogenic differentiation of mesenchymal stem cells(MSCs).In this study,we innovatively synthesized a multifunctional tetrahedral framework in which a nucleic acid(tFNA)-based targeting miRNA codelivery system,named A-T-M,was used.With tFNAs as vehicles,miR-140 and miR-455 were connected to and modified on tFNAs,while Apt19S(a DNA aptamer targeting MSCs)was directly integrated into the nanocomplex.The relevant results showed that A-T-M efficiently delivered miR-140 and miR-455 into MSCs and subsequently regulated MSC chondrogenic differentiation through corresponding mechanisms.Interestingly,a synergistic effect between miR-140 and miR-455 was revealed.Furthermore,A-T-M successfully enhanced the endogenous repair capacity of articular cartilage in vivo and effectively inhibited hypertrophic chondrocyte formation.A-T-M provides a new perspective and strategy for the regeneration of articular cartilage,showing strong clinical application value in the future treatment of ACI.
基金This study was funded by the National Key R&D Program of China[2019YFA0110600]and National Natural Science Foundation of China [81970916, 81671031].
文摘Erythromycin is a commonly used broad-spectrum antibiotic,but resistance to this antibiotic makes its use less effective.Considerable efforts,beside finding alternatives,are needed to enhance its antimicrobial effect and stability against bacteria.Tetrahedral framework nucleic acids(tFNAs),a novel delivery vehicle with a three-dimensional nanostructure,have been studied as a carrying platform of antineoplastic drugs.In this study,the use of tFNAs in delivering erythromycin into Escherichia coli(E.coli)was investigated for the first time.The tFNAs vehicle increased the bacterial uptake of erythromycin and promoted membrane destabilization.Moreover,it increased the permeability of the bacterial cell wall,and reduced drug resistance by improving the movement of the drug across the membrane.The tFNAs-based delivery system enhanced the effects of erythromycin against E.coli.It may therefore provide an effective delivery vehicle for erythromycin in targeting antibiotic-resistant bacteria with thick cell wall.
基金supported by National Natural Science Foundation(No.82072087,China)Key Technologies Research and Development Program(No.2016YFA0201200,China)the Guangdong Natural Science Fund for Distinguished Young Scholars(No.2017A030306016,China)。
文摘DNA is a biological polymer that encodes and stores genetic information in all living organism. Particularly, the precise nucleobase pairing inside DNA is exploited for the self-assembling of nanostructures with defined size, shape and functionality. These DNA nanostructures are known as framework nucleic acids(FNAs) for their skeleton-like features. Recently, FNAs have been explored in various fields ranging from physics, chemistry to biology. In this review, we mainly focus on the recent progress of FNAs in a pharmaceutical perspective. We summarize the advantages and applications of FNAs for drug discovery, drug delivery and drug analysis. We further discuss the drawbacks of FNAs and provide an outlook on the pharmaceutical research direction of FNAs in the future.
基金This study was supported by the National Key R&D Program of China(2019YFA0110600).
文摘Many recent studies have shown that joint-resident mesenchymal stem cells(MSCs)play a vital role in articular cartilage(AC)in situ regeneration.Specifically,synovium-derived MSCs(SMSCs),which have strong chondrogenic differentiation potential,may be the main driver of cartilage repair.However,both the insufficient number of MSCs and the lack of an ideal regenerative microenvironment in the defect area will seriously affect the regeneration of AC.Tetrahedral framework nucleic acids(tFNAs),notable novel nanomaterials,are considered prospective biological regulators in biomedical engineering.Here,we aimed to explore whether tFNAs have positive effects on AC in situ regeneration and to investigate the related mechanism.The results of in vitro experiments showed that the proliferation and migration of SMSCs were significantly enhanced by tFNAs.In addition,tFNAs,which were added to chondrogenic induction medium,were shown to promote the chondrogenic capacity of SMSCs by increasing the phosphorylation of Smad2/3.In animal models,the injection of tFNAs improved the therapeutic outcome of cartilage defects compared with that of the control treatments without tFNAs.In conclusion,this is the first report to demonstrate that tFNAs can promote the chondrogenic differentiation of SMSCs in vitro and enhance AC regeneration in vivo,indicating that tFNAs may become a promising therapeutic for AC regeneration.
基金supported by the National Key R&D Program of China(2019YFA0110600)National Natural Science Foundation of China(81970916,81671031)The National Major Scientific Equipment program(Grant No.2012YQ12008005).
文摘Choroidal neovascularization(CNV)is a common pathological feature of various eye diseases and an important cause of visual impairment in middle-aged and elderly patients.In previous studies,tetrahedral framework nucleic acids(tFNAs)showed good carrier performance.In this experiment,we developed microRNA-155-equipped tFNAs(T-155)and explored its biological effects on CNV.Based on the results of in-vitro experiments,T-155 could regulate macrophages into the antiangiogenic M1 type.Then,we injected T-155 into the vitreous of laser-induced CNV model mice and found that T-155 significantly reduced the size and area of CNV,inhibited blood vessel leakage.In summary,we prove that T-155 could regulate the inflammatory process of CNV by polarizing macrophages,thereby improving the symptoms of CNV.Thus,T-155 might become a new DNA-based drug with great potential for treating CNV.
基金supported by National Key R&D Program of China(No.2019YFA0110600)National Natural Science Foundation of China(Nos.82370929,81970916)+3 种基金Sichuan Science and Technology Program(No.2022NSFSC0002)Sichuan Province Youth Science and Technology Innovation Team(No.2022JDTD0021)Research and Develop Program,West China Hospital of Stomatology Sichuan University(No.RD03202302)Science and technology support plan project of Guizhou Provincial Department of science and technology(No.Qiankehe support[2022]General264)。
文摘This article reviews the latest research advances of tetrahedral framework nucleic acid(t FNA)-based systems in their fabrication,modification,and the potential applications in biomedicine.TFNA arises from the synthesis of four single-stranded DNA chains.Each chain contains brief sequences that complement those found in the other three,culminating in the creation of a pyramid-shaped nanostructure of approximately 10 nanometers in size.The first generation of t FNA demonstrates inherent compatibility with biological systems and the ability to permeate cell membrane effectively.These attributes translate into remarkable capabilities for regulating various cellular biological processes,fostering tissue regeneration,and modulating immune responses.The subsequent evolution of t FNA introduces enhanced adaptability and a relatively higher degree of biological stability.This advancement encompasses structural modifications,such as the addition of functional domains at the vertices or side arms,integration of low molecular weight pharmaceuticals,and the implementation of diverse strategies aimed at reversing multi-drug resistance in tumor cells or microorganisms.These augmentations empower t FNA-based systems to be utilized in different scenarios,thus broadening their potential applications in various biomedical fields.
基金National Key R&D Program of China(2019YFA0110600)National Natural Science Foundation of China(81970916,81671031)the LU JIAXI International team program supported by the K.C.Wong Education Foundation and CAS and the Youth Innovation Promotion Association of CAS(Grant No.2016236).
文摘Obesity-induced insulin resistance is the hallmark of metabolic syndrome,and chronic,low-grade tissue inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune cells.Current therapeutic approaches lack efficacy and immunomodulatory capacity.Thus,a new therapeutic approach is needed to prevent chronic inflammation and alleviate insulin resistance.Here,we synthesized a tetrahedral framework nucleic acid(tFNA)nanoparticle that carried resveratrol(RSV)to inhibit tissue inflammation and improve insulin sensitivity in obese mice.The prepared nanoparticles,namely tFNAs-RSV,possessed the characteristics of simple synthesis,stable properties,good water solubility,and superior biocompatibility.The tFNA-based delivery ameliorated the lability of RSV and enhanced its therapeutic efficacy.In high-fat diet(HFD)-fed mice,the administration of tFNAs-RSV ameliorated insulin resistance by alleviating inflammation status.tFNAs-RSV could reverse M1 phenotype macrophages in tissues to M2 phenotype macrophages.As for adaptive immunity,the prepared nanoparticles could repress the activation of Th1 and Th17 and promote Th2 and Treg,leading to the alleviation of insulin resistance.Furthermore,this study is the first to demonstrate that tFNAs,a nucleic acid material,possess immunomodulatory capacity.Collectively,our findings demonstrate that tFNAs-RSV alleviate insulin resistance and ameliorate inflammation in HFD mice,suggesting that nucleic acid materials or nucleic acid-based delivery systems may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.
基金supported by National Key R&D Program of China (No. 2019YFA0110600)National Natural Science Foundation of China (No. 81970916)+2 种基金Sichuan Province Youth Science and Technology Innovation Team (No. 2022JDTD0021)Research Funding from West China School/Hospital of Stomatology Sichuan University (No. RCDWJS2021-20)China Postdoctoral Science Foundation (No. 2022TQ0381)。
文摘Synthetic antigen-encoding mRNA plays an increasingly significant role in tumor vaccine technology owing to its antigen-specific immune-activation. However, its immune efficacy is challenged by inferior delivery efficiency and demand for suitable adjuvants. Here, we develop a novel mRNA nanovaccine based on a multifunctional nanocapsule, which is a dual-adjuvant formulation composed of cytosine-phosphateguanine motifs loaded tetrahedral framework nucleic acid(CpG-tFNA) and an immunopeptide murine β-defensin 2(mDF2β). This m RNA nanovaccine successfully achieves intracellular delivery, antigen expression and presentation of dendritic cells, and proliferation of antigen-specific T cells. In a tumor prophylactic vaccination model, it exerts an excellent inhibitory effect on lymphoma occurrence through cellular immunity. This mRNA nanovaccine has promising prophylactic applications in tumors and many other diseases.
基金supported by the National Natural Science Foundation of China(Grants 22274029 and 32371439)the Jilin Provincial Scientific and Technological Development Program(Grant 20240207010CX)+3 种基金the Science and Technology Commission of Shanghai Municipality(Grant 22ZR1412000)the State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases(Grant RCGHCRB202405)the Jilin Provincial Science and Technology Development Plan(Grant YDZJ202401113ZYTS)the Jilin Provincial Science and Technology Development Plan(Grant YDZJ202501ZYTS177).
文摘The increasing prevalence of methicillin-resistant Staphylococcus aureus(MRSA)due to antibiotic misuse necessitates novel therapeutic strategies to counter multidrug-resistant infections.Here,we introduce a self-assembling,aggregation-enhanced tetrahedralDNAnanostructure(tFNA)platform that achieves targeted drug delivery through controlled aggregation and sustained release,effectively restoring MRSA susceptibility toβ-lactam antibiotics.These tetrahedral frameworks,termed tFNAs-ASOsceftriaxone sodium(TACs),serve as a dual-functional system that co-encapsulates antisense oligonucleotides(ASOs)targeting the mecA gene and the β-lactam antibiotic ceftriaxone sodium(Cef).Aggregation of TACs plays a pivotal role in maximizing drug retention and stability,prolonging the localized release of both ASOs and antibiotics while maintaining high bioavailability at the infection site.Characterization studies,including size distribution,zeta potential,and fluorescence quenching assays,confirm their robust aggregation stability and encapsulation efficiency,ensuring controlled drug kinetics and prolonged therapeutic effects.Upon interaction with bacterial cells,the locally concentrated TACs facilitate efficient ASO-mediated mecA silencing,thereby disrupting PBP2a expression and re-sensitizing MRSA to β-lactams.Simultaneously,the aggregated ceftriaxone sodium reservoir ensures sustained inhibition of bacterial cell wall synthesis,leading to effective bacterial clearance.In addition,TACs display potent antibiofilm activity by penetrating the biofilm matrix and delivering therapeutics directly to the embedded bacterial population,thereby overcoming the diffusion barriers.In vivo,TACs exhibit superior therapeutic efficacy in an MRSA-induced pneumonia mouse model,significantly improving survival rates,reducing bacterial burden,and mitigating lung tissue damage.These findings highlight the transformative potential of tFNAs as an intelligent drug aggregation and release system,offering a novel paradigm for optimizing antibiotic therapy against multidrug-resistant pathogens.
基金National Key Research and Development Program of China(2019YFA0111300)Thousand Talents Plan,the Guangdong Provincial Pearl River Talents Program(2019QN01Y131)Medical Science and Technology Research Fund of Guangdong Province(A2022112).
文摘The specific induction of hepatic differentiation presents a significant challenge in developing alternative liver cell sources and viable strategies for clinical therapy of acute liver failure (ALF). The past decade has witnessed the blossom of microRNAs in regenerative medicine. Herein, microRNA 122-functionalized tetrahedral framework nucleic acid (FNA-miR-122) has emerged as an unprecedented and potential platform for directing the hepatic differentiation of adipose-derived mesenchymal stem cells (ADMSCs), which offers a straightforward and cost-effective method for generating functional hepatocyte-like cells (FNA-miR-122-iHep). Additionally, we have successfully established a liver organoid synthesis strategy by optimizing the co-culture of FNA-miR-122-iHep with endothelial cells (HUVECs), resulting in functional Hep:HUE-liver spheroids. Transcriptome analysis not only uncovered the potential molecular mechanisms through which miR-122 influences hepatic differentiation in ADMSCs, but also clarified that Hep:HUE-liver spheroids could further facilitate hepatocyte maturation and improved tissue-specific functions, which may provide new hints to be used to develop a hepatic organoid platform. Notably, compared to transplanted ADMSCs and Hep-liver spheroid, respectively, both FNA-miR-122-iHep-based single cell therapy and Hep:HUE-liver spheroid-based therapy showed high efficacy in treating ALF in vivo. Collectively, this research establishes a robust system using microRNA to induce ADMSCs into functional hepatocyte-like cells and to generate hepatic organoids in vitro, promising a highly efficient therapeutic approach for ALF.
基金supported by the Natural Science Foundation of Shandong province(ZR2023QH204 and ZR2024ME024,China).
文摘Chemotherapeutic drugs,such as cisplatin and phenanthriplatin(PhenPt),as STING agonists to induce DNA damage and activate the cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)signaling pathway provides a potential strategy for clinical chemo-immunotherapy.However,treatment with Pt-based drugs leads to irreversible ectopia of phosphatidylserine(PS),a major component of the intracellular membrane,to the surface of the cancer cells by enzymes(Xkr8).Exposed PS can bind to immune cell receptors and inhibit the presentation of tumor antigens,leading to immunosuppression and attenuation of chemotherapy.Herein,we report a novel approach to enhance chemo-immunotherapy by constructing siRNA targeted Xkr8(siXkr8)-mediated tetrahedral framework nucleic acid nanogel structure concurrently loaded with PhenPt(siXkr8-FNG/PhenPt)for co-delivery of siRNA and Pt-based drugs.The results showed that siXkr8-FNG/PhenPt can not only be used as an efficient delivery carrier to deliver siXkr8,block the expression of Xkr8,reduce the exposure of PS on the cancer cells surface,but also act as an immune stimulant to activate cGAS-STING pathway,effectively improve the immunosuppressive microenvironment,produce antitumor immune response,and inhibit tumor growth and metastasis.Overall,this new delivery system is important for improving the effect of Pt-based drug chemotherapy,inducing immune enhancement and nucleic acid drug delivery.
基金supported by the National Natural Science Foundation of China(82370929 and 82401144)Sichuan Science and Technology Program(2022NSFSC0002)+3 种基金Sichuan Province Youth Science and Technology Innovation Team(2022JDTD0021)Research and Develop Program,West China Hospital of Stomatology Sichuan University(RD03202302 and RCDWJS2024-1)China Postdoctoral Science Foundation(CPSF)(2024M752238)Postdoctoral Fellowship Program of CPSF(GZC20231787).
文摘Parkinson’s disease(PD)is one of the most prevalent neurodegenerative diseases.It is usually accompanied by motor and non-motor symptoms that seriously threaten the health and the quality of life.Novel medications are urgently needed because current pharmaceuticals can relieve symptoms but cannot stop disease progression.The microbiota-gut-brain axis(MGBA)is closely associated with the occurrence and development of PD and is an effective therapeutic target.Tetrahedral framework nucleic acids(tFNAs)can modulate the microbiome and immune regulation.However,such nucleic acid nanostructures are very sensitive to acids which hinder this promising approach.Therefore,we prepared exosome-like nanovesicles(Exo@tac)from ginger that are acid resistant and equipped with tFNAs modified by antimicrobial peptides(AMP).We verified that Exo@tac regulates intestinal bacteria associated with the microbial-gut-brain axis in vitro and significantly improves PD symptoms in vivo when administered orally.Microbiota profiling confirmed that Exo@tac normalizes the intestinal flora composition of mouse models of PD.Our findings present a novel strategy for the development of PD drugs and the innovative delivery of nucleic acid nanomedicines.
基金supported by the Natural Science Foundation of China(grant nos.21877030,21735002,and 21778016).
文摘Framework nucleic acids(FNAs)have emerged as intelligent sensing systems for the detection of tumor-related biomarkers in living cells.However,orthogonally controlled manipulation of FNAs-based nanodevices for on-site imaging of microRNAs(miRNAs)remains an intractable challenge.Herein,we report a dual endogenous stimuli-responsive FNA nanodevice that can perform miRNA sensing and imaging in a tumor-specificmanner.The sensing function of the nanodevice is silent(OFF)by rationally incorporating adenosine 5′-triphosphate(ATP)aptamer and an abasic site,which can also be activated(ON)with ATP and human apurinic/apyrimidinic endonuclease 1(APE1)in tumor cells,enabling on-site and efficient miRNA imaging with improved tumor specificity.Furthermore,we demonstrate the capability of the nanodevice for specificmiRNAimagingboth in living cells and in vivo based on the“dual keys”(overexpressed ATP and APE1 in tumors)priming mode.Therefore,this work illustrates a simple biosensing methodology with great potential for precise imaging of tumor biomarkers in clinical diagnosis and therapeutic evaluation.
基金This work was supported by the National Key Research and Development Program of China for International Science&Innovation Cooperation Major Project between Governments(No.2018YFE0113200)the National Natural Science Foundation of China(Grant Nos.21722502,22074041)+1 种基金the Shanghai Rising-Star Program(No.19QA1403000)the Shanghai Science and Technology Committee(STCSM)(Grant No.18490740500).
文摘Main observation and conclusion DNA circuits have been designed for implementation of various functions based on DNA strand displacement in cell-free settings,but their capabilities in biological environments remain limited.In this work,we report framework nucleic acid(FNA)-based circuits enabling intracellular logic computation for mRNA imaging.FNAs as rigid scaffolds enable to deliver our built DNA circuits into cells without aid of transfection reagents,evading a time-consuming and tedious process prior to analysis,and the pendant duplex DNA designed at one vertex of FNA as gate is suitable for four-way strand exchange,minimizing crosstalk with other nucleic acids in the cellular milieu.We demonstrated that such FNA-based circuits can operate both in vitro and in vivo logic computation,including OR and AND logic gates.Moreover,in situ mRNA imaging was also realized by exploiting native mRNA as scaffolds to bind multiple FNA-based gates for the enhanced signal-to-background ratio.We hope that this FNA-based circuit can be applied for disease diagnosis,facilitating the development of biomedicine.
