Early knee osteoarthritis(KOA)is characterized by progressive degeneration of the articular cartilage,synovial inflammation,and excessive accumulation of reactive oxygen species(ROS).At present,intra-articular injecti...Early knee osteoarthritis(KOA)is characterized by progressive degeneration of the articular cartilage,synovial inflammation,and excessive accumulation of reactive oxygen species(ROS).At present,intra-articular injection of hyaluronic acid(HA)is widely used to alleviate symptoms;however,its lubrication persistence,antioxidant,and anti-inflammatory abilities are limited,and it is difficult to effectively delay the early process of cartilage degeneration.Based on this,hyaluronic acid-g-lipoic acid(HA-LA)was synthesized by esterification reaction,and HA-LA microspheres were prepared by a reversed-phase emulsion method,which was combined with a macromolecular HA-LA solution to form injectable hydrogels.The objective of this study was to evaluate the efficacy of an injectable hydrogel based on hyaluronic acid-g-lipoic acid microspheres(HA-LA MS)for the treatment of KOA and to verify its injectability,lubricity,reactive oxygen species(ROS)scavenging ability,and anti-inflammatory effects.The results show that the HA-LA MS hydrogel has excellent shear thinning characteristics and continuous injectability,and its microsphere structure significantly reduces the interfacial friction coefficient through the rolling effect.In vitro experiments have shown that the hydrogel can efficiently scavenge ROS,reduce the expression of inflammatory factors,and is non-cytotoxic.The HA-LA MS injectable hydrogel has excellent lubricity,ROS scavenging ability,and anti-inflammatory effects in vivo,which can effectively delay the degeneration of early KOA cartilage,and its efficacy is significantly better than that of traditional hyaluronic acid,making it a promising intra-articular injection preparation.展开更多
A series of the Guiqi polysaccharides/chitosan/alginate composite hydrogel microspheres(GPcM)with different particle sizes were prepared with Guiqi polysaccharides(GP),chitosan(CS)and sodium alginate(Alg).The optimum ...A series of the Guiqi polysaccharides/chitosan/alginate composite hydrogel microspheres(GPcM)with different particle sizes were prepared with Guiqi polysaccharides(GP),chitosan(CS)and sodium alginate(Alg).The optimum preparation process was also determined by single factor and orthogonal experiment analysis.The GPcM were characterized by fourier transform infrared spectroscopy(FT-IR),scanning electron microscope(SEM),drug loading efficiency test(LE),encapsulation efficiency test(EE)and in vitro release study.The results showed that the Guiqi polysaccharides chitosan hydrogel(GPCH)and sodium alginate hydrogel(SAH)formed a crossover system in GPcM.The GPcM have a uniform particle size ranging from 395.1μm to 841.5μm.The drug loading efficiency and encapsulation efficiency of the GPcM were 56.3%and 72.6%,respectively.The bovine serum albumin(BSA)loaded in the GPcM released slowly within 180 h.The results suggested that the GPcM may have potential application value in drug sustained and controlled release system.展开更多
Background:Therapeutic responses of breast cancer vary among patients and lead to drug resistance and recurrence due to the heterogeneity.Current preclinical models,however,are inadequate for predicting individual pat...Background:Therapeutic responses of breast cancer vary among patients and lead to drug resistance and recurrence due to the heterogeneity.Current preclinical models,however,are inadequate for predicting individual patient responses towards different drugs.This study aimed to investigate the patient-derived breast cancer culture models for drug sensitivity evaluations.Methods:Tumor and adjacent tissues from female breast cancer patients were collected during surgery.Patient-derived breast cancer cells were cultured using the conditional reprogramming technique to establish 2D models.The obtained patient-derived conditional reprogramming breast cancer(CRBC)cells were subsequently embedded in alginate-gelatin methacryloyl hydrogel microspheres to form 3D culture models.Comparisons between 2D and 3D models were made using immunohistochemistry(tumor markers),MTS assays(cell viability),flow cytometry(apoptosis),transwell assays(migration),and Western blotting(protein expression).Drug sensitivity tests were conducted to evaluate patient-specific responses to anti-cancer agents.Results:2D and 3D culture models were successfully established using samples from eight patients.The 3D models retained histological and marker characteristics of the original tumors.Compared to 2D cultures,3D models exhibited increased apoptosis,enhanced drug resistance,elevated stem cell marker expression,and greater migration ability—features more reflective of in vivo tumor behavior.Conclusion:Patient-derived 3D CRBC models effectively mimic the in vivo tumor microenvironment and demonstrate stronger resistance to anti-cancer drugs than 2D models.These hydrogel-based models offer a cost-effective and clinically relevant platform for drug screening and personalized breast cancer treatment.展开更多
This letter reports on the fabrication of hollow,porous and non-porous poly（D,L-lactide-co-glycolide） （PLGA） microspheres（MSs） for the controlled release of protein and promotion of cell compatibility of tough h...This letter reports on the fabrication of hollow,porous and non-porous poly（D,L-lactide-co-glycolide） （PLGA） microspheres（MSs） for the controlled release of protein and promotion of cell compatibility of tough hydrogels.PLGA MSs with different structures were prepared with modified double emulsion methods,using bovine serum albumin（BSA） as a porogen during emulsification.The release of the residual BSA from PLGA MSs was investigated as a function of the MS structure.The hollow PLGA MSs show a faster protein release than the porous MSs,while the non-porous MSs have the slowest protein release.Compositing the PLGA MSs with poly（vinyl alcohol）（PVA） hydrogels promoted chondrocyte adhesion and proliferation on the hydrogels.展开更多
Bone marrow(BM),a natural niche rich in growth factors and bone marrow mesenchymal stem cells(BMSCs),provides an optimal regenerative microenvironment and is widely used in clinical applications.However,the limited pr...Bone marrow(BM),a natural niche rich in growth factors and bone marrow mesenchymal stem cells(BMSCs),provides an optimal regenerative microenvironment and is widely used in clinical applications.However,the limited proliferative capacity of BMSCs and the mismatch between bone regeneration and growth factors release constrain their effectiveness in treating critical bone defects.Drawing inspiration from the regenerative properties of BM,we developed self-assembled hybrid microspheres to replicate its function and address these challenges through a tissue engineering approach.This BM-mimicking niche enriched BMSCs via fast-degrading gelatin methacryloyl(GelMA)microspheres,which were loaded with exogenous BMSCs and conjugated with stem cell homing peptides(SKP)to recruit endogenous BMSCs.SKP further enhanced the stemness of BMSCs,thereby promoting angiogenesis and resolving inflammation.Slow-degrading chitosan methacryloyl(ChitoMA)microspheres facilitated sustained release of angiogenic(KLT)and osteogenic(OGP)peptides,supporting blood vessel maturation and osteogenesis.The early release of BMSCs and SKP,followed by the subsequent release of OGP and KLT,aligned with the dynamic process of bone regeneration.In a rat critical femoral condyle defect model,the BM-mimicking niche formed an in-situ ossification center,significantly enhancing bone regeneration.This study introduces a novel BM-mimicking niche characterized by a BMSC-enriched environment and the sequential release of therapeutic factors,offering a promising strategy for treating critical bone defects.展开更多
Mutations in cytoplasmic DNA-degrading enzymes can lead to the accumulation of cytoplasmic DNA(cytoDNA),which excessively activates DNA-sensing pathways and exacerbates inflammatory aging.Reducing cytoDNA levels to su...Mutations in cytoplasmic DNA-degrading enzymes can lead to the accumulation of cytoplasmic DNA(cytoDNA),which excessively activates DNA-sensing pathways and exacerbates inflammatory aging.Reducing cytoDNA levels to suppress DNA-sensing mechanisms is therefore critical for treating elderly-onset rheumatoid arthritis(EORA).In this study,we constructed Trex1 mRNA loaded lipid nanoparticles(LNPs)via microfluidics and prepared DNase 1 loaded polydopamine(PDA)nanoparticles through oxidative polymerization.These two components were co-encapsulated into methacrylate hyaluronic acid(HAMA)microspheres using microfluidic photopolymerization.The LNPs incorporate cationic lipids to facilitate mRNA loading and promote endosomal escape,enabling efficient translation of TREX1 and subsequent recognition and degradation of cytoDNA.Meanwhile,cationic mesoporous poly-dopamine electrostatically adsorbs and degrades extracellular DNA.The microspheres function as a reservoir for sustained nanoparticles release,enabling synergistic inhibition of DNA sensing pathways.This microsphere based vaccine upregulates TREX1 expression in antigen presenting cells(APCs)and reduces cytoDNA levels,thereby suppressing overactivation of the cGAS-STING signaling axis and promoting immune tolerance.It also attenuates the differentiation of CD4^(+) T cells into Th1,Th2,Th17,and Treg subsets.In an aged rat model of rheumatoid arthritis,vaccination significantly attenuated soft tissue edema,synovial inflammation,and articular cartilage and bone destruction.By clearing excess cytoDNA and restraining DNA-sensing hyperactivation,this vaccine induces cellular immune tolerance and represents a promising therapeutic strategy for rheumatoid arthritis in the elderly.展开更多
The occurrence of osteoarthritis(OA)is highly associated with the reduced lubrication property of the joint,where a progressive and irreversible damage of the articular cartilage and consecutive inflammatory response ...The occurrence of osteoarthritis(OA)is highly associated with the reduced lubrication property of the joint,where a progressive and irreversible damage of the articular cartilage and consecutive inflammatory response dominate the mechanism.In this study,bioinspired by the super-lubrication property of cartilage and catecholamine chemistry of mussel,we successfully developed injectable hydrogel microspheres with enhanced lubrication and controllable drug release for OA treatment.Particularly,the lubricating microspheres(GelMA@DMA-MPC)were fabricated by dip coating a self-adhesive polymer(DMA-MPC,synthesized by free radical copolymerization)on superficial surface of photo-crosslinked methacrylate gelatin hydrogel microspheres(GelMA,prepared via microfluidic technology),and encapsulated with an anti-inflammatory drug of diclofenac sodium(DS)to achieve the dual-functional performance.The tribological test and drug release test showed the enhanced lubrication and sustained drug release of the GelMA@DMA-MPC microspheres.In addition,the functionalized microspheres were intra-articularly injected into the rat knee joint with an OA model,and the biological tests including qRT-PCR,immunofluorescence staining assay,X-ray radiography and histological staining assay all revealed that the biocompatible microspheres provided significant therapeutic effect against the development of OA.In summary,the injectable hydrogel microspheres developed herein greatly improved lubrication and achieved sustained local drug release,therefore representing a facile and promising technique for the treatment of OA.展开更多
Local lactate accumulation greatly hinders tissue repair and regeneration under ischemic condition.Herein,an injectable microsphere(MS@MCL)for local lactate exhaustion was constructed by grafting manganese dioxide(MnO...Local lactate accumulation greatly hinders tissue repair and regeneration under ischemic condition.Herein,an injectable microsphere(MS@MCL)for local lactate exhaustion was constructed by grafting manganese dioxide(MnO_(2))-lactate oxidase(LOX)composite nanozyme on microfluidic hyaluronic acid methacrylate(HAMA)microspheres via chemical bonds,achieving a long-term oxygen-promoted lactate exhaustion effect and a long half-life in vivo.The uniform and porous microspheres synthesized by microfluidic technology is beneficial to in situ injection therapy and improving encapsulation efficiency.Furthermore,chemical grafting into HAMA microspheres through amide reactions promoted local enzymatic concentration and activity enhancement.It was showed that the MS@MCL eliminated oxidative and inflammatory stress and promoted extracellular matrix metabolism and cell survival when co-cultured with nucleus pulposus cells(NPCs)in vitro.In the rat degenerative intervertebral disc model caused by lactate injection,MS@MCL showed a long-term therapeutic effect in reducing intervertebral height narrowing and preventing extracellular matrix(ECM)degradation as well as inflammatory damage in vivo.Altogether,this study confirms that this nanozyme-functionalized injectable MS@MCL effectively improves the regenerative and reparative effect in ischemic tissues by disposing of enriched lactate in local microenvironment.展开更多
Regulating macrophage activation precisely is crucial in treating chronic inflammation in osteoarthritis(OA).However,the stable pro-inflammatory state and deep distribution of macrophages in vivo pose a great challeng...Regulating macrophage activation precisely is crucial in treating chronic inflammation in osteoarthritis(OA).However,the stable pro-inflammatory state and deep distribution of macrophages in vivo pose a great challenge to treatment.In this study,inspired by the innate immune,immune cell mobilized hydrogel microspheres were constructed by microfluidic methods and load chemokines,macrophage antibodies and engineered cell membrane vesicles(sEVs)via covalent and non-covalent junctions.The immune cell mobilized hydrogel microspheres,based on a mixture of streptavidin grafted hyaluronic acid methacrylate(HAMA-SA)and Chondroitin sulfate methacrylate(ChSMA)microspheres(HCM),can recruit,capture and reprogram proinflammatory macrophages in the joint cavity to improve the joint inflammatory microenvironment.In vitro experiments demonstrated that immune cell mobilized hydrogel microspheres had excellent macrophage recruitment,capture,and reprogramming abilities.Pro-inflammatory macrophages can be transformed into anti-inflammatory macrophages with an efficiency of 88.5%.Animal experiments also revealed significant reduction in synovial inflammation and cartilage matrix degradation of OA.Therefore,the immune cell mobilized hydrogel microspheres may be an effective treatment of OA inflammation for the future.展开更多
Despite numerous studies on chondrogenesis,the repair of cartilage—particularly the reconstruction of cartilage lacunae through an all-in-one advanced drug delivery system remains limited.In this study,we developed a...Despite numerous studies on chondrogenesis,the repair of cartilage—particularly the reconstruction of cartilage lacunae through an all-in-one advanced drug delivery system remains limited.In this study,we developed a cartilage lacuna-like hydrogel microsphere system endowed with integrated biological signals,enabling sequential immunomodulation and endogenous articular cartilage regeneration.We first integrated the chondrogenic growth factor transforming growth factor-β3(TGF-β3)into mesoporous silica nanoparticles(MSNs).Then,TGF-β3@MSNs and insulin-like growth factor 1(IGF-1)were encapsulated within microspheres made of polydopamine(pDA).In the final step,growth factor-loaded MSN@pDA and a chitosan(CS)hydrogel containing platelet-derived growth factor-BB(PDGF-BB)were blended to produce growth factors loaded composite microspheres(GFs@μS)using microfluidic technology.The presence of pDA reduced the initial acute inflammatory response,and the early,robust release of PDGF-BB aided in attracting endogenous stem cells.Over the subsequent weeks,the continuous release of IGF-1 and TGF-β3 amplified chondrogenesis and matrix formation.μS were incorporated into an acellular cartilage extracellular matrix(ACECM)and combined with a polydopamine-modified polycaprolactone(PCL)structure to produce a tissue-engineered scaffold that mimicked the structure of the cartilage lacunae evenly distributed in the cartilage matrix,resulting in enhanced cartilage repair and patellar cartilage protection.This research provides a strategic pathway for optimizing growth factor delivery and ensuring prolonged microenvironmental remodeling,leading to efficient articular cartilage regeneration.展开更多
Bone defects are a prevalent category of skeletal tissue disorders in clinical practice,with a range of pathogenic factors and frequently suboptimal clinical treatment effects.In bone regeneration of bone defects,the ...Bone defects are a prevalent category of skeletal tissue disorders in clinical practice,with a range of pathogenic factors and frequently suboptimal clinical treatment effects.In bone regeneration of bone defects,the bone regeneration microenvironment-composed of physiological,chemical,and physical components-is the core element that dynamically coordinates to promote bone regeneration.In recent years,medical biomaterials with bioactivity and functional tunability have been widely researched upon and applied in the fields of tissue replacement/regeneration,and remodelling of organ structure and function.The biomaterial treatment system based on the comprehensive regulation strategy of bone regeneration microenvironment is expected to solve the clinical problem of bone defect.Hydrogel microspheres(HMS)possess a highly specific surface area and porosity,an easily adjustable physical structure,and high encapsulation efficiency for drugs and stem cells.They can serve as highly efficient carriers for bioactive factors,gene agents,and stem cells,showing potential advantages in the comprehensive regulation of bone regeneration microenvironment to enhance bone regeneration.This review aims to clarify the components of the bone regeneration microenvironment,the application of HMS in bone regeneration,and the associated mechanisms.It also discusses various preparation materials and methods of HMS and their applications in bone tissue engineering.Furthermore,it elaborates on the relevant mechanisms by which HMS regulates the physiological,chemical,and physical microenvironment in bone regeneration to achieve bone regeneration.Finally,we discuss the future prospects of the HMS system application for comprehensive regulation of bone regeneration microenvironment,to provide novel perspectives for the research and application of HMS in the bone tissue engineering field.展开更多
Bone,cartilage,and soft tissue regeneration is a complex process involving many cellular activities across various cell types.Autografts remain the“gold standard”for the regeneration of these tissues.However,the use...Bone,cartilage,and soft tissue regeneration is a complex process involving many cellular activities across various cell types.Autografts remain the“gold standard”for the regeneration of these tissues.However,the use of autografts is associated with many disadvantages,including donor scarcity,the requirement of multiple surgeries,and the risk of infection.The development of tissue engineering techniques opens new avenues for enhanced tissue regeneration.Nowadays,the expectations of tissue engineering scaffolds have gone beyond merely providing physical support for cell attachment.Ideal scaffolds should also provide biological cues to actively boost tissue regeneration.As a new type of injectable biomaterial,hydrogel microspheres have been increasingly recognised as promising therapeutic carriers for the local delivery of cells and drugs to enhance tissue regeneration.Compared to traditional tissue engineering scaffolds and bulk hydrogel,hydrogel microspheres possess distinct advantages,including less invasive delivery,larger surface area,higher transparency for visualisation,and greater flexibility for functionalisation.Herein,we review the materials characteristics of hydrogel microspheres and compare their fabrication approaches,including microfluidics,batch emulsion,electrohydrodynamic spraying,lithography,and mechanical fragmentation.Additionally,based on the different requirements for bone,cartilage,nerve,skin,and muscle tissue regeneration,we summarize the applications of hydrogel microspheres as cell and drug delivery carriers for the regeneration of these tissues.Overall,hydrogel microspheres are regarded as effective therapeutic delivery carriers to enhance tissue regeneration in regenerative medicine.However,significant effort is required before hydrogel microspheres become widely accepted as commercial products for clinical use.展开更多
The alterations in glucose metabolism flux induced by mitochondrial function changes are crucial for regulating bone immune homeostasis.The restoration of mitochondrial homeostasis,serving as a pivotal rheostat for ba...The alterations in glucose metabolism flux induced by mitochondrial function changes are crucial for regulating bone immune homeostasis.The restoration of mitochondrial homeostasis,serving as a pivotal rheostat for balancing glucose metabolism in immune cells,can effectively mitigate inflammation and initiate osteogenesis.Herein,an ion-activated mitochondrial rheostat fiber-microsphere polymerization system(FM@CeZnHA)was innovatively constructed.Physical-chemical and molecular biological methods confirmed that CeZnHA,char-acterized by a rapid degradation rate,releases Ce/Zn ions that restore mitochondrial metabolic homeostasis and M1/M2 balance of macrophages through swift redox reactions.This process reduces the glycolysis level of macrophages by down-regulating the NF-κB p65 signaling pathway,enhances their mitochondrial metabolic dependence,alleviates excessive early inflammatory responses,and promptly initiates osteogenesis.The FM network provided a stable platform for macrophage glycolytic transformation and simulated extracellular matrix microenvironment,continuously restoring mitochondrial homeostasis and accelerating ossification center for-mation through the release of metal ions from the internal CeZnHA for efficient bone immune cascade reactions.This strategy of bone immunity mediated by the restoration of macrophage mitochondrial metabolic function and glucose metabolic flux homeostasis opens up a new approach to treating bone defects.展开更多
Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that requires long-term pharmacological management.Melittin,a peptide derived from bee venom,has shown promising therapeutic efficacy for RA by modulati...Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that requires long-term pharmacological management.Melittin,a peptide derived from bee venom,has shown promising therapeutic efficacy for RA by modulating immune balance.Given the critical role of the gut in immune regulation,oral administration of melittin could have significant clinical implications.However,this approach faces substantial challenges,including degradation by gastric fluids and off-target adverse effects,which compromise its efficacy and safety.To address these limitations,we developed an innovative orally administered,gut-targeted micro-nano system(SPM/AlgL)inspired by bacterial colonies.Herein,gas-shearing microfluidics is leveraged to monodisperse sialic acid-decorated peptide nanomedicines within calcium alginate microgels.These microspheres are then coated with probiotic biofilms,leveraging their acid resistance and intestinal adhesion properties.The biofilm coating effectively protects melittin from gastric degradation and enhances its accumulation in the mesenteric lymph nodes,thereby improving its targeting ability to inflammatory sites and reducing adverse effects.By modulating the Th1/Th2 and Th17/Treg ratios in the mesenteric lymph nodes and spleen tissues,this system successfully alleviates immune responses and efficiently mitigates the progression of arthritis.Overall,this oral therapeutic strategy demonstrates significant potential for advancing the immunotherapy of RA and other systemic autoimmune diseases.展开更多
Sustained and intense inflammation is the pathological basis for intervertebral disc degeneration(IVDD).Effective antagonism or reduction of local inflammatory factors may help regulate the IVDD microenvironment and r...Sustained and intense inflammation is the pathological basis for intervertebral disc degeneration(IVDD).Effective antagonism or reduction of local inflammatory factors may help regulate the IVDD microenvironment and reshape the extracellular matrix of the disc.This study reports an immunomodulatory hydrogel microsphere system combining cell membrane-coated mimic technology and surface chemical modification methods by grafting neutrophil membrane-coated polylactic-glycolic acid copolymer nanoparticles loaded with transforming growth factor-beta 1(TGF-β1)(T-NNPs)onto the surface of methacrylic acid gelatin anhydride microspheres(GM)via amide bonds.The nanoparticle-microsphere complex(GM@T-NNPs)sustained the long-term release of T-NNPs with excellent cell-like functions,effectively bound to pro-inflammatory cytokines,and improved the release kinetics of TGF-β1,maintaining a 36 day-acting release.GM@T-NNPs significantly inhibited lipopolysaccharide-induced inflammation in nucleus pulposus cells in vitro,downregulated the expression of inflammatory factors and matrix metalloproteinase,and upregulated the expression of collagen-II and aggrecan.GM@T-NNPs effectively restored intervertebral disc height and significantly improved the structure and biomechanical function of the nucleus pulposus in a rat IVDD model.The integration of biomimetic technology and nano-drug delivery systems expands the application of biomimetic cell membrane-coated materials and provides a new treatment strategy for IVDD.展开更多
Abnormal mitochondrial division in microglia significantly impacts central nervous system(CNS)diseases.However,treating CNS diseases through microglial mitochondria presents several challenges:intracerebral de-livery ...Abnormal mitochondrial division in microglia significantly impacts central nervous system(CNS)diseases.However,treating CNS diseases through microglial mitochondria presents several challenges:intracerebral de-livery of drugs,microglial targeting,and mitochondrial regulation.Herein,a novel three-stage sequential tar-geted nasal drops delivery system that achieves precise drug delivery to the core of brain lesions through noninvasive nasal delivery,targeting microglia,and regulating mitochondria were developed.Firstly,dehy-droepiandrosterone(DHEA),identified from clinical data and transcriptomic analyses as a key neurosteroid regulating mitochondrial fission,was selected.Secondly,surface-positively charged hydrogel microspheres were prepared to adhere to the nasal mucosa,thereby avoiding rapid clearance and achieving the first stage of nasal mucosa targeting.Subsequently,targeted liposomes carrying cytotoxic T lymphocyte-associated protein-4 were constructed and modified into microspheres,which released liposomes through the nasal cavity to enter the brain and bound to the activated microglial surface receptors CD80/86 accomplishing the second stage of cell targeting.In the third stage,the system released DHEA in response to the microenvironment,precisely regulating dynamin-related protein 1 involved in mitochondrial membrane remodeling,which inhibited abnormal mito-chondrial division,stabilized mitochondrial morphology and function,inhibited microglial activation.This study demonstrated that three-stage sequential nasal drops efficiently traversed the nose-to-brain pathway via nasal mucosa in both murine(n=200)and porcine(n=16)models,while significantly ameliorating anesthesia/surgery-induced cognitive dysfunction in mice.Therefore,the three-stage sequential nasal drip is a promising method for the treatment of central nervous system diseases.展开更多
Repair and regeneration of damaged neurons is a promising therapeutic strategy for central nervous system(CNS)diseases such as ischemic stroke(IS).However,achieving efficient neuronal repair and regeneration after CNS...Repair and regeneration of damaged neurons is a promising therapeutic strategy for central nervous system(CNS)diseases such as ischemic stroke(IS).However,achieving efficient neuronal repair and regeneration after CNS injury through noninvasive methods remains a significant challenge.Therefore,this study proposes,for the first time,an ultrasonic nasal drop formulation that induces efficient regeneration of damaged neurons through electropharmacological coupling in an noninvasive manner.Liposomes containing the natural anti-inflammatory drug Timosaponin B-Ⅱ(TB)were coated onto barium titanate nanoparticles(BTO)to form LTO@TB.Using microfluidic technology and a Schiff base reaction,LTO@TB was encapsulated into aldehyde-based and methacrylate-modified microspheres(MS)to create the ultrasonic nasal drop MS@LTO@TB.The aldehyde groups of MS@LTO@TB spontaneously formed amide bonds with the numerous amino groups in the nasal mucosa,facilitating specific adhesion.Due to its enhanced bioadhesion and efficient transmembrane transport,LTO@TB was continuously and noninvasively delivered to the brain when administered nasally.Additionally,under ultrasonic stimulation,LTO@TB in the brain exerted an electropharmacological coupling effect,achieving noninvasive electrical stimulation of damaged neurons.MS@LTO@TB modulated microglial phenotypes,restored electrical signal conduction among damaged neurons,reshaped the inflammatory microenvironment,reduced neuronal apoptosis,activated the PI3K/AKT signaling pathway,and promoted axonal regeneration.MS@LTO@TB also showed the unique ability to alleviate inflammation and promote neuronal remodeling in a mouse model of middle cerebral artery occlusion/reperfusion(MCAO/R).This study presents a promising strategy involving the nasal administration of ultrasonic nasal drops as a noninvasive and efficient treatment for CNS injuries.展开更多
Vascular injury and some chronic ischemic lesions usually lead to insufficient blood supply to tissues,which will lead to tissue ischemia or even necrosis in severe cases.Current artificial blood vessels lack effectiv...Vascular injury and some chronic ischemic lesions usually lead to insufficient blood supply to tissues,which will lead to tissue ischemia or even necrosis in severe cases.Current artificial blood vessels lack effective collateral vascularization capabilities to provide adequate blood supply in areas with restricted blood flow.Herein,inspired by the grafting of tree buds to form lateral branches,the vascular buds model was successfully con-structed by inoculating HUVECs into bioactive hydrogel microspheres.Under the influence of ions dissolved from bioactive glass and three-dimensional culture environment,the cytoskeleton was remodeled,the cells showed obvious outward migration and budding trend,which significantly enhanced the angiogenesis ability.After grafted vascular buds to the lateral wall of the artificial blood vessel,a large number of collateral vessels are formed,which effectively alleviates the tissue ischemia in the region through which blood vessels pass.This study confirms the impact of bioactive ions on angiogenesis in a three-dimensional environment and offers novel insights for the development of lateral branches in artificial blood vessels.展开更多
Rheumatoid arthritis is a chronic autoimmune disease characterised by inflammation and progressive joint damage,necessitating innovative therapeutic strategies.Conventional rheumatoid arthritis treatments,including di...Rheumatoid arthritis is a chronic autoimmune disease characterised by inflammation and progressive joint damage,necessitating innovative therapeutic strategies.Conventional rheumatoid arthritis treatments,including disease-modifying antirheumatic drugs,nonsteroidal anti-inflammatory drugs,glucocorticoids,and biologics,often administered through systemic or intra-articular ways.These drugs often have low accumulation and/or retention in articular cartilage,causing dose-limiting toxicities and reduced efficacy.This review summarises recent advances in injectable drug delivery systems,specifically hydrogels,microspheres,and nanoparticles,highlighting their potential to enhance rheumatoid arthritis therapy.The outstanding potential of these systems was demonstrated;however,substantial research remains to be conducted to optimise their performance and safety.展开更多
Mitochondrial dysfunction in chondrocytes is a key pathogenic factor in osteoarthritis(OA),but directly modulating mitochondria in vivo remains a significant challenge.This study is the first to verify a correlation b...Mitochondrial dysfunction in chondrocytes is a key pathogenic factor in osteoarthritis(OA),but directly modulating mitochondria in vivo remains a significant challenge.This study is the first to verify a correlation between mitochondrial dysfunction and the downregulation of the FOXO3 gene in the cartilage of OA patients,highlighting the potential for regulating mitophagy via FOXO3 gene modulation to alleviate OA.Consequently,we developed a chondrocyte-targeting CRISPR/Cas9-based FOXO3 gene-editing tool(FoxO3)and integrated it within a nanoengineered‘truck’(NETT,FoxO3--NETT).This was further encapsulated in injectable hydrogel microspheres(FoxO3-NETT@SMs)to harness the antioxidant properties of sodium alginate and the enhanced lubrication of hybrid exosomes.Collectively,these FoxO3-NETT@SMs successfully activate mitophagy and rebalance mitochondrial function in OA chondrocytes through the Foxo3 gene-modulated PINK1/Parkin pathway.As a result,FoxO3-NETT@SMs stimulate chondrocytes proliferation,migration,and ECM production in vitro,and effectively alleviate OA progression in vivo,demonstrating significant potential for clinical applications.展开更多
基金financially supported by the National Natural Science Foundation of China(Nos.82272472 and 52373146)。
文摘Early knee osteoarthritis(KOA)is characterized by progressive degeneration of the articular cartilage,synovial inflammation,and excessive accumulation of reactive oxygen species(ROS).At present,intra-articular injection of hyaluronic acid(HA)is widely used to alleviate symptoms;however,its lubrication persistence,antioxidant,and anti-inflammatory abilities are limited,and it is difficult to effectively delay the early process of cartilage degeneration.Based on this,hyaluronic acid-g-lipoic acid(HA-LA)was synthesized by esterification reaction,and HA-LA microspheres were prepared by a reversed-phase emulsion method,which was combined with a macromolecular HA-LA solution to form injectable hydrogels.The objective of this study was to evaluate the efficacy of an injectable hydrogel based on hyaluronic acid-g-lipoic acid microspheres(HA-LA MS)for the treatment of KOA and to verify its injectability,lubricity,reactive oxygen species(ROS)scavenging ability,and anti-inflammatory effects.The results show that the HA-LA MS hydrogel has excellent shear thinning characteristics and continuous injectability,and its microsphere structure significantly reduces the interfacial friction coefficient through the rolling effect.In vitro experiments have shown that the hydrogel can efficiently scavenge ROS,reduce the expression of inflammatory factors,and is non-cytotoxic.The HA-LA MS injectable hydrogel has excellent lubricity,ROS scavenging ability,and anti-inflammatory effects in vivo,which can effectively delay the degeneration of early KOA cartilage,and its efficacy is significantly better than that of traditional hyaluronic acid,making it a promising intra-articular injection preparation.
基金by National Natural Science Foundation of China(81560737,31860250)Natural Science Foundation of Gansu Province(18JR3RA148)+1 种基金Guangxi Provincial Natural Science Fund of China(2016GXNSFAA380234)Fundamental Research Funds for Key Laboratory of Drug Screening and Deep Processing for Traditional Chinese and Tibetan Medicine of Gansu Province(20180801).
文摘A series of the Guiqi polysaccharides/chitosan/alginate composite hydrogel microspheres(GPcM)with different particle sizes were prepared with Guiqi polysaccharides(GP),chitosan(CS)and sodium alginate(Alg).The optimum preparation process was also determined by single factor and orthogonal experiment analysis.The GPcM were characterized by fourier transform infrared spectroscopy(FT-IR),scanning electron microscope(SEM),drug loading efficiency test(LE),encapsulation efficiency test(EE)and in vitro release study.The results showed that the Guiqi polysaccharides chitosan hydrogel(GPCH)and sodium alginate hydrogel(SAH)formed a crossover system in GPcM.The GPcM have a uniform particle size ranging from 395.1μm to 841.5μm.The drug loading efficiency and encapsulation efficiency of the GPcM were 56.3%and 72.6%,respectively.The bovine serum albumin(BSA)loaded in the GPcM released slowly within 180 h.The results suggested that the GPcM may have potential application value in drug sustained and controlled release system.
基金supported by the Natural Science Foundation of Guangdong Province(No.2021B1515120053)Guangdong Basic and Applied Basic Research Foundation(Grant No.2024A1515140166).
文摘Background:Therapeutic responses of breast cancer vary among patients and lead to drug resistance and recurrence due to the heterogeneity.Current preclinical models,however,are inadequate for predicting individual patient responses towards different drugs.This study aimed to investigate the patient-derived breast cancer culture models for drug sensitivity evaluations.Methods:Tumor and adjacent tissues from female breast cancer patients were collected during surgery.Patient-derived breast cancer cells were cultured using the conditional reprogramming technique to establish 2D models.The obtained patient-derived conditional reprogramming breast cancer(CRBC)cells were subsequently embedded in alginate-gelatin methacryloyl hydrogel microspheres to form 3D culture models.Comparisons between 2D and 3D models were made using immunohistochemistry(tumor markers),MTS assays(cell viability),flow cytometry(apoptosis),transwell assays(migration),and Western blotting(protein expression).Drug sensitivity tests were conducted to evaluate patient-specific responses to anti-cancer agents.Results:2D and 3D culture models were successfully established using samples from eight patients.The 3D models retained histological and marker characteristics of the original tumors.Compared to 2D cultures,3D models exhibited increased apoptosis,enhanced drug resistance,elevated stem cell marker expression,and greater migration ability—features more reflective of in vivo tumor behavior.Conclusion:Patient-derived 3D CRBC models effectively mimic the in vivo tumor microenvironment and demonstrate stronger resistance to anti-cancer drugs than 2D models.These hydrogel-based models offer a cost-effective and clinically relevant platform for drug screening and personalized breast cancer treatment.
基金funded by the Natural Science Foundation of China(Nos.21004074,51103172,212101064)the Hundred Talents Program of the Chinese Academy of Sciences(J.F.)+2 种基金the Ningbo Natural Science Foundation(Nos.2011A610120, 2012A610176)the Program for Ningbo Innovative Research Team (No.2012B82019)the Scientific Research Foundation for the Returned Overseas Chinese Scholars,State Education Ministry
文摘This letter reports on the fabrication of hollow,porous and non-porous poly（D,L-lactide-co-glycolide） （PLGA） microspheres（MSs） for the controlled release of protein and promotion of cell compatibility of tough hydrogels.PLGA MSs with different structures were prepared with modified double emulsion methods,using bovine serum albumin（BSA） as a porogen during emulsification.The release of the residual BSA from PLGA MSs was investigated as a function of the MS structure.The hollow PLGA MSs show a faster protein release than the porous MSs,while the non-porous MSs have the slowest protein release.Compositing the PLGA MSs with poly（vinyl alcohol）（PVA） hydrogels promoted chondrocyte adhesion and proliferation on the hydrogels.
基金funding support from the Beijing Science and Technology Project(Z241100009324005)National Key Research and Development Program of China(2023YFC2412302).
文摘Bone marrow(BM),a natural niche rich in growth factors and bone marrow mesenchymal stem cells(BMSCs),provides an optimal regenerative microenvironment and is widely used in clinical applications.However,the limited proliferative capacity of BMSCs and the mismatch between bone regeneration and growth factors release constrain their effectiveness in treating critical bone defects.Drawing inspiration from the regenerative properties of BM,we developed self-assembled hybrid microspheres to replicate its function and address these challenges through a tissue engineering approach.This BM-mimicking niche enriched BMSCs via fast-degrading gelatin methacryloyl(GelMA)microspheres,which were loaded with exogenous BMSCs and conjugated with stem cell homing peptides(SKP)to recruit endogenous BMSCs.SKP further enhanced the stemness of BMSCs,thereby promoting angiogenesis and resolving inflammation.Slow-degrading chitosan methacryloyl(ChitoMA)microspheres facilitated sustained release of angiogenic(KLT)and osteogenic(OGP)peptides,supporting blood vessel maturation and osteogenesis.The early release of BMSCs and SKP,followed by the subsequent release of OGP and KLT,aligned with the dynamic process of bone regeneration.In a rat critical femoral condyle defect model,the BM-mimicking niche formed an in-situ ossification center,significantly enhancing bone regeneration.This study introduces a novel BM-mimicking niche characterized by a BMSC-enriched environment and the sequential release of therapeutic factors,offering a promising strategy for treating critical bone defects.
基金supported by the Leading Project of the Oriental Talent Program(Shanghai Leading Talent,No.039)the National Natural Science Foundation of China(W2411085 and 82502557)+2 种基金the Leading Project of the Oriental Talent Program(LJ2024012)the Postdoctoral Fellowship Program of CPSF(GZB20230444,China)the Shanghai Municipal Health Commission(2022XD055).
文摘Mutations in cytoplasmic DNA-degrading enzymes can lead to the accumulation of cytoplasmic DNA(cytoDNA),which excessively activates DNA-sensing pathways and exacerbates inflammatory aging.Reducing cytoDNA levels to suppress DNA-sensing mechanisms is therefore critical for treating elderly-onset rheumatoid arthritis(EORA).In this study,we constructed Trex1 mRNA loaded lipid nanoparticles(LNPs)via microfluidics and prepared DNase 1 loaded polydopamine(PDA)nanoparticles through oxidative polymerization.These two components were co-encapsulated into methacrylate hyaluronic acid(HAMA)microspheres using microfluidic photopolymerization.The LNPs incorporate cationic lipids to facilitate mRNA loading and promote endosomal escape,enabling efficient translation of TREX1 and subsequent recognition and degradation of cytoDNA.Meanwhile,cationic mesoporous poly-dopamine electrostatically adsorbs and degrades extracellular DNA.The microspheres function as a reservoir for sustained nanoparticles release,enabling synergistic inhibition of DNA sensing pathways.This microsphere based vaccine upregulates TREX1 expression in antigen presenting cells(APCs)and reduces cytoDNA levels,thereby suppressing overactivation of the cGAS-STING signaling axis and promoting immune tolerance.It also attenuates the differentiation of CD4^(+) T cells into Th1,Th2,Th17,and Treg subsets.In an aged rat model of rheumatoid arthritis,vaccination significantly attenuated soft tissue edema,synovial inflammation,and articular cartilage and bone destruction.By clearing excess cytoDNA and restraining DNA-sensing hyperactivation,this vaccine induces cellular immune tolerance and represents a promising therapeutic strategy for rheumatoid arthritis in the elderly.
基金This study was financially supported by National Natural Science Foundation of China(52022043 and 81930051)Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program(20191080593)+3 种基金Precision Medicine Foundation,Tsinghua University,China(10001020107)Shanghai Jiao Tong University“Medical and Research”Program(ZH2018ZDA04)Science and Technology Commission of Shanghai Municipality(18ZR1434200,18140901500 and 19440760400)Research Fund of State Key Laboratory of Tribology,Tsinghua University,China(SKLT2020C11).
文摘The occurrence of osteoarthritis(OA)is highly associated with the reduced lubrication property of the joint,where a progressive and irreversible damage of the articular cartilage and consecutive inflammatory response dominate the mechanism.In this study,bioinspired by the super-lubrication property of cartilage and catecholamine chemistry of mussel,we successfully developed injectable hydrogel microspheres with enhanced lubrication and controllable drug release for OA treatment.Particularly,the lubricating microspheres(GelMA@DMA-MPC)were fabricated by dip coating a self-adhesive polymer(DMA-MPC,synthesized by free radical copolymerization)on superficial surface of photo-crosslinked methacrylate gelatin hydrogel microspheres(GelMA,prepared via microfluidic technology),and encapsulated with an anti-inflammatory drug of diclofenac sodium(DS)to achieve the dual-functional performance.The tribological test and drug release test showed the enhanced lubrication and sustained drug release of the GelMA@DMA-MPC microspheres.In addition,the functionalized microspheres were intra-articularly injected into the rat knee joint with an OA model,and the biological tests including qRT-PCR,immunofluorescence staining assay,X-ray radiography and histological staining assay all revealed that the biocompatible microspheres provided significant therapeutic effect against the development of OA.In summary,the injectable hydrogel microspheres developed herein greatly improved lubrication and achieved sustained local drug release,therefore representing a facile and promising technique for the treatment of OA.
基金financially supported by the National Natural Science Foundation of China(82102578,81922045,81772314 and 21604052)the National Natural Science Foundation of Chongqing(cstc2018jcyjAX0059 and cstc2018jcyjAX0797)Applied Basic Research Programs of the Science and Technology Department of Sichuan Province(2021YJ0467).
文摘Local lactate accumulation greatly hinders tissue repair and regeneration under ischemic condition.Herein,an injectable microsphere(MS@MCL)for local lactate exhaustion was constructed by grafting manganese dioxide(MnO_(2))-lactate oxidase(LOX)composite nanozyme on microfluidic hyaluronic acid methacrylate(HAMA)microspheres via chemical bonds,achieving a long-term oxygen-promoted lactate exhaustion effect and a long half-life in vivo.The uniform and porous microspheres synthesized by microfluidic technology is beneficial to in situ injection therapy and improving encapsulation efficiency.Furthermore,chemical grafting into HAMA microspheres through amide reactions promoted local enzymatic concentration and activity enhancement.It was showed that the MS@MCL eliminated oxidative and inflammatory stress and promoted extracellular matrix metabolism and cell survival when co-cultured with nucleus pulposus cells(NPCs)in vitro.In the rat degenerative intervertebral disc model caused by lactate injection,MS@MCL showed a long-term therapeutic effect in reducing intervertebral height narrowing and preventing extracellular matrix(ECM)degradation as well as inflammatory damage in vivo.Altogether,this study confirms that this nanozyme-functionalized injectable MS@MCL effectively improves the regenerative and reparative effect in ischemic tissues by disposing of enriched lactate in local microenvironment.
基金supported by the National Natural Science Foundation of China-Joint Fund Project(U22A20284)the National Natural Science Foundation of China(81972069,82202724)+1 种基金Doctoral Cultivating Project of the First Affiliated Hospital of Chongqing Medical University(CYYY-BSYJSCXXM-202227202204).
文摘Regulating macrophage activation precisely is crucial in treating chronic inflammation in osteoarthritis(OA).However,the stable pro-inflammatory state and deep distribution of macrophages in vivo pose a great challenge to treatment.In this study,inspired by the innate immune,immune cell mobilized hydrogel microspheres were constructed by microfluidic methods and load chemokines,macrophage antibodies and engineered cell membrane vesicles(sEVs)via covalent and non-covalent junctions.The immune cell mobilized hydrogel microspheres,based on a mixture of streptavidin grafted hyaluronic acid methacrylate(HAMA-SA)and Chondroitin sulfate methacrylate(ChSMA)microspheres(HCM),can recruit,capture and reprogram proinflammatory macrophages in the joint cavity to improve the joint inflammatory microenvironment.In vitro experiments demonstrated that immune cell mobilized hydrogel microspheres had excellent macrophage recruitment,capture,and reprogramming abilities.Pro-inflammatory macrophages can be transformed into anti-inflammatory macrophages with an efficiency of 88.5%.Animal experiments also revealed significant reduction in synovial inflammation and cartilage matrix degradation of OA.Therefore,the immune cell mobilized hydrogel microspheres may be an effective treatment of OA inflammation for the future.
基金Beijing Natural Science Foundation(L234024)Natural Science Foundation of China(82272481,323B2043)National Key R&D Program of China(2023YFB4605800).
文摘Despite numerous studies on chondrogenesis,the repair of cartilage—particularly the reconstruction of cartilage lacunae through an all-in-one advanced drug delivery system remains limited.In this study,we developed a cartilage lacuna-like hydrogel microsphere system endowed with integrated biological signals,enabling sequential immunomodulation and endogenous articular cartilage regeneration.We first integrated the chondrogenic growth factor transforming growth factor-β3(TGF-β3)into mesoporous silica nanoparticles(MSNs).Then,TGF-β3@MSNs and insulin-like growth factor 1(IGF-1)were encapsulated within microspheres made of polydopamine(pDA).In the final step,growth factor-loaded MSN@pDA and a chitosan(CS)hydrogel containing platelet-derived growth factor-BB(PDGF-BB)were blended to produce growth factors loaded composite microspheres(GFs@μS)using microfluidic technology.The presence of pDA reduced the initial acute inflammatory response,and the early,robust release of PDGF-BB aided in attracting endogenous stem cells.Over the subsequent weeks,the continuous release of IGF-1 and TGF-β3 amplified chondrogenesis and matrix formation.μS were incorporated into an acellular cartilage extracellular matrix(ACECM)and combined with a polydopamine-modified polycaprolactone(PCL)structure to produce a tissue-engineered scaffold that mimicked the structure of the cartilage lacunae evenly distributed in the cartilage matrix,resulting in enhanced cartilage repair and patellar cartilage protection.This research provides a strategic pathway for optimizing growth factor delivery and ensuring prolonged microenvironmental remodeling,leading to efficient articular cartilage regeneration.
基金supported by the National Natural Science Foundation of China(Nos.82102578,82472404)Special Project for the Central Government to Guide the Development of Local Science and Technology in Sichuan Province(No.2023ZYD0071)+5 种基金China Postdoctoral Science Foundation(No.2022M720603)National Natural Science Foundation of Sichuan(No.2024NSFSC0678)Natural Science Foundation of Chongqing(No.CSTB2022NSCQ-MSX0104)Research Project of Health Commission of Sichuan Province(No.2023-1601)Research Project of Nanchong Science and Technology Bureau(Nos.22SXJCQN0004,22SXQT0308)Research Project of the Affiliated Hospital of North Sichuan Medical College(Nos.2023ZD002,2023-2ZD001).
文摘Bone defects are a prevalent category of skeletal tissue disorders in clinical practice,with a range of pathogenic factors and frequently suboptimal clinical treatment effects.In bone regeneration of bone defects,the bone regeneration microenvironment-composed of physiological,chemical,and physical components-is the core element that dynamically coordinates to promote bone regeneration.In recent years,medical biomaterials with bioactivity and functional tunability have been widely researched upon and applied in the fields of tissue replacement/regeneration,and remodelling of organ structure and function.The biomaterial treatment system based on the comprehensive regulation strategy of bone regeneration microenvironment is expected to solve the clinical problem of bone defect.Hydrogel microspheres(HMS)possess a highly specific surface area and porosity,an easily adjustable physical structure,and high encapsulation efficiency for drugs and stem cells.They can serve as highly efficient carriers for bioactive factors,gene agents,and stem cells,showing potential advantages in the comprehensive regulation of bone regeneration microenvironment to enhance bone regeneration.This review aims to clarify the components of the bone regeneration microenvironment,the application of HMS in bone regeneration,and the associated mechanisms.It also discusses various preparation materials and methods of HMS and their applications in bone tissue engineering.Furthermore,it elaborates on the relevant mechanisms by which HMS regulates the physiological,chemical,and physical microenvironment in bone regeneration to achieve bone regeneration.Finally,we discuss the future prospects of the HMS system application for comprehensive regulation of bone regeneration microenvironment,to provide novel perspectives for the research and application of HMS in the bone tissue engineering field.
基金supported by Nationals Institute of Health grants(Nos.R01NS123433,and R01HL158204).
文摘Bone,cartilage,and soft tissue regeneration is a complex process involving many cellular activities across various cell types.Autografts remain the“gold standard”for the regeneration of these tissues.However,the use of autografts is associated with many disadvantages,including donor scarcity,the requirement of multiple surgeries,and the risk of infection.The development of tissue engineering techniques opens new avenues for enhanced tissue regeneration.Nowadays,the expectations of tissue engineering scaffolds have gone beyond merely providing physical support for cell attachment.Ideal scaffolds should also provide biological cues to actively boost tissue regeneration.As a new type of injectable biomaterial,hydrogel microspheres have been increasingly recognised as promising therapeutic carriers for the local delivery of cells and drugs to enhance tissue regeneration.Compared to traditional tissue engineering scaffolds and bulk hydrogel,hydrogel microspheres possess distinct advantages,including less invasive delivery,larger surface area,higher transparency for visualisation,and greater flexibility for functionalisation.Herein,we review the materials characteristics of hydrogel microspheres and compare their fabrication approaches,including microfluidics,batch emulsion,electrohydrodynamic spraying,lithography,and mechanical fragmentation.Additionally,based on the different requirements for bone,cartilage,nerve,skin,and muscle tissue regeneration,we summarize the applications of hydrogel microspheres as cell and drug delivery carriers for the regeneration of these tissues.Overall,hydrogel microspheres are regarded as effective therapeutic delivery carriers to enhance tissue regeneration in regenerative medicine.However,significant effort is required before hydrogel microspheres become widely accepted as commercial products for clinical use.
基金supported by the Program of Shanghai Academic/Technology Research Leader(22XD1422600)the Research Fellow(Grant No.353146)+2 种基金Research Project(347897)Solution for Health Profile(336355)InFLAMES Flagship(337531)grants and Printed Intelligence Infrastructure"(PII-FIRI)from Research Council of Finland.
文摘The alterations in glucose metabolism flux induced by mitochondrial function changes are crucial for regulating bone immune homeostasis.The restoration of mitochondrial homeostasis,serving as a pivotal rheostat for balancing glucose metabolism in immune cells,can effectively mitigate inflammation and initiate osteogenesis.Herein,an ion-activated mitochondrial rheostat fiber-microsphere polymerization system(FM@CeZnHA)was innovatively constructed.Physical-chemical and molecular biological methods confirmed that CeZnHA,char-acterized by a rapid degradation rate,releases Ce/Zn ions that restore mitochondrial metabolic homeostasis and M1/M2 balance of macrophages through swift redox reactions.This process reduces the glycolysis level of macrophages by down-regulating the NF-κB p65 signaling pathway,enhances their mitochondrial metabolic dependence,alleviates excessive early inflammatory responses,and promptly initiates osteogenesis.The FM network provided a stable platform for macrophage glycolytic transformation and simulated extracellular matrix microenvironment,continuously restoring mitochondrial homeostasis and accelerating ossification center for-mation through the release of metal ions from the internal CeZnHA for efficient bone immune cascade reactions.This strategy of bone immunity mediated by the restoration of macrophage mitochondrial metabolic function and glucose metabolic flux homeostasis opens up a new approach to treating bone defects.
基金supported by grants from the National Natural Science Foundation of China(U23A20489 and 82372128)the Natural Science Foundation Distinguished Young Scholars grant of Guangdong Province(2023B1515020071,China)+1 种基金the Educational Commission of Guangdong Province of China key Project(2020ZDZX2001,China)the Postdoctoral Fellowship Program of CPSF(GZB20230444,China).
文摘Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that requires long-term pharmacological management.Melittin,a peptide derived from bee venom,has shown promising therapeutic efficacy for RA by modulating immune balance.Given the critical role of the gut in immune regulation,oral administration of melittin could have significant clinical implications.However,this approach faces substantial challenges,including degradation by gastric fluids and off-target adverse effects,which compromise its efficacy and safety.To address these limitations,we developed an innovative orally administered,gut-targeted micro-nano system(SPM/AlgL)inspired by bacterial colonies.Herein,gas-shearing microfluidics is leveraged to monodisperse sialic acid-decorated peptide nanomedicines within calcium alginate microgels.These microspheres are then coated with probiotic biofilms,leveraging their acid resistance and intestinal adhesion properties.The biofilm coating effectively protects melittin from gastric degradation and enhances its accumulation in the mesenteric lymph nodes,thereby improving its targeting ability to inflammatory sites and reducing adverse effects.By modulating the Th1/Th2 and Th17/Treg ratios in the mesenteric lymph nodes and spleen tissues,this system successfully alleviates immune responses and efficiently mitigates the progression of arthritis.Overall,this oral therapeutic strategy demonstrates significant potential for advancing the immunotherapy of RA and other systemic autoimmune diseases.
基金supported by the National Natural Science Foundation of China (82072438,82272501,81972078,82120108017,82102589,82372484,82302683)Natural Science Foundation of Jiangsu Province (BK20211504)+4 种基金Social Development Project of Jiangsu Province (BE2021646)Jiangsu Province"333 Project"talent project (2069999)Suzhou Gusu Health Talent Program (GSWS2020001,GSWS2021009,GSWS2021007)Jiangsu Innovative and Enterpreneurial Talent Program (JSSCBS20211570)Medical Health Science and Technology Innovation Program of Suzhou (SKY2022119).
文摘Sustained and intense inflammation is the pathological basis for intervertebral disc degeneration(IVDD).Effective antagonism or reduction of local inflammatory factors may help regulate the IVDD microenvironment and reshape the extracellular matrix of the disc.This study reports an immunomodulatory hydrogel microsphere system combining cell membrane-coated mimic technology and surface chemical modification methods by grafting neutrophil membrane-coated polylactic-glycolic acid copolymer nanoparticles loaded with transforming growth factor-beta 1(TGF-β1)(T-NNPs)onto the surface of methacrylic acid gelatin anhydride microspheres(GM)via amide bonds.The nanoparticle-microsphere complex(GM@T-NNPs)sustained the long-term release of T-NNPs with excellent cell-like functions,effectively bound to pro-inflammatory cytokines,and improved the release kinetics of TGF-β1,maintaining a 36 day-acting release.GM@T-NNPs significantly inhibited lipopolysaccharide-induced inflammation in nucleus pulposus cells in vitro,downregulated the expression of inflammatory factors and matrix metalloproteinase,and upregulated the expression of collagen-II and aggrecan.GM@T-NNPs effectively restored intervertebral disc height and significantly improved the structure and biomechanical function of the nucleus pulposus in a rat IVDD model.The integration of biomimetic technology and nano-drug delivery systems expands the application of biomimetic cell membrane-coated materials and provides a new treatment strategy for IVDD.
基金supported by the National Natural Science Foundation(52273133,52303190,82271223,82271220,82301369)Shanghai Municipal Health and Family Planning Commission(2022XD055)+3 种基金Shanghai Nat-ural Science Foundation(25ZR1402458)Shanghai Municipal Health Commission(20244Z0007)Shanghai Municipal Committee of Science and Technology(23XD1422900)Hongkou district Health Commission(Hongwei2401-03,HKLCFC202405,HKLCYQ2024-02,HKLCYQ2024-04).
文摘Abnormal mitochondrial division in microglia significantly impacts central nervous system(CNS)diseases.However,treating CNS diseases through microglial mitochondria presents several challenges:intracerebral de-livery of drugs,microglial targeting,and mitochondrial regulation.Herein,a novel three-stage sequential tar-geted nasal drops delivery system that achieves precise drug delivery to the core of brain lesions through noninvasive nasal delivery,targeting microglia,and regulating mitochondria were developed.Firstly,dehy-droepiandrosterone(DHEA),identified from clinical data and transcriptomic analyses as a key neurosteroid regulating mitochondrial fission,was selected.Secondly,surface-positively charged hydrogel microspheres were prepared to adhere to the nasal mucosa,thereby avoiding rapid clearance and achieving the first stage of nasal mucosa targeting.Subsequently,targeted liposomes carrying cytotoxic T lymphocyte-associated protein-4 were constructed and modified into microspheres,which released liposomes through the nasal cavity to enter the brain and bound to the activated microglial surface receptors CD80/86 accomplishing the second stage of cell targeting.In the third stage,the system released DHEA in response to the microenvironment,precisely regulating dynamin-related protein 1 involved in mitochondrial membrane remodeling,which inhibited abnormal mito-chondrial division,stabilized mitochondrial morphology and function,inhibited microglial activation.This study demonstrated that three-stage sequential nasal drops efficiently traversed the nose-to-brain pathway via nasal mucosa in both murine(n=200)and porcine(n=16)models,while significantly ameliorating anesthesia/surgery-induced cognitive dysfunction in mice.Therefore,the three-stage sequential nasal drip is a promising method for the treatment of central nervous system diseases.
基金Funded by Outstanding Leaders Training Program of Pudong New Area Health System of Shanghai(Grant No.PWRl 2020–08)Important Weak Subject Construction Project of Pudong Health and Family Planning Commission of Shanghai(Grant No.PWZbr2022-13)+3 种基金National Natural Science Foundation of China(82372120,82272128)“Chenguang Program”(22CGA16)supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission,“Two Hundred Talent”Program supported by Shanghai Jiao Tong University School of Medicine(20240701)China Postdoctoral Science Foundation(2023M742360,2023M742361,and GZB20230443)China National Postdoctoral Program for Innovative Talents(BX20230228).
文摘Repair and regeneration of damaged neurons is a promising therapeutic strategy for central nervous system(CNS)diseases such as ischemic stroke(IS).However,achieving efficient neuronal repair and regeneration after CNS injury through noninvasive methods remains a significant challenge.Therefore,this study proposes,for the first time,an ultrasonic nasal drop formulation that induces efficient regeneration of damaged neurons through electropharmacological coupling in an noninvasive manner.Liposomes containing the natural anti-inflammatory drug Timosaponin B-Ⅱ(TB)were coated onto barium titanate nanoparticles(BTO)to form LTO@TB.Using microfluidic technology and a Schiff base reaction,LTO@TB was encapsulated into aldehyde-based and methacrylate-modified microspheres(MS)to create the ultrasonic nasal drop MS@LTO@TB.The aldehyde groups of MS@LTO@TB spontaneously formed amide bonds with the numerous amino groups in the nasal mucosa,facilitating specific adhesion.Due to its enhanced bioadhesion and efficient transmembrane transport,LTO@TB was continuously and noninvasively delivered to the brain when administered nasally.Additionally,under ultrasonic stimulation,LTO@TB in the brain exerted an electropharmacological coupling effect,achieving noninvasive electrical stimulation of damaged neurons.MS@LTO@TB modulated microglial phenotypes,restored electrical signal conduction among damaged neurons,reshaped the inflammatory microenvironment,reduced neuronal apoptosis,activated the PI3K/AKT signaling pathway,and promoted axonal regeneration.MS@LTO@TB also showed the unique ability to alleviate inflammation and promote neuronal remodeling in a mouse model of middle cerebral artery occlusion/reperfusion(MCAO/R).This study presents a promising strategy involving the nasal administration of ultrasonic nasal drops as a noninvasive and efficient treatment for CNS injuries.
基金supported by the National Natural Science Foundation of China(No.U23A20692,32171311,52402343)the National Key Research and Development Program of China(No.2024YFC3407500)the Science and Technology Projects in Guangzhou(No.202206010179).
文摘Vascular injury and some chronic ischemic lesions usually lead to insufficient blood supply to tissues,which will lead to tissue ischemia or even necrosis in severe cases.Current artificial blood vessels lack effective collateral vascularization capabilities to provide adequate blood supply in areas with restricted blood flow.Herein,inspired by the grafting of tree buds to form lateral branches,the vascular buds model was successfully con-structed by inoculating HUVECs into bioactive hydrogel microspheres.Under the influence of ions dissolved from bioactive glass and three-dimensional culture environment,the cytoskeleton was remodeled,the cells showed obvious outward migration and budding trend,which significantly enhanced the angiogenesis ability.After grafted vascular buds to the lateral wall of the artificial blood vessel,a large number of collateral vessels are formed,which effectively alleviates the tissue ischemia in the region through which blood vessels pass.This study confirms the impact of bioactive ions on angiogenesis in a three-dimensional environment and offers novel insights for the development of lateral branches in artificial blood vessels.
基金financially supported by National Natural Science Foundation of China(Nos.82102225,and 52333011)National Key Research and Development Program of China(No.2022YFB3804400)Venture&Innovation Support Program for Chongqing Overseas Returnees(No.cx2023095).
文摘Rheumatoid arthritis is a chronic autoimmune disease characterised by inflammation and progressive joint damage,necessitating innovative therapeutic strategies.Conventional rheumatoid arthritis treatments,including disease-modifying antirheumatic drugs,nonsteroidal anti-inflammatory drugs,glucocorticoids,and biologics,often administered through systemic or intra-articular ways.These drugs often have low accumulation and/or retention in articular cartilage,causing dose-limiting toxicities and reduced efficacy.This review summarises recent advances in injectable drug delivery systems,specifically hydrogels,microspheres,and nanoparticles,highlighting their potential to enhance rheumatoid arthritis therapy.The outstanding potential of these systems was demonstrated;however,substantial research remains to be conducted to optimise their performance and safety.
基金supported by the National Key Research and Development Project of China(2023YFB4605800)the Natural Science Foundation of China(32071353 and 82272561)+1 种基金the Natural Science Foundation of Sichuan Province(2024NSFSC0671,China)the 111 Project of China(B16033).
文摘Mitochondrial dysfunction in chondrocytes is a key pathogenic factor in osteoarthritis(OA),but directly modulating mitochondria in vivo remains a significant challenge.This study is the first to verify a correlation between mitochondrial dysfunction and the downregulation of the FOXO3 gene in the cartilage of OA patients,highlighting the potential for regulating mitophagy via FOXO3 gene modulation to alleviate OA.Consequently,we developed a chondrocyte-targeting CRISPR/Cas9-based FOXO3 gene-editing tool(FoxO3)and integrated it within a nanoengineered‘truck’(NETT,FoxO3--NETT).This was further encapsulated in injectable hydrogel microspheres(FoxO3-NETT@SMs)to harness the antioxidant properties of sodium alginate and the enhanced lubrication of hybrid exosomes.Collectively,these FoxO3-NETT@SMs successfully activate mitophagy and rebalance mitochondrial function in OA chondrocytes through the Foxo3 gene-modulated PINK1/Parkin pathway.As a result,FoxO3-NETT@SMs stimulate chondrocytes proliferation,migration,and ECM production in vitro,and effectively alleviate OA progression in vivo,demonstrating significant potential for clinical applications.
