Aging is a multifaceted biological process marked by a gradual decline in physiological functions, driven by cellular senescence, oxidative stress, chronic inflammation, and stem cell exhaustion. Extracellular vesicles (EVs), naturally occurring nanoscale vesicles secreted by various cell types, have gained attention as potential therapeutic agents due to their ability to mediate intercellular communication by delivering bioactive molecules, including proteins, lipids, and RNAs. This review provides a comprehensive overview of EV biogenesis, cargo composition, and their mechanistic roles in counteracting aging processes. EVs from diverse sources-such as mesenchymal stem cells, embryonic stem cells, dermal fibroblasts, and colostrum-exhibit regenerative properties by modulating immune responses, enhancing tissue repair, and promoting extracellular matrix homeostasis. Recent preclinical and clinical studies further highlight their potential in addressing age-related diseases and skin rejuvenation. However, significant challenges remain, including standardization of EV production, large-scale manufacturing, safety profiling, and regulatory approval. By leveraging advancements in EV engineering, targeted delivery systems, and combination strategies with existing anti-aging interventions, EV-based therapies hold promise as next-generation approaches in regenerative medicine and longevity enhancement.

Chronic rotator cuff tears (RCTs) often lead to poor surgical outcomes, requiring innovative therapies. This study explores the potential of exosomes from chondrogenic stem/progenitor cells (CSPCs), encapsulated in a GelMA/HA-NB hydrogel, to improve rotator cuff healing. Adipose-derived stem cells (ASCs) were isolated and sorted to obtain CSPCs, from which exosomes (sub-Exos) were extracted and characterized. Unsorted ASCs exosomes (un-Exos) were also isolated for comparison. The hydrogel-exosome system was evaluated for biocompatibility, chondrogenic differentiation, and sustained release in vitro and in a chronic RCT rat model. 112 rats were divided into four groups: control, hydrogel alone, un-Exos with hydrogel, and sub-Exos with hydrogel. Healing was assessed at 4 and 8 weeks using micro-CT, histology, and biomechanical testing. In vitro, sub-Exos with hydrogel demonstrated excellent biocompatibility and enhanced chondrogenic potential. In vivo, sub-Exos were retained at the injury site for up to 14 days, significantly improving histological scores, bone mineral density, bone volume/total volume, and trabecular thickness. Biomechanical tests revealed superior failure load and stiffness in the sub-Exos group. These findings demonstrate that localized delivery of GelMA/HA-NB hydrogel-encapsulated sub-Exos significantly enhances enthesis healing, offering a promising cell-free therapeutic strategy for chronic RCTs.

The aging population has led to a global issue of osteoarthritis (OA), which not only impacts the quality of life for patients but also poses a significant economic burden on society. While biotherapy offers hope for OA treatment, currently available treatments are unable to delay or prevent the onset or progression of OA. Recent studies have shown that as nanoscale bioactive substances that mediate cell communication, exosomes from stem cell sources have led to some breakthroughs in the treatment of OA and have important clinical significance. This paper summarizes the mechanism and function of stem cell exosomes in delaying OA and looks forward to the development prospects and challenges of exosomes.

The crosstalk between H-type endothelial cells (ECs) and macrophages is critical for maintaining angiogenesis and osteogenesis in bone homeostasis. As core components of type H vessels, ECs respond to various pro-angiogenic signals, forming specialized vascular structures characterized by high expression of platelet-endothelial cell adhesion molecule-1 (CD31) and endothelial mucin (EMCN), thereby facilitating angiogenesis-osteogenesis coupling during bone formation. Macrophages, as key immune cells in the perivascular region, are primarily classified into the classically activated pro-inflammatory M1 phenotype and the selectively activated anti-inflammatory M2 phenotype, thereby performing dual functions in regulating local tissue homeostasis and innate immunity. In recent years, the complex crosstalk between type H vessel ECs and macrophages has garnered significant interest in the context of bone-related diseases. Orderly regulation of angiogenesis and bone immunity provides a new direction for preventing bone metabolic disorders such as osteoporosis and osteoarthritis. However, their interactions in bone homeostasis remain insufficiently understood, with limited clinical data available. This review comprehensively examines the intricate interactions between type H vessel ECs and macrophages with diverse phenotypes, and Insights into the signaling pathways that regulate their crosstalk, focusing on their roles in angiogenesis and osteogenesis. Furthermore, the review discusses recent interventions targeting this crosstalk and the challenges that remain. These insights may offer new perspectives on bone homeostasis and provide a theoretical foundation for developing novel therapeutic strategies.

Exosomes have emerged as a crucial focus in advancing the diagnosis and treatment of osteoarthritis (OA). However, there are limited bibliometric studies on this topic. This study aimed to delineate the literature landscape on exosomes in OA, identifying global research trends and key areas. We utilised the Web of Science Core Collection to retrieve articles published from 2004 to 2023. Our analysis included 456 publications across 671 institutions from 40 countries/regions. Publication volume, citations, and emerging research foci and trends were examined. Our results reveal a consistently increased interest in exosomes related to OA over the past two decades. Prominent institutions contributing to this research include Shanghai Jiao Tong University and Shenzhen University. The leading journal for these publications is the International Journal of Molecular Sciences, with Stem Cell Research & Therapy being the most frequently co-cited journal. Notable scholars in this field are Li Duan, Yujie Liang, Xiao Xu, and Wei Seong Toh, with Shipin Zhang emerging as the most co-cited author. The principal research themes were elucidating how exosomes contribute to OA pathology and developing novel therapeutic approaches. Research hotspots and new trends are linked to terms such as "cartilage," "mesenchymal stem cell," "miRNA," "treatment," and "biomarkers." This comprehensive analysis offers valuable insights into the prevailing scientific discourse, pivotal topics, and potential future directions. It could serve as a foundational reference for researchers exploring exosomes and their utility in OA diagnostics and therapeutics.

Cell-secreted nanovesicles of endosomal origin, called exosomes, are vital for mediating intracellular communication. As local or distal transporters of intracellular cargo, they reflect the unique characteristics of secretory cells and establish cell-specific interactions via characteristic surface proteins and receptors. With the advent of rapid isolation, purification, and identification techniques, exosomes have become an attractive choice for disease diagnosis (exosomal content as biomarkers), cell-free therapy, and tissue regeneration. Mesenchymal stem cell (MSC)-derived exosomes (MSC-exosomes) display angiogenic, immune-modulatory, and other therapeutic effects crucial for cytoprotection, ischemic wound repair, myocardial regeneration, etc. The primary focus of this review is to highlight the widespread application of MSC-exosomes in therapeutics, theranostics, and tissue regeneration. After a brief introduction of exosome properties, biogenesis, isolation, and functions, recent studies on therapeutic and regenerative applications of MSC-exosomes are described, focusing on bone, cartilage, periodontal, cardiovascular, skin, and nerve regeneration. Finally, the review highlights the theranostic potential of exosomes followed by challenges, summary, and outlook.

The incidence of osteoarthritis (OA) is increasing, yet its pathogenesis remains largely unknown. Recent studies suggest that abnormal subchondral bone remodeling plays a crucial role in OA development, highlighting a gap in clinical treatments targeting this aspect. Soybean Isoflavone (SI) has shown potential in treating OA, although its mechanisms are not fully understood.

This research investigated the effects of SI on subchondral bone remodeling in an OA rat model, assessing joint damage, OARSI scores, and type H vessel formation (CD31hiEmcnhi expression). Additionally, the expression of ALP, OCN, BMP, and TSC1 was evaluated to determine involvement of the mTORC1 pathway. In vitro studies on IL-1β-induced osteoblasts further examined the impact of SI on TSC1/mTORC1 signaling and related markers.

SI treatment reduced joint damage and OARSI scores in the rat OA model, significantly decreasing CD31hiEmcnhi expression, indicating a reduction in type H vessel formation. SI also downregulated ALP, OCN, and BMP expression while upregulating TSC1, suggesting inhibition of the mTORC1 signaling pathway and VEGF release. In vitro, SI increased TSC1 expression and decreased mTORC1 signaling, VEGF, ALP, OCN, and BMP levels in IL-1β-induced osteoblasts.

SI targets the TSC1/mTORC1 signaling pathway to suppress osteoblast activation and VEGF release, inhibiting type H vessel formation and slowing abnormal subchondral bone remodeling. These findings provide a novel therapeutic approach for OA by focusing on subchondral bone remodeling mechanisms.

Osteoarthritis (OA) is a prevalent musculoskeletal disease affecting middle-aged and elderly individuals, with knee pain as a common complaint. Standard therapy approaches generally attempt to alleviate pain and inflammation, using various pharmacological and non-pharmacological options. However, the efficacy of these therapies in long-term tissue repair remains debated. As an alternative, regenerative medicine offers a promising strategy, with decreased adverse event rates and increasing evidence of safety and efficacy. This review will outline current advances in regenerative medicine for knee OA, emphasizing outpatient clinic-based therapies that use orthobiological and non-biological products. Different strategies based on orthobiologics are discussed as potential regenerative options for the management of knee OA. Cell-free therapies including platelet-rich plasma, autologous anti-inflammatories, exosomes, human placenta extract, and mitochondrial transplantation are discussed, focusing on their potential for cartilage regeneration. Additionally, cell-based therapies with regenerative properties including bone marrow aspirate concentrate, adipose stromal vascular fraction, microfat, nanofat, stem cell therapy, and genetically modified cells as part of orthobiologics, are being investigated. Also, this study is looking into non-biological approaches such as using gold-induced cytokines, extracorporeal shockwave therapy, and ozone therapy. The mechanisms of action, effectiveness, and clinical applications of each therapy are being explored, providing insights into their role in the management of knee OA.

Osteoarthritis (OA) is a degenerative joint condition that contributes to years lived with disability. Current therapeutic approaches are limited as there are no disease-modifying interventions able to delay or inhibit the progression of disease. In recent years there has been an increasing interest in the immunomodulatory and regenerative properties of mesenchymal stem/stromal cells (MSCs) to develop new OA therapies. Extracellular vesicles (EVs) mediate many of the biological effects of these cells and may represent an alternative avoiding the limitations of cell-based therapy. There is also a growing interest in EV modifications to enhance their efficacy and applications. Recent preclinical studies have provided strong evidence supporting the potential of MSC EVs for the development of OA treatments. Thus, MSC EVs may regulate chondrocyte functions to avoid cartilage destruction, inhibit abnormal subchondral bone metabolism and synovial tissue alterations, and control pain behavior. EV actions may be mediated by the transfer of their cargo to target cells, with an important role for proteins and non-coding RNAs modulating signaling pathways relevant for OA progression. Nevertheless, additional investigations are needed concerning EV optimization, and standardization of preparation procedures. More research is also required for a better knowledge of possible effects on different OA phenotypes, pharmacokinetics, mechanism of action, long-term effects and safety profile. Furthermore, MSC EVs have a high potential as vehicles for drug delivery or as adjuvant therapy to potentiate or complement the effects of other approaches.

Endomucin (MUC14), encoded by EMCN gene, is an O-glycosylated transmembrane mucin that is mainly found in venous endothelial cells (ECs) and highly expressed in type H vessels of bone tissue. Its main biological functions include promoting endothelial generation and migration through the vascular endothelial growth factor (VEGF) signaling pathway and inhibiting the adhesion of inflammatory cells to ECs. In addition, it induces angiogenesis and promotes bone formation. Due to the excellent functions of Endomucin in the above aspects, it provides a new research target for the treatment of vascular inflammatory-related diseases and bone diseases. Based on the current understanding of its function, the research of Endomucin mainly focuses on the above two diseases. As it is known, the progression of cancer is closely related to angiogenesis. Endomucin recently is found to be differentially expressed in a variety of tumors and correlated with survival rate. The biological role of Endomucin in cancer is opaque. This article introduces the research progress of Endomucin in vascular inflammatory-related diseases and bone diseases, discusses its application value and prospect in the treatment, and collects the latest research situation of Endomucin in tumors, to provide meaningful evidence for expanding the research field of Endomucin.

Joint diseases greatly impact the daily lives and occupational functioning of patients globally. However, conventional treatments for joint diseases have several limitations, such as unsatisfatory efficacy and side effects, necessitating the exploration of more efficacious therapeutic strategies. Mesenchymal stem cell (MSC)-derived EVs (MSC-EVs) have demonstrated high therapeutic efficacyin tissue repair and regeneration, with low immunogenicity and tumorigenicity. Recent studies have reported that EVs-based therapy has considerable therapeutic effects against joint diseases, including osteoarthritis, tendon and ligament injuries, femoral head osteonecrosis, and rheumatoid arthritis. Herein, we review the therapeutic potential of various types of MSC-EVs in the aforementioned joint diseases, summarise the mechanisms underlying specific biological effects of MSC-EVs, and discuss future prospects for basic research on MSC-EV-based therapeutic modalities and their clinical translation. In general, this review provides an in-depth understanding of the therapeutic effects of MSC-EVs in joint diseases, as well as the underlying mechanisms, which may be beneficial to the clinical translation of MSC-EV-based treatment. The translational potential of this article: MSC-EV-based cell-free therapy can effectively promote regeneration and tissue repair. When used to treat joint diseases, MSC-EVs have demonstrated desirable therapeutic effects in preclinical research. This review may supplement further research on MSC-EV-based treatment of joint diseases and its clinical translation.

Extracellular vesicles have gained wide momentum as potential therapeutics for osteoarthritis, a highly prevalent chronic disease that still lacks an approved treatment. The membrane-bound vesicles are secreted by all cells carrying different cargos that can serve as both disease biomarkers and disease modifiers. Nonetheless, despite a significant peak in research regarding EVs as OA therapeutics, clinical implementation seems distant. In addition to scalability and standardization challenges, researchers often omit to focus on and consider the proper tropism of the vesicles, the practicality and relevance of their source, their low native therapeutic efficacy, and whether they address the disease as a whole. These considerations are necessary to better understand EVs in a clinical light and have been comprehensively discussed and ultimately summarized in this review into a conceptualized framework termed the nanodiamond concept. Future perspectives are also discussed, and alternatives are presented to address some of the challenges and concerns.

Osteoporosis (OP) is a chronic systemic bone metabolism disease characterized by decreased bone mass, microarchitectural deterioration, and fragility fractures. With the demographic change caused by long lifespans and population aging, OP is a growing health problem. The role of miRNA in the pathogenesis of OP has also attracted widespread attention from scholars in recent years. Type H vessels are unique microvessels of the bone and have become a new focus in the pathogenesis of OP because they play an essential role in osteogenesis-angiogenesis coupling. Previous studies found some miRNAs regulate type H vessel formation through the regulatory factors, including platelet-derived growth factor-BB (PDGF-BB), hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), and so on. These findings help us gain a more in-depth understanding of the relationship among miRNAs, type H vessels, and OP to find a new perspective on treating OP. In the present mini-review, we will introduce the role of type H vessels in the pathogenesis of OP and the regulation of miRNAs on type H vessel formation by affecting regulatory factors to provide some valuable insights for future studies of OP treatment.

Bone is a metabolically dynamic structure that is generally remodeled throughout the lifetime of an individual but often causes problems with increasing age. A key player for bone development and homeostasis, but also under pathological conditions, is the bone vasculature. This complex system of arteries, veins, and capillaries forms distinct structures where each subset of endothelial cells has important functions. Starting with the basic process of angiogenesis and bone-specific blood vessel formation, coupled with initial bone formation, the importance of different vascular structures is highlighted with respect to how these structures are maintained or changed during homeostasis, aging, and pathological conditions. After exemplifying the current knowledge on bone vasculature, this review will move on to exosomes, a novel hotspot of scientific research. Exosomes will be introduced starting from their discovery via current isolation procedures and state-of-the-art characterization to their role in bone vascular development, homeostasis, and bone regeneration and repair while summarizing the underlying signal transduction pathways. With respect to their role in these processes, especially mesenchymal stem cell-derived extracellular vesicles are of interest, which leads to a discussion on patented applications and an update on ongoing clinical trials. Taken together, this review provides an overview of bone vasculature and bone regeneration, with a major focus on how exosomes influence this intricate system, as they might be useful for therapeutic purposes in the near future.

The escalating threat of bone-related diseases poses a significant challenge to human health. Mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs), as inherent cell-secreted natural products, have emerged as promising treatments for bone-related diseases. Leveraging outstanding features such as high biocompatibility, low immunogenicity, superior biological barrier penetration, and extended circulating half-life, MSC-EVs serve as potent carriers for microRNAs (miRNAs), long no-code RNAs (lncRNAs), and other biomolecules. These cargo molecules play pivotal roles in orchestrating bone metabolism and vascularity through diverse mechanisms, thereby contributing to the amelioration of bone diseases. Additionally, engineering modifications enhance the bone-targeting ability of MSC-EVs, mitigating systemic side effects and bolstering their clinical translational potential. This review comprehensively explores the mechanisms through which MSC-EVs regulate bone-related disease progression. It delves into the therapeutic potential of MSC-EVs as adept drug carriers, augmented by engineered modification strategies tailored for osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis, and osteosarcoma. In conclusion, the exceptional promise exhibited by MSC-EVs positions them as an excellent solution with considerable translational applications in clinical orthopedics.

Osteoarthritis (OA) is the most common degenerative disease of the joint with irreversible cartilage damage as the main pathological feature. With the development of regenerative medicine, mesenchymal stem cells (MSCs) have been found to have strong therapeutic potential. However, intraarticular MSCs injection therapy is limited by economic costs and ethics. Exosomes derived from MSC (MSC-Exos), as the important intercellular communication mode of MSCs, contain nucleic acid, proteins, lipids, microRNAs, and other biologically active substances. With excellent editability and specificity, MSC-Exos function as a targeted delivery system for OA treatment, modulating immunity, inhibiting apoptosis, and promoting regeneration. This article reviews the mechanism of action of MSC-Exos in the treatment of osteoarthritis, the current research status of the preparation of MSC-Exos and its application of drug delivery in OA therapy.

In recent years, human umbilical cord mesenchymal stem cell (hUC-MSC) extracellular vesicles (EVs) have been used as a cell replacement therapy and have been shown to effectively overcome some of the disadvantages of cell therapy. However, the specific mechanism of action of EVs is still unclear, and there is no appropriate system for characterizing the differences in the molecular active substances of EVs produced by cells in different physiological states. We used a data-independent acquisition (DIA) quantitative proteomics method to identify and quantify the protein composition of two generations EVs from three different donors and analysed the function and possible mechanism of action of the proteins in EVs of hUC-MSCs via bioinformatics. By comparative proteomic analysis, we characterized the different passages EVs. Furthermore, we found that adaptor-related protein complex 2 subunit alpha 1 (AP2A1) and adaptor-related protein complex 2 subunit beta 1 (AP2B1) in hUC-MSC-derived EVs may play a significant role in the treatment of Alzheimer's disease (AD) by regulating the synaptic vesicle cycle signalling pathway. Our work provides a direction for batch-to-batch quality control of hUC-MSC-derived EVs and their application in AD treatment.

Osteoarthritis (OA) is a chronic disease characterized by the progressive loss of cartilage and failure of the diarrheal joint. Quercetin has been reported to attenuate the development of OA. Bone marrow derived mesenchymal stem cell (BMSC)-derived exosomes are involved in OA progression. However, the role of BMSC-derived exosomes in quercetin-mediated progression of OA remains unclear. Western blotting and RT-qPCR were used to assess protein and mRNA levels, respectively. CCK8 assay was performed to assess cell viability, and cell apoptosis was assessed using flow cytometry. A dual-luciferase assay was performed to assess the relationship between miR-124-3p and TRAF6 expression. Furthermore, in vivo experiments were performed to test the function of exosomes derived from Quercetin-treated BMSCs in OA patients. IL-1β significantly inhibited the viability of chondrocytes, whereas the conditioned medium of Quercetin-treated BMSCs (BMSCsQUE-CM) reversed this phenomenon through exosomes. IL-1β notably upregulated MMP13 and ADAMT5 and reduced the expression of COL2A1 in chondrocytes, which were rescued by BMSCsQUE-CM. The effects of BMSCsQUE-CM on these three proteins were reversed in the absence of exosomes. Exosomes can be transferred from BMSCs to chondrocytes, and exosomes derived from Quercetin-treated BMSCs (BMSCsQue-Exo) can reverse the apoptotic effects of IL-1β on chondrocytes. The level of miR-124-3p in BMSCs was significantly upregulated by quercetin, and miR-124-3p was enriched in BMSCsQue-Exo. TRAF6 was identified as a direct target of miR-124-3p, and BMSCsQue-Exo abolished the IL-1β-induced activation of MAPK/p38 and NF-κB signaling. Furthermore, BMSCsQue-Exo significantly attenuated OA progression in vivo. Exosomes derived from Quercetin-treated BMSCs inhibited OA progression through the upregulation of miR-124-3p.

Osteoarthritis (OA) is a chronic, degenerative joint disease presenting a significant global health threat. While current therapeutic approaches primarily target symptom relief, their efficacy in repairing joint damage remains limited. Recent research has highlighted mesenchymal stem cells (MSCs) as potential contributors to cartilage repair, anti-inflammatory modulation, and immune regulation in OA patients. Notably, MSCs from different sources and their derivatives exhibit variations in their effectiveness in treating OA. Moreover, pretreatment and gene editing techniques of MSCs can enhance their therapeutic outcomes in OA. Additionally, the combination of novel biomaterials with MSCs has shown promise in facilitating the repair of damaged cartilage. This review summarizes recent studies on the role of MSCs in the treatment of OA, delving into their advantages and exploring potential directions for development, with the aim of providing fresh insights for future research in this critical field.

OA is the most common joint disease that affects approximately 7% of the global population. Current treatment methods mainly relieve its symptoms with limited repairing effect on joint destructions, which ultimately contributes to the high morbidity rate of OA. Stem cell treatment is a potential regenerative medical therapy for joint repair in OA, but the uncertainty in differentiation direction and immunogenicity limits its clinical usage. Small extracellular vesicles (sEVs), the by-products secreted by stem cells, show similar efficacy levels but have safer regenerative repair effect without potential adverse outcomes, and have recently drawn attention from the broader research community. A series of research works and reviews have been performed in the last decade, providing references for the application of various exogenous therapeutic sEVs for treating OA. However, the clinical potential of target intervention involving endogenous pathogenic sEVs in the treatment of OA is still under-explored and under-discussed. In this review, and for the first time, we emphasize the dual role of sEVs in OA and explain the effects of sEVs on various joint tissues from both the pathogenic and therapeutic aspects. Our aim is to provide a reference for future research in the field.

Osteoarthritis (OA) causes disability and significant economic and social burden. Cartilage injury is one of the main pathological features of OA, and is often manifested by excessive chondrocyte death, inflammatory response, abnormal bone metabolism, imbalance of extracellular matrix (ECM) metabolism, and abnormal vascular or nerve growth. Regrettably, due to the avascular nature of cartilage, its capacity to repair is notably limited. Mesenchymal stem cells-derived extracellular vesicles (MSCs-EVs) play a pivotal role in intercellular communication, presenting promising potential not only as early diagnostic biomarkers in OA but also as efficacious therapeutic strategy. MSCs-EVs were confirmed to play a therapeutic role in the pathological process of cartilage injury mentioned above. This paper comprehensively provides the functions and mechanisms of MSCs-EVs in cartilage repair.

Osteoarthritis (OA), a common joint disorder with articular cartilage degradation as the main pathological change, is the major source of pain and disability worldwide. Despite current treatments, the overall treatment outcome is unsatisfactory. Thus, patients with severe OA often require joint replacement surgery. In recent years, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic option for preclinical and clinical palliation of OA. MSC-derived exosomes (MSC-Exos) carrying bioactive molecules of the parental cells, including non-coding RNAs (ncRNAs) and proteins, have demonstrated a significant impact on the modulation of various physiological behaviors of cells in the joint cavity, making them promising candidates for cell-free therapy for OA. This review provides a comprehensive overview of the biosynthesis and composition of MSC-Exos and their mechanisms of action in OA. We also discussed the potential of MSC-Exos as a therapeutic tool for modulating intercellular communication in OA. Additionally, we explored bioengineering approaches to enhance MSC-Exos' therapeutic potential, which may help to overcome challenges and achieve clinically meaningful OA therapies.

Exosomes, remarkable extracellular vesicles, have emerged as an advanced frontier in intercellular communication. This remarkable capacity positions them as promising contenders in drug delivery systems (DDSs) for osteoarthritis (OA) therapy, capitalizing on their inherent biocompatibility, stability, and minimal immunogenicity. In this comprehensive review, we summarize the emerging developments surrounding exosome-based DDSs for OA therapy. Focusing on exosome origins, we meticulously explore the diverse sources contributing to their production, including invaluable stem cells, immune cells, and an array of other cell types. In addition, we unravel the underlying mechanisms of action that govern these exosome-borne therapeutics, illuminating the intricate interplay between exosomes and recipient cells. In summary, this review highlights the present challenges that permeate exosome-based DDSs for OA therapy. Through an in-depth exploration of the intricacies within this emerging field, this review aims to shed light on the future direction of exosome-based DDSs in OA. It serves as a bridge for fostering collaboration and collective efforts in reshaping the treatment landscape of OA.

Although the exosomes derived from mesenchymal stem cells (MSCs) display a therapeutic effect on inflammatory diseases, its application on OA has great limitations due to lack of specificity and targeting. The current study aimed to elucidate the potential therapeutic role of bone morphogenetic proteins-7(BMP-7) modified synovial mesenchymal stem cells-derived exosomes (SMSCs-exo) on OA and mechanism.

For in vitro experiments, LPS-treated macrophages RAW264.7 were treated with SMSCs-exo (exo) or BMP-7 modified SMSCs-exos (BMP-7-exo). The levels of inflammatory factors were assessed by ELISA. Also, the proportion of iNOS and CD206 positive cells were quantified by flow cytometry. Chondrocytes and RAW264.7 were co-culture to evaluate the effects of macrophage polarization on chondrocytes cellular behaviors. This effect on KOA was verified by an experiment in vivo. HE staining and Safranin fast green staining were used to observe the damage of articular cartilage. Immunohistochemistry was used to determine the expression of collagen II and aggrecan in articular cartilage, as well as the expression of iNOS and CD206 in synovial tissues.

Our in vitro results showed that BMP-7-exo treatment promoted LPS-induced proliferation of macrophages and chondrocytes, and showed a better ability to reduce inflammation by promoting macrophages M2 polarization. After co-culture with LPS treated macrophages, the proliferation rate and migration of chondrocytes were significantly decreased, while the apoptosis was significantly increased. The macrophages treated with BMP-7-exo and exo partially reversed these changes. The chondrocytes in BMP-7-exo group had higher proliferation rate and migration, as well as lower apoptosis compared with the exo group. Also, the in vivo results showed BMP-7-exo treatment improved the pathological changes of KOA and promoted synovial macrophages M2 polarization.

Our results demonstrated that BMP-7-exo attenuated KOA inflammation and cartilage injury by synovial macrophages M2 polarization, suggesting that BMP-7-exo carry much therapeutic potential for OA.

Osteoarthritis (OA) is the most common joint disease and affects an estimated 240 million people worldwide [...].

Synovial mesenchymal stem cell (SMSC) exerts chondroprotective effects in osteoarthritis (OA) clinical models. However, the regulatory potentials of SMSC-derived exosomes (SMSC-Exo) in OA still need to be discovered, which attracted our attention.

The destabilization of the medial meniscus surgery was performed on the knee joints of a mouse OA model, followed by injection of SMSC-Exo. In addition, SMSC-Exo was administrated to mouse chondrocytes to observe the functional and molecular alterations.

Both of SMSC-Exo and overexpression of Matrilin-3 (MATN3) alleviated cartilage destruction and suppressed degradation of extracellular matrix (ECM) in the OA rat model. In addition, assays concerning the in vitro OA model induced by IL-1β showed that SMSC-Exo could promote chondrocyte viability and inhibit autophagy defects. Furthermore, SMSC-Exo achieved the chondroprotective effects through the delivery of MATN3/IL-17A, and MATN3 could suppress the activation of PI3K/AKT/mTOR signaling through IL-17A.

SMSC-Exo exerts beneficial therapeutic effects on OA by preventing ECM degradation and autophagy defects by delivering MATN3/IL-17A.

The translational potential of this study is not only limited to the treatment of knee osteoarthritis but also provides new insights for the treatment of other joint diseases by exploring the mechanism of MATN3. In addition, SMSCExo, as a novel drug carrier, has great potential for treating and diagnosing other diseases. With further research, these findings will provide new directions for developing personalized and innovative treatment options.

Osteoarthritis (OA) is the most common musculoskeletal disease, and it is a major cause of pain, disability and health burden. Pain is the most common and bothersome presentation of OA, but its treatment is still suboptimal, due to the short-term action of employed analgesics and their poor adverse effect profile. Due to their regenerative and anti-inflammatory properties, mesenchymal stem cells (MSCs) have been extensively investigated as a potential therapy for OA, and numerous preclinical and clinical studies found a significant improvement in joint pathology and function, pain scores and/or quality of life after administration of MSCs. Only a limited number of studies, however, addressed pain control as the primary end-point or investigated the potential mechanisms of analgesia induced by MSCs. In this paper, we review the evidence reported in literature that support the analgesic action of MSCs in OA, and we summarize the potential mechanisms of these antinociceptive effects.

Osteoarthritis (OA) has been proven as the second primary cause of pain and disability in the elderly population, impact patients both physically and mentally, as well as imposing a heavy burden on the global healthcare system. Current treatment methods, whether conservative or surgical, that aim at relieving symptoms can not delay or reverse the degenerative process in the structure. Scientists and clinicians are facing a revolution in OA treatment strategies. The emergence of exosomes brings hope for OA treatment based on pathology, which is attributed to its full potential in protecting chondrocytes from excessive death, alleviating inflammation, maintaining cartilage matrix metabolism, and regulating angiogenesis and subchondral bone remodeling. Therefore, we summarized the recent studies of exosomes in OA, aiming to comprehensively understand the functions and mechanisms of exosomes in OA treatment, which may provide direction and theoretical support for formulating therapeutic strategies in the future.

The regeneration strategy for bone defects is greatly limited by the bone microenvironment, and excessive reactive oxygen species (ROS) seriously hinder the formation of new bone. Reduced graphene oxide (rGO) is expected to meet the requirements because of its ability to scavenge free radicals through electron transfer. Antioxidant hydrogels based on gelatine methacrylate (GM), acrylyl-β-cyclodextrin (Ac-CD), and rGO functionalized with β-cyclodextrin (β-CD) are developed for skull defect regeneration, but the mechanism of how rGO-based hydrogels enhance bone repair remains unclear. In this work, it is confirmed that the GM/Ac-CD/rGO hydrogel has good antioxidant capacity, and promotes osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and angiogenesis of human umbilical vein endothelial cells (HUVECs). The rGO-based hydrogel affects ZEB1/Notch1 to promote tube formation. Furthermore, two-photon laser scanning microscopy is used to observe the ROS in a skull defect. The rGO-based hydrogel promotes type H vessel formation in a skull defect. In conclusion, the hydrogel neutralizes ROS in the vicinity of a skull defect and stimulates ZEB1/Notch1 to promote the coupling of osteogenesis and angiogenesis, which may be a possible approach for bone regeneration.

Osteoarthritis (OA) is a degenerative joint disease and is the main cause of chronic pain and functional disability in adults. Articular cartilage is a hydrated soft tissue that is composed of normally quiescent chondrocytes at a low density, a dense network of collagen fibrils with a pore size of 60-200 nm, and aggrecan proteoglycans with high-density negative charge. Although certain drugs, nucleic acids, and proteins have the potential to slow the progression of OA and restore the joints, these treatments have not been clinically applied owing to the lack of an effective delivery system capable of breaking through the cartilage barrier. Recently, the development of nanotechnology for delivery systems renders new ideas and treatment methods viable in overcoming the limited penetration. In this review, we focus on current research on such applications of nanotechnology, including exosomes, protein-based cationic nanocarriers, cationic liposomes/solid lipid nanoparticles, amino acid-based nanocarriers, polyamide derivatives-based nanocarriers, manganese dioxide, and carbon nanotubes. Exosomes are the smallest known nanoscale extracellular vesicles, and they can quickly deliver nucleic acids or proteins to the required depth. Through electrostatic interactions, nanocarriers with appropriate balance in cationic property and particle size have a strong ability to penetrate cartilage. Although substantial preclinical evidence has been obtained, further optimization is necessary for clinical transformation. STATEMENT OF SIGNIFICANCE: The dense cartilage matrix with high-negative charge was associated with reduced therapeutic effect in osteoarthritis patients with deep pathological changes. However, a systematic review in nanodevices for deep cartilage penetration is still lacking. Current approaches to assure penetration of nanosystems into the depth of cartilage were reviewed, including nanoscale extracellular vesicles from different cell lines and nanocarriers with appropriate balance in cationic property and size particle. Moreover, nanodevices entering clinical trials and further optimization were also discussed, providing important guiding significance to future research.

Osteoarthritis (OA) is a common disease that endangers millions of middle-aged and elderly people worldwide. Researchers from different fields have made great efforts and achieved remarkable progress in the pathogenesis and treatment of OA. However, there is still no cure for OA. In this review, we discuss the pathogenesis of OA and summarize the current clinical therapies. Moreover, we introduce various natural and synthetic biomaterials for drug release, cartilage transplantation, and joint lubricant during the OA treatment. We also present our perspectives and insights on OA treatment in the future. We hope that this review will foster communication and collaboration among biological, clinical, and biomaterial researchers, paving the way for OA therapeutic breakthroughs.