Mesenchymal stem cells (MSCs), a vital component of the adult stem cell repertoire, are distinguished by their dual capacity for self-renewal and multilineage differentiation. The therapeutic effects of MSCs are primarily mediated through mechanisms such as homing, paracrine signaling, and cellular differentiation. Exosomes (Exos), a type of extracellular vesicles (EVs) secreted by MSCs via the paracrine pathway, play a pivotal role in conveying the biological functions of MSCs. Accumulating evidence from extensive research underscores the remarkable anti-aging potential of both MSCs and their Exos. This review comprehensively explores the impact of MSCs and their Exos on key hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, impaired macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. Furthermore, this paper highlights emerging strategies and novel approaches for modulating the aging process, offering insights into potential therapeutic interventions.

The rapidly advancing field of theranostics aims to integrate therapeutic and diagnostic functionalities into a single platform for precision medicine, enabling the simultaneous treatment and monitoring of diseases. Photo-energy conversion-based nanomaterials have emerged as a versatile platform that utilizes the unique properties of light to activate theranostics with high spatial and temporal precision. This review provides a comprehensive overview of recent developments in photo-energy conversion using nanomaterials, highlighting their applications in disease theranostics. The discussion begins by exploring the fundamental principles of photo-energy conversion in nanomaterials, including the types of materials used and various light-triggered mechanisms, such as photoluminescence, photothermal, photoelectric, photoacoustic, photo-triggered SERS, and photodynamic processes. Following this, the review delves into the broad spectrum of applications of photo-energy conversion in nanomaterials, emphasizing their role in the diagnosis and treatment of major diseases, including cancer, neurodegenerative disorders, retinal degeneration, and osteoarthritis. Finally, the challenges and opportunities of photo-energy conversion-based technologies for precision theranostics are discussed, aiming to advance personalized medicine.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by low-grade inflammation, cartilage breakdown, and persistent pain. Despite its prevalence, current therapeutic strategies primarily focus on symptom management rather than modifying disease progression. Monoclonal antibodies and cytokine inhibitors targeting inflammatory pathways, including TNF-α and IL-1, have shown promise but remain limited by inconsistent efficacy and safety concerns. Long-acting biologic therapies-ranging from extended-release formulations, such as monoclonal antibodies and cytokine inhibitors, to gene therapy approaches-have emerged as promising strategies to enhance treatment durability and improve patient outcomes. Extracellular vesicles (EVs) have gained particular attention as a novel delivery platform due to their inherent stability, biocompatibility, and ability to transport therapeutic cargo, including biologics and immunomodulatory agents, directly to joint tissues. This review explores the evolving role of EVs in OA treatment, highlighting their ability to extend drug half-life, improve targeting, and modulate inflammatory responses. Additionally, strategies for EV engineering, including endogenous and exogenous cargo loading, genetic modifications, and biomaterial-based delivery systems, are discussed.

Heterotopic Ossification (HO), refers to pathological extra skeletal bone formation, and there are currently no reliable methods except surgery to reverse these unexpected calcified tissues. Apoptotic vesicles (ApoEVs) are membrane-bound vesicles released by apoptotic cells, which are involved in metabolism regulation and intercellular communication. Due to its superior trauma-healing ability, the hard palate mucosa is expected to become an essential resource for tissue engineering. This work presents a minimally invasive nanotherapy based on an engineered apoEV. Briefly, apoEVs were extracted from hard palate mucosa and engineered with bone-targeting peptide SDSSD to treat HO. This engineered apoEV not only can achieve directed localization of heterotopic bones but also has the compelling dual function of promoting osteoclastic differentiation while inhibiting osteogenic differentiation. The underlying mechanism involves the activation of Hippo and Notch pathways, as well as the regulation of pyrimidine metabolism. We envision that this engineered apoEV may be a feasible and effective strategy for reversing HO.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show powerful potential in the treatment of multiple diseases. However, the low yield of MSC-EVs severely restricts their clinical application. Here, heat shock (HS), a moderate external stimulus, can enhance EVs release of MSCs by upregulating autophagosome formation. Mechanistically, HS elevates TRPV2 expression to induce Ca2+ influx and then promotes the activity of two succinylases, SUCLG2 and OXCT1, followed by increasing the succinylation of YWHAZ (a 14-3-3 protein) at lysine 11 (K11). Acting as an adaptor protein, YWHAZ's succinylation at K11 inhibits its degradation, reinforcing YWHAZ-ULK1 binding, which upregulates ULK1 S555 phosphorylation to promote autophagosome formation and enhance EV release of MSCs. Additionally, the improved therapeutic efficacy of HS-treated MSCs via EV release has been shown in two liver injury models-hepatic ischemia/reperfusion injury (HIRI) and acetaminophen-induced liver injury. These findings proved that HS, an easily implementable and cost-effective method, can be used to elevate MSC-EV yield in mass production.

Cartilage is crucial for joints, and its damage can lead to pain and functional impairment, causing financial burden to patients. Due to its weak self-repair, cartilage injury control is a research focus. Cartilage injury naturally with age, but mechanical trauma, lifestyle factors and certain genetic abnormalities can increase the likelihood of symptomatic disease progression. Current treatments for cartilage injury include pharmacological and surgical interventions, but these lack the ability to stop the progression of disease and restore the regeneration of the cartilage. Biological therapies have been evaluated but show varying degrees of efficacy in cartilage regeneration long-term. The mesenchymal stem cell (MSC) therapy attracts attention as it is easily harvested and expanded. Once thought to repair via differentiation, MSCs are now known to secrete extracellular vesicles (EVs) paracrinely. These EVs, rich in bioactive molecules, enable cell communication, boost growth factor secretion, regulate the synthesis and degradation of extracellular matrix (ECM), and modulate inflammation, vital for cartilage repair. However, further research and clinical validation are still required for the application of MSC and MSC-EVs. This review highlights the current state of research on the use of MSC and MSC-EVs in the treatment of cartilage injury. It is hoped that the review in this paper will provide valuable references and inspiration for future researchers in therapeutic studies of cartilage repair.

It has been shown that low testosterone levels are associated with the development of osteoarthritis (OA). In our study, we aimed to investigate a bidirectional causal relationship between bioavailable testosterone levels and OA using Mendelian randomization (MR) analysis.

In our study, the datasets from publicly available genome-wide association study (GWAS) were adopted, including the OA-related dataset (ukb-b-14486) and the bioavailable testosterone levels-related dataset (ebi-a-GCST90012104). The UKB-B-14,486 dataset contains 462,933 samples in total, including 38,472 OA samples, 424,461 control samples, and 9,851,867 SNPs, all collected from the European population in 2018. Additionally, the EBI-A-GCST90012104 dataset includes 382,988 samples and 16,137,327 SNPs, which reflect data from the European population in 2020. In total, five methods were utilized, namely MR Egger, Weighted median, Inverse variance weighted (IVW), Simple mode, and Weighted mode. Among them, IVW was the main analytical method. Additionally, the sensitivity analysis was carried out through the heterogeneity test, the horizontal pleiotropy test, and the Leave-One-Out (LOO) method.

The result of forward MR analysis demonstrated that bioavailable testosterone levels were considerably relevant to OA, and were a risk factor for OA (OR = 1.01, 95% CI: [1.00, 1.02], P = 0.02). However, through reverse MR analysis, we did not find a causal relationship between OA and bioavailable testosterone levels. Moreover, the results of the sensitivity analysis suggested that our results were reliable.

The results of our study supported a causal relationship between bioavailable testosterone levels and OA.

Osteoarthritis (OA) is a chronic degenerative joint disease. Our previous study demonstrated that extracellular vesicles (EVs) secreted by human umbilical cord mesenchymal stem cells (HUCMSCs), which play a crucial role in regenerative medicine, have therapeutic effects on OA. Additionally, platelet-rich plasma (PRP) has been widely used in musculoskeletal diseases as it promotes wound healing, angiogenesis, and tissue remodeling; however, its efficacy as a stand-alone therapy remains controversial. Therefore, we investigated the therapeutic effects of combining stem cell-derived EVs with PRP in an OA model. HUCMSC-derived EVs treated with PRP were used as the experimental group, whereas HUCMSC-derived EVs cultured with serum-free (SF) or exosome-depleted fetal bovine serum (exo(-)FBS) and PRP served as controls. PRP-treated HUCMSCs maintained their surface antigen characteristics and potential to differentiate into adipocytes, osteoblasts, and chondrocytes. In the OA model, mice treated with HUCMSCs + 5% PRP-derived EVs showed significantly improved motor function compared to controls and were comparable to those treated with HUCMSCs +SF and +exo(-)FBS-derived EVs. Additionally, increased type II collagen and aggrecan and decreased IL-1β expression were observed in cartilage transplanted with various EVs. In conclusion, PRP enhances HUCMSC differentiation, whereas treatment with EVs improves OA outcomes, providing a promising strategy for future clinical applications.

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) hold promise as a cell-free therapy for osteoarthritis (OA), due to their immunomodulatory and anti-inflammatory properties. However, the need for large-scale expansion to obtain MSC-EVs for clinical use can lead to senescence-related changes and loss of stem-like properties. In this scenario, induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) offer the unique opportunity to address obstacles associated with traditional MSC-based therapies. This study used a xeno-free (XFS) medium for long-term expansion of both MSCs and iMSCs, and their EVs comparison. Characterization of both cells and EVs was conducted across different passages, and the anti-inflammatory potential of EVs and iEVs was assessed using an in vitro model of osteoarthritis. Long-term expansion of MSCs resulted in cellular senescence and a reduction in trilineage differentiation capacity by passage five, accompanied by diminished anti-inflammatory properties of EVs. On the other hand, iMSCs exhibited batch-to-batch variability in differentiation and EV biological properties. However, the effects of iMSC-EVs were prolonged compared to MSC-EVs, providing a wider window of activity for therapeutic purposes. Despite this, the variability among iMSC batches poses challenges for their reliability in OA treatment. Further work is needed to overcome these limitations for clinical application.

With the rapid development of extracellular vesicles (EVs) in regenerative medicine research, they have become a promising new direction in the mechanistic, diagnosis and treatment studies of degenerative musculoskeletal diseases (DMDs), and has attracted increasing attention. However, there is currently a lack of comprehensive and objective summary analysis to help researchers quickly and conveniently understand the development trajectory and future trends of this field.

This study collected articles and reviews published from 2006 to 2024 on EVs in DMDs from the Web of Science database. Bibliometric and visual analysis was conducted using several tools, including Microsoft Excel Office, VOSviewer, CiteSpace, Pajek, and R packages.

1,182 publications were included in the analysis from 2006 to 2024. Notably, there was a rapid increase in the number of publications starting in 2016, suggesting that this field remains in a developmental stage. Co-authorship analysis revealed that China ranked first in terms of publications, whereas the United States led in citations. The journal with the highest number of publications was International Journal of Molecular Sciences (INT J MOL SCI). The most prolific authors were Ragni, E with 23 publications, while the most cited author was Toh, WS. Additionally, nine of the top 10 institutions were from China, with Shanghai Jiao Tong University leading in the number of publications. The most cited article was "MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity", authored by Zhang, S, and published in BIOMATERIALS in 2018.

This study, through bibliometric and visual analysis, clearly illustrates the collaborative relationships among countries, authors, institutions, and journals, providing valuable insights for researchers seeking academic collaboration opportunities. Moreover, the analysis of keywords and citations allows researchers to better understand key research hotspots and frontiers in this field, and points toward promising directions for future research. The growing interest in EV research in DMDs over recent years indicates increasing attention and a dynamic progression in this field.

In this research, we want to find out whether extracellular vesicles (EVs) from adipose-derived mesenchymal stem cells (MSCs) can improve ligament-bone integration after primary Anterior Cruciate Ligament (ACL) repair by performing immunological and biomechanical tests.

All of the rabbits underwent ACL resection at the proximal attachment to the femur bone, and then were divided into four groups. We performed an ELISA examination from the tissue at the bone-ligament interface of iNOS, CD206, MMP-3, and TIMP-1 to evaluate their levels at the inflammatory stage at the end of the first week. Immunoexpression of type I and III collagen and failure load biomechanical tests were performed at the end of the sixth week.

The group that underwent ACL repair with EVs augmentation had significantly higher levels of CD206, significantly lower MMP-3 levels, and significantly higher TIMP-1 levels in the first week. The iNOS levels in the group that underwent ACL repair with EVs augmentation were significantly different compared to the control group that did not receive any. The number of type I collagen fibers and the failure load levels in the group that underwent ACL repair with EVs augmentation were significantly higher.

EVs from adipose-derived MSCs can improve the outcome of primary ACL repair in rabbits by regulating the inflammatory process during the healing period.

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.

Elucidation of the paracrine interaction between chondrocytes and macrophages is useful for understanding the mechanisms of cartilage regeneration. Extracellular vesicles are granular substances with a diameter of approximately 150 nm, surrounded by a phospholipid bilayer membrane. In recent years, research has been conducted on clinical applications of extracellular vesicles. It has been shown that macrophages promote cartilage maturation, and macrophages acquire anti-inflammatory properties through cartilage, but the detailed mechanism of paracrine action involving extracellular vesicles remains unclear. Therefore, we focused on the effect of chondrocyte-derived extracellular vesicles on changes in macrophage characteristics.

Macrophages induced with granulocyte-macrophage colony stimulating factor (M1-like macrophages) and auricular chondrocytes were co-cultured using cell culture inserts and exosome inhibitors, and the expression of macrophage markers were analyzed. Next, extracellular vesicles separated from auricular chondrocytes were added to in vitro macrophage culture medium, and time-lapse observations of macrophage uptake of auricular chondrocyte-derived extracellular vesicles were performed. In addition, the effects of extracellular vesicles on the expression of macrophage markers were also analyzed.

The expression of CD206, an M2 macrophage marker, was increased in macrophages due to the paracrine effect of chondrocytes, and CD206 expression was further increased by pharmacological inhibition of chondrocyte-derived exosomes. It was shown that chondrocyte-derived extracellular vesicles were taken up by macrophages and promoted the production of interleukin-10, an anti-inflammatory cytokine while reducing CD206 expression.

Auricular chondrocyte-derived extracellular vesicles promoted the production of interleukin-10 in bone marrow M1-like macrophages but reduced CD206 expression.

Exosomes are integral to the pathophysiology of osteoarthritis (OA) due to their roles in mediating intercellular communication and regulating inflammatory processes. Exosomes are integral to the transport of bioactive molecules, such as proteins, lipids and nucleic acids, which can influence chondrocyte behavior and joint homeostasis. Given their properties of regeneration and ability to target damaged tissues, exosomes represent a promising therapeutic avenue for OA treatment. Exosomes have potential in promoting cartilage repair, reducing inflammation and improving overall joint function. However, several challenges remain, including the need for standardized isolation and characterization methods, variability in exosomal content, and regulatory hurdles. The present review aims to provide a comprehensive overview of the current understanding of exosome mechanisms in OA and their therapeutic potential, while also addressing the ongoing challenges faced in translating these findings into clinical practice. By consolidating existing research, the present review aims to pave the way for future studies aimed at optimizing exosome‑based therapies for effective OA management.

This study investigates the application of decellularized tissue matrices (DSCM) hydrogels functionalized with extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) for spinal cord injury (SCI) treatment. The primary focus is on how these composites influence macrophage reprogramming and neural stem cell (NSC) differentiation by modulating Slamf9 expression. MSC-derived EVs were successfully isolated, and DSCM hydrogels were prepared from porcine spinal cords. The composite material, EVs derived from MSCs (DSCM@EVs), was constructed and applied to a mouse SCI model, showing significant enhancement in NSC differentiation and axonal growth, thereby alleviating SCI. Bioinformatics and in vitro cell experiments revealed that DSCM@EVs promote the reprogramming of M1 macrophages to the M2 phenotype, reducing inflammatory responses and facilitating NSC differentiation. RNA-seq analysis identified Slamf9 as a key regulatory gene, with its suppression linked to the observed therapeutic effects. This novel approach demonstrates the potential of DSCM@EVs in SCI repair by modulating the inflammatory environment and promoting neural regeneration, offering a promising strategy for treating SCI and potentially other inflammatory neurological disorders.

Cancer vaccines are promising therapeutic approaches to enhance specific T-cell immunity against most solid tumors. By stimulating anti-tumor immunity, clearing minimal residual disease, and minimizing adverse effects, these vaccines target tumor cells and are effective when combined with immune checkpoint blockade or other immunotherapies. However, the development of tumor cell-based vaccines faces quality issues due to poor immunogenicity, tumor heterogeneity, a suppressive tumor immune microenvironment, and ineffective delivery methods. In contrast, extracellular vesicles (EVs), naturally released by cells, are considered the ideal drug carriers and vaccine platforms. EVs offer highly organ-specific targeting, induce broader and more effective immune responses, and demonstrate superior tissue delivery ability. The development of EV vaccines is crucial for advancing cancer immunotherapy. Compared to cell-based vaccines, EV vaccines produced under Good Manufacturing Practices (GMP) offer advantages such as high safety, ease of preservation and transport, and a wide range of sources. This review summarizes the latest research findings on EV vaccine and potential applications in this field. It also highlights novel neoantigens for the development of EV vaccines against cancer.

Chondrocyte senescence is an important pathogenic factor causing osteoarthritis (OA) progression through persistently producing pro-inflammatory factors. Mesenchymal stem cells-derived small extracellular vesicles (MSC-sEVs) have shown anti-inflammatory effects in OA models, while persistent existence of senescent chondrocytes still promotes cartilage destruction. Therefore, improving the targeted elimination ability on senescent chondrocytes is required to facilitate the translation of MSC-sEVs in OA treatment. In this study, versatile engineered MSC-sEVs are developed to targetedly clear senescent chondrocytes and maintain cartilage metabolic homeostasis. Specifically, MSC-sEVs are loaded with siRNA mouse double minute 2 homologue (siMDM2) and modified with cartilage-targeting peptide WYRGRL-PEG2K-DSPE (WPD), named WPD-sEVssiMDM2. The results demonstrate versatile modification improves the cellular uptake of MSC-sEVs in chondrocytes, and thus improves the antiaging effects. Importantly, multifunctional modification enhances cartilage penetration ability and extends joint retention time of MSC-sEVs. In both post-traumatic OA mice and naturally aged mice, WPD-sEVssiMDM2 more effectively eliminates senescent chondrocytes and maintained matrix metabolic homeostasis. By using the P53 phosphorylation inhibitor, the essential role MDM2-P53 pathway in the antiaging function of WPD-sEVssiMDM2 on chondrocytes is verified. In ex vivo cultured human OA cartilage explants, it is confirmed that WPD-sEVssiMDM2 alleviates senescent phenotype. Altogether, the findings suggest that WPD-sEVssiMDM2 have promising translational potential for OA treatment.

Background: Osteoarthritis (OA) is a prevalent degenerative joint disease that causes disability and diminishes quality of life. The pathogenesis of OA remains poorly understood, creating an urgent need for biomarkers to aid research, diagnosis, and treatment. Methods: This study integrated transcriptome data from the GEO database with bioinformatics analyses to identify biomarkers associated with OA. The bioinformatics methods utilized include the Limma package, WGCNA, PPI network analysis, and machine learning algorithms. Genetic variants were used as instrumental variables to evaluate the potential causal impact of circulating white blood cell (WBC) counts on OA. Data sources encompassed the largest genome-wide analysis for OA and a comprehensive GWAS summary for circulating WBC counts. Four mendelian randomization (MR) methods were employed to investigate the genetic association, with a primary focus on findings from the inverse variance-weighted (IVW) method. Results: Total of 233 OA-related genes were identified, showing significant enrichment in pathways associated with WBC function. Key biomarkers, including CD4, CSF1R, and TYROBP, were upregulated in OA samples and exhibited strong diagnostic potential. MR analysis findings provided evidence of a genetic association between elevated neutrophil counts and a reduced risk of OA across sites (IVW: OR = 0.97, 95% CI 0.93-1.00, p = 0.047). Additionally, higher circulating WBC counts, particularly neutrophil counts, were associated with a suggestive decrease in hip OA (WBC IVW: OR = 0.94, 95% CI 0.89-0.99, p = 0.015; neutrophil IVW: OR = 0.93, 95% CI 0.88-0.99, p = 0.017). Conversely, reverse MR analysis found no evidence to support a genetic effect of OA on circulating WBC counts. Conclusion: Our findings suggest that elevated neutrophil counts may offer protective effects against OA, underscoring the interplay between the immune functions and OA pathogenesis. CD4, CSF1R, and TYROBP emerge as promising OA biomarkers, meriting further validation in prospective studies.

Osteoarthritis is a progressive, irreversible debilitating whole joint disease that affects millions of people worldwide. Despite the availability of various options (non-pharmacological and pharmacological treatments and therapy, orthobiologics, and surgical interventions), none of them can definitively cure osteoarthritis in patients. Strategies based on the controlled release of therapeutic compounds via biocompatible materials may provide powerful tools to enhance the spatiotemporal delivery, expression, and activities of the candidate agents as a means to durably manage the pathological progression of osteoarthritis in the affected joints upon convenient intra-articular (injectable) delivery while reducing their clearance, dissemination, or side effects. The goal of this review is to describe the current knowledge and advancements of controlled release to treat osteoarthritis, from basic principles to applications in vivo using therapeutic recombinant molecules and drugs and more innovatively gene sequences, providing a degree of confidence to manage the disease in patients in a close future.

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.

Previous studies confirmed the regenerative capacity of the mammalian neonatal heart. We recently found that adult heart tissue-derived EVs can protect the heart from myocardial ischemia-reperfusion (I/R). However, the role of EVs from neonatal heart tissue in cardiac healing post-ischemia remains unclear. In the present study, we revealed that intramyocardial administration of neonatal cardiac tissue-derived EVs (ncEVs) alleviated cardiac inflammation, mitigated reperfusion injury, and improved cardiac function in murine I/R models. In vitro, ncEVs inhibited M1 polarization of macrophages induced by LPS while up-regulated their phagocytic function via the miR-133a-3p-Ash1l signaling pathway. Moreover, the administration of ncEVs contributed to cardiac angiogenesis and improved cardiac function in murine myocardial infarction models. Collectively, these results suggested that neonatal heart-derived EVs can regulate the function of macrophages and contribute to cardiac regeneration and function recovery in murine cardiac ischemic models. Therefore, the derivatives in neonatal heart tissue-derived EVs might serve as a potential therapeutic strategy in ischemic diseases.

Psoriasis is a chronic inflammatory polygenic disease with significant impacts on skin and joints, leading to substantial treatment challenges and healthcare costs. The quest for novel therapeutic avenues has recently highlighted extracellular vesicles (EVs) due to their potential as biomarkers and therapeutic agents in autoimmune diseases, including psoriasis. EVs are nano-sized, lipid membrane-bound particles secreted by cells that have emerged as promising tools for targeted drug delivery, owing to their unique structure. This review delves into how EVs, either as mediators of cell communication or via their cargo (such as miRNA), directly participate in the pathology of psoriasis, influencing processes such as immune regulation, cell proliferation, and differentiation. Furthermore, this review explores the innovative application of EVs in psoriasis treatment, both as direct therapeutic agents and as vehicles for drug delivery, offering a novel approach to overcoming the current treatment limitations.

Organ-on-a-chip, also known as "tissue chip," is an advanced platform based on microfluidic systems for constructing miniature organ models in vitro. They can replicate the complex physiological and pathological responses of human organs. In recent years, the development of bone and joint-on-chip platforms aims to simulate the complex physiological and pathological processes occurring in human bones and joints, including cell-cell interactions, the interplay of various biochemical factors, the effects of mechanical stimuli, and the intricate connections between multiple organs. In the future, bone and joint-on-chip platforms will integrate the advantages of multiple disciplines, bringing more possibilities for exploring disease mechanisms, drug screening, and personalized medicine. This review explores the construction and application of Organ-on-a-chip technology in bone and joint disease research, proposes a modular construction concept, and discusses the new opportunities and future challenges in the construction and application of bone and joint-on-chip platforms.

Cartilage degeneration is a key feature of aging and osteoarthritis, characterized by the progressive deterioration of joint function, pain, and limited mobility. Current treatments focus on symptom relief, not cartilage regeneration. Mesenchymal stromal cells (MSCs) offer a promising therapeutic option due to their capability to differentiate into chondrocytes, modulate inflammation, and promote tissue regeneration. This review explores the potential of MSCs for cartilage regeneration, examining their biological properties, action mechanisms, and applications in preclinical and clinical settings. MSCs derived from bone marrow, adipose tissue, and other sources can self-renew and differentiate into multiple cell types. In aging cartilage, they aid in tissue regeneration by secreting growth factors and cytokines that enhance repair and modulate immune responses. Recent preclinical studies show that MSCs can restore cartilage integrity, reduce inflammation, and improve joint function, although clinical translation remains challenging due to limitations such as cell viability, scalability, and regulatory concerns. Advancements in MSC delivery, including scaffold-based approaches and engineered exosomes, may improve therapeutic effectiveness. Potential risks, such as tumorigenicity and immune rejection, are also discussed, emphasizing the need for optimized treatment protocols and large-scale clinical trials to develop effective, minimally invasive therapies for cartilage regeneration.

The disappearance of the protective barrier after skin injury leads to the overproduction of reactive oxygen species (ROS) in response to various stimuli. Oxidative stress is one of the most important causes of delayed wound healing, leading to negative outcomes, such as excessive inflammatory response and impaired angiogenesis. In this study, we used microfluidic technology to integrate Prussian blue nanozymes and vascular endothelial growth factor and constructed multifunctional microspheres that improved local oxidative stress. In order to enhance the adhesion of the microspheres on the wound surface and prolong the release of the drug, we coated them with dopamine, ensuring uniform encapsulation on their surface. The microspheres adhered well to the wound surface and promoted wound healing by scavenging ROS, reducing the inflammatory response, and promoting angiogenesis. This strategy of integrating nanozymes and growth factors can have a synergistic effect, which is significant for wound healing.

Osteoarthritis (OA), degenerative joint disease, is the most prevalent form of arthritis worldwide. Besides its substantial burden on society, the high OA morbidity greatly diminishes patients' quality of life. According to recent research, patients-derived serum extracellular vesicles (EVs) are critically involved in sustaining the corresponding disease progression. However, limited research has fully explored the specific functions and molecular mechanisms of OA serum-derived EVs in disease progression. Consequently, we aimed to investigate the underlying mechanism of OA rats-derived serum EVs in regulating OA progression. Before constructing the exosome-cell co-culture system, EVs were extracted from OA and control rat serum and co-cultured with bone marrow mesenchymal stem cells (BM-MSCs). Western blotting (WB), RT-qPCR, and enzyme-linked immunosorbent assay (ELISA) results revealed that OA rat serum-derived EVs upregulated cell pyroptosis-related markers, including nod-Like receptor protein-3 (NLRP3), apoptosis-associated speck-like protein (ASC), gasdermin D (GSDMD), and cleaved caspase-1. The OA rat-EVs also induced the release of LDH and inflammatory cytokines, including interleukin (IL)-1β, IL-18, IL-6, and TNF-α. Additional experiments revealed that OA rat-EVs delivered miR-133a-3p to BM-MSCs and upregulated miR-133a-3p to degrade sirtuin 1 (SIRT1), and activating the downstream NF-κB signaling pathway. Furthermore, the rescuing experiments confirmed that silencing SIRT1 abrogated the miR-133a-3p-induced protective effects in OA-EVs-treated BM-MSCs. In conclusion, OA rats-derived miR-133a-3p-containing EVs modulated the downstream SIRT1/NF-κB pathway-mediated pyroptotic cell death and inflammation in OA. In other words, this study confirmed the role and underlying mechanisms by which OA-associated serum EVs regulate pyroptosis and inflammation response in OA development.

Osteoarthritis (OA) is a common joint degenerative disease which currently lacks satisfactory disease-modifying treatments. Oxidative stress-mediated senescent chondrocytes accumulation is closely associated with OA progression, which abrogates cartilage metabolism homeostasis by secreting senescence-associated secretory phenotype (SASP) factors. Numerous studies suggested mesenchymal stem cells-derived small extracellular vesicles (MSC-sEVs) have been regarded as promising candidates for OA therapy. However, MSC-sEVs were applied before the occurrence of cartilage degeneration or at early-stage OA, while in clinical practice, most OA patients who present with pain are already in non-early-stage. Recently, embryonic stem cells-derived sEVs (ESC-sEVs) have been reported to possess powerful anti-aging effects. However, whether ESC-sEVs could attenuate non-early-stage OA progression remains unknown. In this study, we demonstrated ESC-sEVs ameliorated senescent phenotype and cartilage destruction in both mechanical stress-induced non-early-stage posttraumatic OA and naturally aged mice. More importantly, we found ESC-sEVs alleviated senescent phenotype by rejuvenating aged chondrocytes but not inducing apoptosis. We also provided evidence that the FOXO1A-autophagy axis played an important role in the anti-aging effects of ESC-sEVs. To promote clinical translation, we confirmed ESC-sEVs reversed senescent phenotype in ex-vivo cultured human end-stage OA cartilage explants. Collectively, our findings reveal that ESC-sEVs-based therapy is of high translational value in non-early-stage OA treatment.

Bone and joint-related diseases, including osteoarthritis (OA), rheumatoid arthritis (RA), and bone tumors, pose significant health challenges due to their debilitating effects on the musculoskeletal system. 14-3-3 proteins, a family of conserved regulatory molecules, play a critical role in the pathology of these diseases. This review discusses the intricate structure and multifunctionality of 14-3-3 proteins, their regulation of signaling pathways, and their interactions with other proteins. We underscore the significance of 14-3-3 proteins in the regulation of osteoblasts, osteoclasts, chondrocytes, and bone remodeling, all key factors in the maintenance and dysfunction of bone and joint systems. Specific focus is directed toward elucidating the contribution of 14-3-3 proteins in the pathology of OA, RA, and bone malignancies, where dysregulated 14-3-3-mediated signaling cascades have been implicated in the disease processes. This review illuminates how the perturbation of 14-3-3 protein interactions can lead to the pathological manifestations observed in these disorders, including joint destruction and osteolytic activity. We highlight cutting-edge research that positions 14-3-3 proteins as potential biomarkers for disease progression and as innovative therapeutic targets, offering new avenues for disease intervention and management.

Extracellular vesicles (EVs) are highly heterogeneous, and different EV subpopulations from various origins mediate different biological effects. The separation of different subpopulations of EVs from mixtures is critical but challenging. Epididymosomes are secreted by the epididymal epithelium and play a key role in sperm maturation and function. However, limited access to human epididymal tissue and epididymal fluid has hampered further study of epididymosomes and their potential clinical applications. Here, we established a novel strategy based on flow cytometry sorting to isolate human CD63-positive epididymosomes from ejaculate. We identified CD52, a membrane-located protein expressed exclusively in the epididymis, as the sorting marker for human epididymosomes. Then, CD63-positive epididymosomes were isolated from human semen using a flow cytometry sorting instrument and concentrated. Additionally, we observed that isolated CD63-positive epididymosomes improved sperm function more than other CD63-positive seminal EV subpopulations did, demonstrating the successful isolation of a subpopulation of epididymosomes from human semen and their potential application in the clinic.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant health challenge, characterized by its widespread prevalence, intricate natural progression and multifaceted pathogenesis. Although NAFLD initially presents as benign fat accumulation, it may progress to steatosis, non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Mesenchymal stem cells (MSCs) are recognized for their intrinsic self-renewal, superior biocompatibility, and minimal immunogenicity, positioning them as a therapeutic innovation for liver diseases. Therefore, this review aims to elucidate the potential roles of MSCs in alleviating the progression of NAFLD by alteration of underlying molecular pathways, including glycolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. The insights are expected to provide further understanding of the potential of MSCs in NAFLD therapeutics, and support the development of MSC-based therapy in the treatment of NAFLD.

Recently, the therapeutic potential of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) has been extensively studied in both human and veterinary medicine. EVs are nano-sized particles containing biological components commonly found in other biological materials. For that reason, EV isolation and characterization are critical to draw precise conclusions during their investigation. Research on EVs within veterinary medicine is still considered in its early phases, yet numerous papers were published in recent years. The conventional adult tissues for deriving MSCs include adipose tissue and bone marrow. Nonetheless, alternative sources such as synovial fluid, endometrium, gingiva, and milk have also been intermittently used. Fetal adnexa are amniotic membrane/fluid, umbilical cord and Wharton's jelly. Cells derived from fetal adnexa exhibit an intermediate state between embryonic and adult cells, demonstrating higher proliferative and differentiative potential and longer telomeres compared to cells from adult tissues. Summarized here are the principal and recent preclinical and clinical studies performed in domestic animals such as horse, cattle, dog and cat. To minimize the use of antibiotics and address the serious issue of antibiotic resistance as a public health concern, they will undoubtedly also be utilized in the future to treat infections in domestic animals. A number of concerns, including large-scale production with standardization of EV separation and characterization techniques, must be resolved for clinical application.

To effectively treat osteoarthritis (OA), the existing inflammation must be reduced before the cartilage damage can be repaired; this cannot be achieved with a single type of extracellular vesicles (EVs). Here, a hydrogel complex with logic-gates function is proposed that can spatiotemporally controlled release two types of EVs: interleukin 10 (IL-10)+ EVs to promote M2 polarization of macrophage, and SRY-box transcription factor 9 (SOX9)+ EVs to increase cartilage matrix synthesis. Following dose-of-action screening, the dual EVs are loaded into a matrix metalloporoteinase 13 (MMP13)-sensitive self-assembled peptide hydrogel (KM13E) and polyethylene glycol diacrylate/gelatin methacryloyl-hydrogel microspheres (PGE), respectively. These materials are mixed to form a "microspheres-in-gel" KM13E@PGE system. In vitro, KM13E@PGE abruptly released IL-10+ EVs after 3 days and slowly released SOX9+ EVs for more than 30 days. In vivo, KM13E@PGE increased the CD206+ M2 macrophage proportion in the synovial tissue and decreased the tumor necrosis factor-α and IL-1β levels. The aggrecan and SOX9 expressions in the cartilage tissues are significantly elevated following inflammation subsidence. This performance is not achieved using anti-inflammatory or cartilage repair therapy alone. The present study provides an injectable, integrated delivery system with spatiotemporal control release of dual EVs, and may inspire logic-gates strategies for OA treatment.

Numerous approaches have been utilized to optimize mesenchymal stem cells (MSCs) performance in treating osteoarthritis (OA), however, the constrained diminished activity and chondrogenic differentiation capacity impede their therapeutic efficacy. Previous investigations have successfully shown that pretreatment with nanosecond pulsed electric fields (nsPEFs) significantly enhances the chondrogenic differentiation of MSCs. Therefore, this study aims to explore nsPEFs as a strategy to improve OA therapy by enhancing MSCs' activity and chondrogenic differentiation and also investigate its potential mechanism.

In this study, a million MSCs were carefully suspended within a 0.4-cm gap cuvette and subjected to five pulses of nsPEFs (100 ns at 10 kV/cm, 1 Hz), with a 1-s interval between each pulse. A control group of MSCs was maintained without nsPEFs treatment for comparative analysis. nsPEFs were applied to regulate the MSCs performance and hinder OA progresses. In order to further explore the corresponding mechanism, we examined the changes of MSCs transcriptome after nsPEF pretreatment. Finally, we studied the properties of extracellular vesicles (EVs) secreted by MSCs affected by nsPEF and the therapeutic effect on OA.

We found that nsPEFs pretreatment promoted MSCs migration and viability, particularly enhancing their viability temporarily in vivo, which is also confirmed by mRNA sequencing analysis. It also significantly inhibited the development of OA-like chondrocytes in vitro and prevented OA progression in rat models. Additionally, we discovered that nsPEFs pretreatment reprogrammed MSC performance by enhancing EVs production (5.77 ± 0.92 folds), and consequently optimizing their therapeutic potential.

In conclusion, nsPEFs pretreatment provides a simple and effective strategy for improving the MSCs performance and the therapeutic effects of MSCs for OA. EVs-nsPEFs may serve as a potent therapeutic material for OA and hold promise for future clinical applications.

This study indicates that MSCs pretreated by nsPEFs greatly inhibited the development of OA. nsPEFs pretreatment will be a promising and effective method to optimize the therapeutic effect of MSCs in the future.

Numerous studies have confirmed the involvement of extracellular vesicles (EVs) in various physiological processes, including cellular death and tissue damage. Recently, we reported that EVs derived from ischemia-reperfusion heart exacerbate cardiac injury. However, the role of EVs from healthy heart tissue (heart-derived EVs, or cEVs) on myocardial ischemia-reperfusion (MI/R) injury remains unclear.

Here, we demonstrated that intramyocardial administration of cEVs significantly enhanced cardiac function and reduced cardiac damage in murine MI/R injury models. cEVs treatment effectively inhibited ferroptosis and maintained mitochondrial homeostasis in cardiomyocytes subjected to ischemia-reperfusion injury. Further results revealed that cEVs can transfer ATP5a1 into cardiomyocytes, thereby suppressing mitochondrial ROS production, alleviating mitochondrial damage, and inhibiting cardiomyocyte ferroptosis. Knockdown of ATP5a1 abolished the protective effects of cEVs. Furthermore, we found that the majority of cEVs are derived from cardiomyocytes, and ATP5a1 in cEVs primarily originates from cardiomyocytes of the healthy murine heart. Moreover, we demonstrated that adipose-derived stem cells (ADSC)-derived EVs with ATP5a1 overexpression showed much better efficacy on the therapy of MI/R injury compared to control ADSC-derived EVs.

These findings emphasized the protective role of cEVs in cardiac injury and highlighted the therapeutic potential of targeting ATP5a1 as an important approach for managing myocardial damage induced by MI/R injury.