Abstract

Keywords:Mesenchymal Stem Cell; Systemic Lupus Erythematosus; Exosomes; Immunomodulatory Effects; Mechanisms

Abbreviations: SLE: Systemic Lupus Erythematosus; MSCs: Mesenchymal Stem Cells; EVs: Extracellular Vesicles; Exos: Exosomes; MSC-Exos:MSC-Derived Exosomes; DCs: Dendritic Cells

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by dysregulated immune responses, autoantibody production, and multi-organ damage, particularly affecting the kidneys, skin, and joints [1]. Despite advances in traditional therapies (e.g., glucocorticoids, immunosuppressants), long-term use of serious iatrogenic diseases such as osteoporosis, metabolic syndrome, and increased risk of infection remain difficult to treat for many patients and require new treatment strategies [2]. Mesenchymal stem cells (MSCs) and their secreted extracellular vesicles (EVs), especially exosomes (Exos), have emerged as promising candidates for SLE treatment due to their immunomodulatory and regenerative properties. This review synthesizes current researches on MSC-derived exosomes (MSC-Exos) in SLE, focusing on their mechanisms of action, therapeutic efficacy, and clinical application challenges.

Biology of MSCs and MSC-Exos

MSCs

MSCs are multipotent stromal cells isolated from bone marrow, adipose tissue, umbilical cord, and other tissues. MSCs have emerged as a research hotspot in SLE treatment due to their unique biological properties, including multidirectional differentiation potential, low immunogenicity, and potent immunomodulatory capabilities (e.g., suppressing abnormal activation of T/B cells, promoting regulatory T cell proliferation, and balancing Th1/Th17 and Th2/Treg subsets). By secreting cytokines and EVs, MSCs regulate macrophage polarization, inhibit dendritic cells (DCs) antigen presentation, and reshape the immune microenvironment, thereby alleviating organ damage and reducing autoantibody levels in SLE patients [3]. However, the treatment of MSCs still faces key defects. Some patients have insufficient response due to their own MSCs dysfunction, and the long-term safety is not clear. In addition, large-scale production and standardized treatment procedures have not yet been perfected, and high costs also limit clinical promotion.

MSC-Exos

MSC-Exos encapsulate and transport essential bioactive components of MSC, including nucleic acids, proteins, and lipids, and play a pivotal role in fundamental biological processes such as intercellular material transport, immune regulation, and pathological signaling. Compared to MSCs, MSC-Exos exhibit significant advantages in treating SLE. Firstly, MSC-Exos inherit the immunomodulatory functions of MSCs while avoiding the risks associated with live-cell therapies, such as immune rejection, vascular embolism, or potential tumorigenicity. Moreover, their low immunogenicity reduces therapeutic complexity and safety risks. Secondly, their nanoscale size (30-150 nm) enables easier penetration of tissue barriers and targeted delivery of bioactive molecules, enhancing treatment precision. Finally, MSC-Exos can be stored and transported at low temperatures, circumventing issues like batch heterogeneity and viability fluctuations inherent in live MSC therapies, thereby offering greater convenience for clinical applications. These characteristics position MSC-Exos as a potentially superior alternative to traditional MSC-based strategies for SLE treatment [4].

Immunomodulatory Effects of MSC-Exos in SLE

SLE is a systemic immune disorder, the core mechanism of which involves the abnormal interaction of multiple immune cells and cytokines. Including, the overactivation of autoreactive B cells produced a large number of pathogenic autoantibodies, and the imbalance of T cell subpopulation (such as excessive proliferation of Th17/Tfh cells and dysfunction of Treg cells) further aggravated B cell abnormalities and the collapse of immune tolerance. Macrophages promote the release of inflammatory cytokines and organ damage through polarization (such as the pro-inflammatory M1 phenotype) and abnormal phagocytosis [5]. In addition, dysregulated cytokine networks create inflammatory storms that activate innate immunity and amplify adaptive immune responses, leading to multi-organ immune complex deposition, complement activation, and tissue damage. The synergistic disorder of these immune links ultimately leads to chronic inflammation and selfaggressive pathological features of SLE. MSC-Exos remodeled SLE immune homeostasis in multiple dimensions.

Regulation of T Cells

MSC-EVs plays multiple roles in regulating T cell function in SLE. First, MSC-EVs inhibits excessive immune responses by regulating T cell differentiation and function. Studies have shown that MSCEVs can significantly inhibit Th1 cell differentiation, reduce IFN-γ secretion, and induce the generation of Foxp3+ regulatory T cells (Tregs), especially IFN-γ+/Foxp3+ double-positive T cell subsets. These cells have the ability to inhibit T cell proliferation [6]. In addition, MSC-EVs upregulates the expression of TGF-β receptor 2 through activates TGF-β signaling, thereby inhibiting glycolysis and mitochondrial metabolism, and impacting T cell activation and proliferation. This metabolic reprogramming may alleviate inflammation in SLE by inhibiting the mTOR pathway and reducing the production of pro-inflammatory factors [6]. Secondly, MSCEVs directly inhibits T cell proliferation by regulating cell cycle and apoptosis. Experiments have shown that MSC-EVs can induce T cell cycle stagnation in the G0/G1 phase through mechanisms involving up-regulation of p27kip1 protein and inhibition of cell cycle-dependent kinase 2, thereby blocking cell cycle progression [7]. In addition, MSC-EVs regulates T cell subpopulation balance, for example, by increasing IL-10 levels and regulating the Treg/ Th17 ratio, a dual effect that helps rebuild immune homeostasis in SLE patients [8].

Modulation of B Cells

MSC-EVs has significant regulatory ability on B cells. On the one hand, it can directly act on B cells and regulate the proliferation, differentiation and antibody secretion of B cells. For example, miRNA-155-5p and miRNA-497-5p in MSC-EVs have been confirmed to regulate the PI3K-AKT signaling pathway and actin cytoskeleton, inhibiting the proliferation, migration and signaling of B cells [9]. On the other hand, MSC-EVs can also indirectly affect B cell function by regulating the immune microenvironment. Under inflammatory conditions, MSC-EVs inhibits the overactivation of B cells and the production of autoantibodies, while promoting the formation of B cell subpopulations with immunomodulatory functions, such as Bregs [10]. In addition, the regulation of MSCEVs on B cell function in SLE is also reflected in its effects on the expression of B cell surface molecules and cytokines. MSC-EVs can regulate the expression of the co-stimulatory molecule PDL1 on the surface of B cells, thereby affecting the migration and activation of B cells. At the same time, MSC-EVs also inhibits the production of pro-inflammatory cytokines (such as IFN-γ and TNF-α) by B cells, thereby regulating the balance of the immune response as a whole [11].

Function regulation of macrophages and DCs

MSCs-EVs regulate macrophage polarization through delivery of specific miRNAs, which play an anti-inflammatory role. For example, the bone marrow-derived MSCs-EVs carry miRNA-16 and miRNA-21, which target to inhibit the expression of PDCD4 and PTEN in macrophages and promote their transformation to anti-inflammatory M2 phenotype, which is represented by upregulation of CD206, Arg-1 and other markers. At the same time, efferocytosis was enhanced and IL-17+ regulatory T cells were recruited to alleviate the inflammatory damage of SLE [12]. In addition, EVs released by hypoxia-pretreated MSCs enriched miRNAs such as miRNA-223 and miRNA-146b, significantly inhibited the expression of pro-inflammatory related factors (such as IL-1β, IL-6, NOS2) in macrophages, and upregulated antiinflammatory related factors (IL-10, Arg-1, Ym1). M2 polarization is enhanced by SOCS3 signaling pathway [13].

MSC-EVs inhibit antigen uptake by immature DCs, prevent DCs maturation, and reduce the expression of maturation and activation markers (such as CD83, CD38, and CD80). Decreased the secretion of pro-inflammatory cytokines (such as IL-6 and IL-12p70) and increased the production of anti-inflammatory cytokines (such as TGF-β), and decreased the expression of CCR7 and the migration ability of DCs to CCL21 after stimulation by LPS, but did not affect its ability to stimulate the proliferation of allogeneic T cells; In addition, specific miRNAs rich in MSC-EVs (such as miR-21-5p, miR-142-3p, etc.) may participate in this immune regulatory process by regulating the expression of DCrelated genes (such as CCR7) [14].

Challenges and Future Directions

Compared with MSCs and traditional drugs, MSC-EVs have significant advantages in the treatment of SLE, and they can restore the immune homeostasis of SLE through multidimensional immune regulation. However, at present, the clinical application of MSC-EVs still face several challenges, three core challenges: Firstly, standardized production and quality control are issues that need to be addressed. The heterogeneity of natural nanomaterials results in significant differences in efficacy among MSC-EVs derived from different sources or prepared using different techniques. Therefore, there is a need to establish unified standards for production and quality evaluation; Secondly, the efficacy of MSC-EVs used alone is limited, and the specific regulatory mechanisms have not been fully elucidated. For example, the interaction between immune metabolic pathways and the disease microenvironment still requires in-depth exploration; Thirdly, the optimization of delivery systems and stability is another challenge. Current delivery routes struggle to achieve precise delivery, and the impact of storage conditions on the function of MSC-EVs has not been clearly defined [15,16].

The future development direction focuses on three breakthroughs:
1) Through engineering transformation such as gene editing or drug loading technology, enhance targeting and therapeutic efficacy.
2) Combining transcriptome and metabolome data to reveal the mechanism of stem cell regulatory network and deepen the scientific cognition of “stem cell strategy”.
3) Develop new delivery systems such as atomizing inhalation technology, and establish standardized clinical trial protocols to accelerate application. Through the collaborative innovation of technology, mechanism and clinical practice, MSC-EVs is expected to become a new paradigm of “cell-free therapy” for autoimmune refractory diseases such as SLE.

Acknowledgements

This project was supported by the National Natural Science Foundation of China (No.32300784), Shenzhen Medical Research Fund (No. A2403018), National Key Research and Development Program of China (No. 2022YFA1104900), Shenzhen Science and Technology Program (Grant No. JCYJ20220818102605012).

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