The Potential Application of Exosomes as Therapeutic Agents, Carriers, and Biomarkers in Skin Diseases

Wenjing Li; Haiyan Li; Liangliang Fan; Ronghua Zhao; Fusong Dong; Xuxia Jia; Lijia Yin; Song Yang; Daqing Zhao; Jiawen Wang

doi:10.2147/IJN.S547871

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Review

The Potential Application of Exosomes as Therapeutic Agents, Carriers, and Biomarkers in Skin Diseases

Authors Li W, Li H, Fan L, Zhao R, Dong F, Jia X, Yin L, Yang S, Zhao D , Wang J

Received 3 July 2025

Accepted for publication 28 September 2025

Published 15 October 2025 Volume 2025:20 Pages 12627—12658

DOI https://doi.org/10.2147/IJN.S547871

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Krishna Nune

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Wenjing Li,¹ Haiyan Li,² Liangliang Fan,¹ Ronghua Zhao,¹ Fusong Dong,¹ Xuxia Jia,¹ Lijia Yin,¹ Song Yang,¹ Daqing Zhao,¹ Jiawen Wang¹

¹Northeast Asia Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, People’s Republic of China; ²Experimental Centre, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, People’s Republic of China

Correspondence: Jiawen Wang, Northeast Asia Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Boshuo Road, Nanguan District, Changchun, Jilin, 130117, People’s Republic of China, Email [email protected]

Abstract: Exosomes, owing to their potent capabilities for intercellular communication, have great potential in modern medicine. The pathogenesis of skin diseases is predominantly characterized by immune imbalance and impaired regenerative processes. Exosomes are rich in microRNAs, lipids, and proteins, which play a crucial role in immune regulation and regenerative medicine. Recent studies have highlighted the involvement of exosomes in the therapeutic management of dermatological disorders. This review provides a comprehensive overview of the potential therapeutic applications of exosomes in autoimmune skin conditions, such as systemic lupus erythematosus, systemic sclerosis, psoriasis, and vitiligo, as well as their roles in skin wound healing, skin aging, scar formation, skin flap regeneration, hair regeneration, and other skin regenerative disorders. The paper examines various exosome delivery methods and evaluates current clinical trials, identifying challenges related to exosome isolation, preservation, active components, mechanistic understanding, and clinical translation. Furthermore, it delineates future research directions and proposes innovative strategies for advancing exosome-based therapies in dermatology.

Keywords: Exosomes, Autoimmune skin diseases, Skin regeneration, Engineered exosomes

Introduction

The skin, recognized as the largest organ in vertebrates, consists of diverse layers, including the epidermis, dermis, and subcutaneous tissue, along with their associated appendages, all supported by a complex neurovascular network^1,2 (Figure 1). The stratum corneum (SC), the outermost layer of the skin, measures approximately 10–20 μm in thickness. Within the intercellular spaces of the SC, a highly organized lipid layer is present. These lipids are essential for the permeation of compounds through the SC, thereby facilitating its barrier function on the skin surface.^1,3 Therefore, examining the lipid composition of the SC is essential for elucidating both normal skin function and conditions involving a compromised skin barrier. Located beneath the epidermis, the dermis serves as the primary structural component of the skin, composed of collagen, elastin, and glycosaminoglycans (GAGs). Fibroblasts, which are the most abundant cell type in the dermis, can synthesize remodeling enzymes like proteases and collagenases. These enzymes play a vital role in the wound repair process. The deepest layer of the skin is the subcutaneous tissue, primarily made up of highly vascularized adipose tissue and a layer of loose connective tissue. This composition plays a vital role in regulating skin temperature and mechanical properties. Collectively, these three layers are essential for protecting the body against mechanical injury.² Skin appendages, such as hair follicles, sweat glands, and sebaceous glands, are fundamental components of the integumentary system. During embryogenesis, these structures originate from epidermal buds that extend into the dermis, forming the respective appendages. Sweat glands are characterized by a coiled secretory portion and an elongated duct that traverses the dermis to reach the epidermis. These glands are crucial for sweat secretion, maintaining electrolyte balance, regulating body temperature, and enhancing skin defense by inhibiting bacterial growth through lactate production.^4,5 Sebaceous glands are situated within the middle layer of the dermis, with an outer layer of proliferating cells and an inner layer comprising sebocytes. Sebaceous glands secrete sebum into the ducts at the junction of the hair follicle. This secretion plays a crucial role in minimizing water loss from the epithelium located between hair follicles and contributes to the regulation of body temperature.⁵ Hair follicles are embedded within the dermis and subcutaneous tissue and consist of the hair papilla and dermal fibers. These follicles are dynamic structures characterized by their cyclical regenerative capabilities.⁶ They are integral to temperature regulation, the distribution of sebum and sweat, and the provision of physical protection.⁵ Collectively, these tissues function to protect the body from harmful microorganisms and other external environmental threats.

Figure 1 Composition of skin.

Cells possess the capacity to release extracellular vesicles enveloped by a phospholipid bilayer. Among these vesicles, those with diameters ranging from 30 to 150 nm are classified as exosomes. Intracellular lipids, RNA, and proteins are selectively incorporated into the intraluminal vesicles (ILVs) within multivesicular bodies (MVBs). Cells release exosomes via exocytosis, following the fusion of the plasma membrane with MVBs^7,8 (Figure 2).

Figure 2 Source, Secretion, Composition and Function of Exosomes.

Exosomes originate from a wide range of sources, including human body fluids, cells, and tumors; animal-derived substances such as bovine milk and cells; plant materials like ginger, ginseng, and grapefruit; and microorganisms, including bacteria and fungi.⁹ The methods employed for the extraction and isolation of exosomes differ based on their source, as well as the desired extraction efficiency and purity. Techniques utilized for exosome extraction encompass ultracentrifugation, ultrafiltration, size-exclusion chromatography, field-flow fractionation, immunoaffinity approaches, ion exchange chromatography, and microfluidic-based technologies.¹⁰ Of these, differential ultracentrifugation is the most commonly employed method. Researchers frequently utilize differential ultracentrifugation to isolate exosomes from cells and plant sources, subsequently employing sucrose gradient centrifugation to enhance the purity of the exosomes obtained¹¹ (Figure 2).

Exosomes fulfill diverse roles, encompassing diagnostics, therapy, and drug delivery, and are integral to human medicine, particularly in the treatment of cancer,¹² cardiovascular diseases,⁹ immune disorders,¹³ degenerative diseases,¹⁴ diabetes,¹⁵ cardiac protection,¹⁶ liver injury,¹⁷ peripheral nerve regeneration,¹⁸ inflammation,^19,20 and aging²¹ (Figure 2).

Dermatological conditions, also known as dermatoses, encompass all diseases affecting the skin, hair, nails, and their associated structures. As a global public health concern, skin diseases exert complex impacts across physiological, psychological, and social dimensions. Conventional therapies are often protracted, susceptible to recurrence, and may induce systemic side effects due to improper administration methods, leading to suboptimal treatment outcomes.²² Exosomes, as nanoscale therapeutic agents, exhibit enhanced targeting capabilities, functioning as carriers to deliver therapeutic molecules to affected sites. Due to their unique regenerative properties, exosomes hold significant therapeutic potential in the treatment of skin disorders.

This review provides a comprehensive summary of exosome delivery methods within the field of dermatology. It elucidates their therapeutic potential as therapeutic agents, carriers, and biomarkers in the context of autoimmune skin diseases, skin regenerative disorders, and cutaneous malignancies. Additionally, it addresses the limitations associated with exosomes development, particularly in terms of extraction, characterization, preservation, compositional and mechanistic research, and clinical trials. By building upon existing research foundations and acknowledging current constraints, the review delineates future developmental directions and explores the therapeutic potential of exosomes in dermatological conditions.

Administration Methods of Exosomes in the Treatment of Skin Diseases

In disease management, exosomes can be administered through diverse routes including systemic delivery, topical application, and targeted delivery. For dermatological conditions, topical application and subcutaneous/intradermal injection are the primary approaches. Herein, we summarise and compare the administration methods of exosomes for treating skin diseases, alongside their respective advantages and disadvantages (Table 1).

Table 1 Administration Methods of Exosomes in the Treatment of Skin Diseases

The Therapeutic Role of Exosomes in Autoimmune Skin Diseases

Autoimmune skin diseases are characterized by heterogeneity and complex pathogenesis, where genetic, infectious, environmental, and psychological factors interact to trigger innate and adaptive immune responses.²⁸ Cutaneous manifestations of autoimmune diseases encompass conditions such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), psoriasis, and vitiligo, among others. Exosomes contribute to the pathogenesis of autoimmune diseases through intercellular communication and modulation of immune cell responses.²⁹ (Figure 3).

Figure 3 The therapeutic role of exosomes in autoimmune skin diseases (“+”:activate, “-”: inhibit).

SLE

SLE is characterized as a multisystem autoimmune disease. This disruption in immune tolerance results in the aberrant activation of various immune cells, notably autoreactive T and B cells, leading to clinical manifestations such as butterfly or discoid rash, mucosal ulcers, and alopecia.³⁰ The predominant causes of mortality in patients with SLE are renal disease, cardiovascular complications, and infections.³¹ Existing pharmacological treatments for SLE are associated with numerous side effects and exhibit limited efficacy in certain patient subgroups. Recent studies have demonstrated that exosomes have the capacity to modulate immune responses, either stimulating or inhibiting them based on the environmental context, thereby highlighting their therapeutic potential in the management of SLE.³²

Mesenchymal stem cells (MSCs), derived from diverse tissues and organs throughout the human body, are multipotent stromal cells capable of differentiating into various cell types, such as osteoblasts, adipocytes, and chondrocytes.³³ MSCs demonstrate advantageous immunomodulatory properties that can be leveraged for the treatment of SLE.³⁴ Exosomes derived from MSCs (MSC-Exos) also exhibit extensive immunomodulatory and regenerative functions.¹³ Research suggests that exosomes from bone marrow MSCs (BMMSC-Exos) ameliorate SLE by promoting the upregulation of cytokines such as CD206 and B7H4, inducing macrophage polarization, and recruiting IL-17+ regulatory T cells.³⁵ Similarly, exosomes derived from human umbilical cord MSCs (hUCMSC-Exos) can enhance the polarization of CD206-induced M2 macrophages and T regulatory (Treg) cells, as well as facilitate the expansion of regulatory T cells, thereby improving SLE.³⁶ Stem cells from human exfoliated deciduous teeth (SHED) exhibit MSC-like characteristics.³⁷ SHED-Exos enhance the functionality of recipient BMMSCs in SLE by restoring Tert mRNA-associated telomerase activity, facilitating hematopoietic niche formation, and modulating immune responses, thereby playing a pivotal role in the disease process.³⁸

The expression of microRNAs (miRNAs) is stringently regulated during the development, differentiation, and effector functions of immune cells, including those involved in the immunological disorders associated with SLE.³⁹ miRNAs derived from exosomes in the plasma of SLE patients specifically target TLR7 and TLR8 signaling pathways, thereby inhibiting autoimmune-mediated inflammation in SLE.⁴⁰ Exosomes are found in all biological fluids and their unique contents are regarded as indicators of autoimmune diseases. In patients with SLE, the miRNA profile within exosomes markedly deviates from that of healthy individuals, underscoring their potential as key biomarkers for renal damage.⁴¹ For example, miR-21, miR-29a, miR-29b, miR-146a, miR-26a, miR-150, and miR-146a-5p are typically found to be abnormally elevated in patients with SLE, thereby facilitating early diagnosis and treatment of the disease.^40–45

Beyond the role of miRNAs as biomarkers for SLE, additional substances have been identified that may aid in diagnosing the condition. Yan et al found the metabolic fingerprint of urinary exosomes that could serve as a potential biomarker for SLE.⁴⁶ Renal damage represents one of the most severe complications associated with SLE. In plasma exosomes, four long non-coding RNAs and two miRNAs (miR-16-5p and miR-101-3p) linked to renal damage target the TGF-β, WNT/β-catenin, and fibroblast growth factors (FGFs), which may emerge as potential diagnostic and therapeutic targets for SLE.⁴⁷ Bactericidal/Permeability-Increasing Protein (BPI), originating from SLE T cells and T cell-derived exosomes, functions as a negative regulator of regulatory T cell differentiation. The overexpression of BPI in T cell-derived exosomes has the potential to serve as both a biomarker and a pathogenic factor for human SLE.⁴⁸ Identifying these biomarkers could enhance the early diagnosis and treatment of SLE in clinical settings.

SSc

SSc, commonly referred to as scleroderma, is an immune-mediated rheumatic disease characterized by fibrosis and vascular alterations in the skin and internal organs. Complications associated with SSc include inflammatory skin conditions, digital swelling, musculoskeletal inflammation, pulmonary fibrosis, and pulmonary arterial hypertension.⁴⁹ The pathogenesis of SSC involves vascular lesions, immune system dysfunction, and ultimately cutaneous fibrosis.⁵⁰ Due to the characteristics of exosomes, potentially establishing a communication network among endothelial cells (ECs), immune cells, and specific target organs, thereby acting as mediators of vascular damage and parenchymal fibrosis.⁵¹ Exosomes are implicated in various pathological and physiological aspects of SSc, playing a crucial role in its diagnosis and treatment.

MSCs exhibit significant immunomodulatory properties; however, MSC-Exos may offer distinct advantages over the use of MSCs alone in the treatment of autoimmune diseases.⁵² Human myofibroblasts induced by TGFβ1 contribute to the pathogenesis of SSc. Research has shown that exosomes derived from adipose MSCs (AMSC-Exos) more effectively ameliorate the myofibroblast phenotype than their parental cells, suggesting that extracellular vesicles exert more potent anti-fibrotic effects in vitro models of SSc compared to adipose mesenchymal stromal cells.⁵² Furthermore, as a cell-free therapeutic approach, MSC-Exos present a reduced risk of immune rejection and tumorigenesis compared to MSCs. This study further underscores the importance of investigating MSC-Exos in SSc. MSC-Exos, which are abundant in various bioactive factors, have the potential to ameliorate SSc through multiple mechanisms, potentially including the promotion of angiogenesis and the modulation of inflammation and fibrosis.⁵³

The miRNAs and proteins encapsulated within exosomes are crucial components of signal transduction and play a significant role in the diagnosis and treatment of SSc (Table 2). A distinctive feature of SSc is the extension of fibrotic changes to previously unaffected tissues. This phenomenon may be mediated by exosomes derived from SSc-affected cells, which can induce the activation of profibrotic phenotypes in normal or unaffected cells.⁵⁴ Skin ulcers are among the common complications experienced by SSc patients.⁵⁵ The vascular abnormalities observed in SSc may be attributed to a disruption in the transfer of exosomes from skin tissue to the bloodstream, resulting in decreased serum exosome levels. This disruption may lead to delayed wound healing due to the downregulation of collagen, thereby increasing susceptibility to atrophic scars and/or ulcers.⁵⁶ These findings suggest that modulating exosome activity in SSc patients could potentially arrest the progression of the disease.

Table 2 Components and Mechanisms of Effect of Exosomes in the Treatment of SSC

Psoriasis

Psoriasis is a prevalent chronic papulosquamous dermatosis characterized by clinical manifestations such as chronic plaques, erythroderma, and pustular psoriasis. The etiology of psoriasis is primarily attributed to genetic predispositions, environmental influences, and immune-related factors.⁶⁴ Key elements in its pathogenesis include tumor necrosis factor alpha (TNF-α), dendritic cells, and T cells.⁶⁵ In psoriasis, there is excessive proliferation of keratinocytes (KCs), accompanied by parakeratosis, which ultimately results in acanthosis. Exosomes serve as long-distance molecular signals in immune responses, positioning them as crucial contributors to the pathogenesis of psoriasis.⁶⁶

The immunomodulatory properties of MSCs have shown significant therapeutic efficacy in psoriasis, advancing into clinical research.⁶⁷ Numerous studies have confirmed that MSC-Exos can mitigate the onset and progression of psoriasis by modulating inflammatory factors and immune responses.^68–70 Moreover, MSC-Exos have been shown to mitigate the proliferation of psoriasis by inducing TGF-β1/2.^71,72 Similarly, UCMSC-Exos have demonstrated significant efficacy in repairing tissue damage in psoriasis mouse models by modulating the local immune microenvironment.⁷³ Researchers have innovatively combined exosomes derived from grapefruit with those from gingiva-derived mesenchymal stem cells (GMSCs) to create multifunctional fusion vesicles for the treatment of autoimmune skin diseases. These vesicles effectively reduce the secretion of inflammatory factors, inhibit the activation of Th17 cells, and promote the infiltration of Treg cells. Furthermore, they reestablish the disrupted immune microenvironment and have shown remarkable therapeutic effects in psoriasis disease models.⁷⁴ These multifunctional fusion vesicles offer advantages such as enhanced targeting and reduced side effects in the treatment of immune-related diseases.

In the pathogenesis of psoriasis, the interaction among inflammation, Th17-mediated immune activation, and keratinocyte hyperproliferation plays a pivotal role.⁷⁵ Engineered keratinocyte-derived extracellular vesicles have demonstrated therapeutic potential in psoriasis by inhibiting LAT1-mTOR-mediated keratinocyte overproliferation and Th17 cell expansion, as well as suppressing IL-1/NF-κB-mediated inflammatory responses.⁷⁶ Similarly, small extracellular vesicles derived from umbilical cord blood mononuclear cells (UCB-EVs) and neutrophil-derived exosomes have shown efficacy in treating psoriasis through the modulation of inflammation, immune responses, and keratinocyte proliferation.^77,78

Beyond immune dysregulation, dysbiosis of the skin microbiome also contributes to the etiology of psoriasis.⁷⁹ In patients with psoriasis, there is an increased expression of Bacillales, Staphylococcus, and Sphingomonas, along with a higher abundance of Propionibacterium acnes in plasma exosomes. Conversely, there is a decreased abundance of Lactobacillales, Brucellaceae, Streptococcus, Kingella, and Aquabacterium.⁸⁰ Exosomes derived from Cutibacterium acnes have been shown to ameliorate psoriasis symptoms by modulating the differentiation of innate lymphoid cell (ILC) subsets and re-establishing the long-term homeostasis of the skin microbiome.⁸¹ Similarly, exosomes from Staphylococcus epidermidis have demonstrated efficacy in mitigating imiquimod-induced psoriasis by reducing acanthosis, cellular infiltration, and the expression of vascular endothelial growth factor (VEGF).⁸²

Psoriasis is linked to abnormalities in epidermal Langerhans cells (LC),⁸³ with CD1a, a molecule that is highly and constitutively expressed by LC, playing a crucial role in the disease’s pathogenesis.⁸⁴ Exosomes released from mast cells, upon induction by IFN-α, transfer cytosolic phospholipase A2 (PLA2) activity to adjacent CD1a-expressing cells, resulting in the formation of novel lipid antigens. These antigens are subsequently recognized by lipid-specific CD1a-reactive T cells, which in turn produce IL-22 and IL-17A, thereby exacerbating the inflammatory response characteristic of psoriasis.⁸⁵ In a similar vein, the interaction between keratinocytes and macrophages through extracellular vesicles enriched with leucine-rich alpha-2-glycoprotein 1 (LRG1) has been shown to exacerbate psoriasis-like dermatitis.⁸⁶ This finding suggests that inhibiting specific exosome-mediated communications could potentially serve as a therapeutic strategy for psoriasis.

miRNAs, which act as essential mediators of cellular communication within exosomes, play a significant role in the diagnosis of psoriasis. Studies have demonstrated that various miRNAs exhibit abnormal expression levels, either increased or decreased, in the plasma and skin keratinocyte exosomes of patients with psoriasis, with mechanisms primarily involving anti-inflammatory and immunomodulatory effects (Table 3). Psoriatic arthritis (PsA), a prevalent complication of psoriasis, affects approximately 30% of individuals with the condition.⁸⁷ Exosome miRNAs not only serve as biomarkers for the onset and progression of psoriasis but also facilitate the differentiation between PsA and Psoriasis vulgaris (PsV). For example, in patients with PsA, serum extracellular vesicles exhibit a marked decrease in hsa-miR-671-3p levels, while hsa-miR-33-5p levels tend to increase.⁸⁸ Furthermore, lipids, which are critical constituents of exosomes, exhibit significant alterations in the plasma exosomes of patients with psoriasis. Notably, there is an observed increase in the levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol, and PC.⁸⁹ These findings suggest that exosomal miRNAs and lipids have potential as biomarkers for the early detection and monitoring of the onset and progression of psoriasis.

Table 3 Biomarkers in Psoriasis

Vitiligo

Vitiligo is an idiopathic acquired pigmentation disorder characterized by the formation of white patches resulting from the loss of functional melanocytes in the skin, hair, or both. The pathogenesis of vitiligo is linked to autoimmune mechanisms, inflammation, and oxidative stress.¹⁰⁷ Exosomes exhibit extensive immunomodulatory properties, participating in antigen presentation, synapse formation, and acting as mediators of intercellular communication to exert immunomodulatory effects.^77,108,109

In patients with vitiligo, autoreactive cytotoxic CD8⁺ T cells interact with melanocytes through the local production of IFN-γ, thereby promoting disease progression.¹¹⁰ hUMSCs-Exos effectively ameliorate vitiligo by delivering miR-132-3p and miR-125b-5p, which concurrently reduce CD8⁺ T cell infiltration, enhance Treg cell-mediated immune suppression, and inhibit oxidative stress-induced melanocyte damage.¹¹¹ Circulating exosomal miRNAs have emerged as promising indicators for a range of diseases. In vitiligo patients, circulating exosomal miR-493-3p is significantly elevated, which is associated with its capacity to induce reactive oxygen species in keratinocytes and promote melanocyte apoptosis.¹¹² miR-200c activates β-catenin and upregulates genes associated with melanogenesis through the suppression of SOX1. Consequently, it is significantly downregulated in exosomes derived from keratinocytes in vitiligo lesions.¹¹³ These exosomes are internalized by NK cells, thereby enhancing their proliferative activity and capacity for IFN-γ secretion, which contributes to the elevated levels of miR-1469 in the circulating exosomes of non-segmental vitiligo (NSV) patients. CD122, a potential target of miR-1469, can partially mitigate the effects of miR-1469 on NK cells.¹¹⁴ In conclusion, considering the pathogenesis of vitiligo and the role of exosomes in immune modulation, exosomes may offer significant potential for the diagnosis and treatment of vitiligo.

The Therapeutic Role of Exosomes in Skin Rejuvenation

Skin injury and regeneration are tightly coupled through intricate interactions among skin cells. Exosomes, acting as endogenous mediators of tissue repair, exert potent regenerative effects.¹¹⁵ In the context of skin regeneration, exosomes commonly utilized are derived from sources such as stem cells, neutrophils, body fluids, macrophages, plasma, and plants. These exosomes have demonstrated beneficial diagnostic and therapeutic effects on a range of skin regenerative disorders, including skin wound,¹¹⁶ skin aging,¹¹⁷ hypertrophic scarring,¹¹⁸ flap regeneration,¹¹⁹ and hair regeneration¹²⁰ (Figure 4).

Figure 4 The therapeutic role of exosomes in skin rejuvenation.

Wound Healing of the Skin

The skin is frequently exposed to chronic and acute wounds resulting from conditions like diabetic foot ulcers or extensive burns. The wound healing process is intricate, comprising four distinct phases: hemostasis, inflammation, proliferation, and tissue remodeling or regression.¹²¹ Initially, a clot forms at the site of tissue injury to provide a temporary seal over the wound gap. Following the initial response, innate immune cells, including neutrophils and macrophages, are recruited to the wound site. These cells orchestrate the development of granulation tissue, which functions to replace the lost connective tissue and drive processes such as angiogenesis, fibroblast migration, and collagen matrix deposition. As granulation tissue accumulates, epidermal cells migrate and proliferate, aiding in the restoration of the skin surface and barrier function. Wound healing is ultimately achieved when the wound edges approximate.^122,123 Exosomes are involved in a range of biological processes, such as cell differentiation and proliferation, angiogenesis, stress response, and immune signaling.¹²⁴ As a cell-free therapeutic approach, Exosomes have shown notable efficacy in promoting wound healing.

General Wounds

Stem cells, defined by their undifferentiated status and capacity for self-renewal, self-replication, and multidirectional differentiation, are pivotal in tissue repair. They help minimize scar formation, reduce wound contraction, and enhance collagen synthesis.¹¹⁶ Exosomes derived from stem cells (SC-Exos) have been the subject of extensive research due to their significant therapeutic potential in wound healing, attributed to their exceptional biocompatibility and targeted delivery capabilities. Exosomes derived from multiple types of stem cells, such as adipose-derived mesenchymal stem cells, human umbilical cord mesenchymal stem cells, human amniotic stem cells, and mesenchymal stem cells from induced pluripotent stem cells, have demonstrated the ability to promote fibroblast and vascular endothelial cell proliferation, as well as collagen synthesis at the wound site. These actions collectively accelerate the wound healing process (Table 4).

Table 4 Effects and Mechanisms of Stem Cell Exosomes in Promoting Wound Healing

Effective wound healing following skin injury relies on dynamic cellular processes that are orchestrated through bidirectional communication between cells. In particular, autophagy is essential for coordinating the interactions between keratinocytes and fibroblasts during the skin repair process.¹³⁵ To prevent wound infection, neutrophils are recruited to recognize inflammatory signals, while macrophages phagocytose apoptotic neutrophils to mitigate wound inflammation.¹²³ SHED-Exos transport miR-1246 to regulate the AKT/ERK1/2/STAT3 signaling pathway, which in turn enhances autophagy and facilitates wound healing.¹³⁶ Engineered keratinocyte-derived exosomes can be selectively phagocytosed by wound macrophages within granulation tissue, leading to elevated levels of pro-inflammatory cytokines and epithelial junction proteins, and preserving barrier function in murine models. This highlights the interplay between keratinocytes and macrophages during the wound healing process.¹³⁷ Bovine milk exosomes (BM-Exos) encompass a variety of anti-inflammatory agents that facilitate the shift from the inflammatory phase to the proliferative phase.¹³⁸ Additionally, they contain factors essential for tissue remodeling and angiogenesis, thereby promoting epithelial regeneration, activating angiogenesis, and enhancing extracellular matrix (ECM) maturation to support wound healing.¹³⁹ Exosomes derived from activated neutrophils, which are enriched with antimicrobial proteins, contribute to the healing of infected wounds by reducing inflammatory cytokines and enhancing collagen deposition.¹⁴⁰

As significant paracrine mediators, exosomes can facilitate regenerative processes through the delivery of bioactive molecules. Exosomes sourced from human umbilical cord plasma (hUCP-Exos) expedite wound re-epithelialization, diminish scar width, and promote angiogenesis by delivering miR-21-3p. This miRNA inhibits key regulators of fibroblast and endothelial cell functions, specifically phosphatase and tensin homolog (PTEN) and sprouty homolog 1 (SPRY1).¹⁴¹ Exosomes derived from saliva are enriched with ubiquitin-conjugating enzyme E2O (UBE2O), which diminishes the levels of SMAD family member 6 (SMAD6), subsequently activating bone morphogenetic protein 2 (BMP2) and inducing angiogenesis.¹⁴² Additionally, exosomes mediate the transfer of miR-125b from young to senescent fibroblasts, where it inhibits sirtuin 7, thereby facilitating fibroblast migration and transition, ultimately promoting wound healing.¹⁴³ Exosomes originating from primary skin fibroblasts that encapsulate Gstm2 mRNA mitigate oxidative stress damage in senescent dermal fibroblasts by modulating mitochondrial oxidative phosphorylation. They also promote the regulation of epidermal cell function by dermal fibroblasts through the paracrine secretion of the nascent peptide-associated complex alpha subunit (NACA), thereby facilitating the repair of aged wounds.¹⁴⁴

The skin microbiota is vital to the skin diseases, and skin injuries can disrupt this balance.¹⁴⁵ Furthermore, bacteria have been reported to secrete exosomes, which contribute to wound healing. Exosomes secreted by Synechococcus elongatus PCC7942 have been shown to exert anti-inflammatory effects by inhibiting the expression of IL-6, thereby promoting angiogenesis and facilitating wound healing.¹⁴⁶ Similarly, extracellular vesicles derived from Lactobacillus rhamnosus GG contribute to wound healing by mediating re-epithelialization and angiogenesis through miR-21-5p.¹⁴⁷

In recent years, exosomes derived from naturally green plants have demonstrated significant therapeutic potential in regenerative medicine, attributed to their excellent tissue compatibility and low toxicity.¹⁴⁸ Exosomes isolated from ginseng have been shown to enhance the secretion of MMP-1, fibronectin-1, elastin-1, and COL1A1, and to regulate the ERK/AKT/mTOR signaling pathway, thereby enhancing cell proliferation, facilitating skin wound healing, and reducing inflammation.¹⁴⁹ Furthermore, exosomes derived from Aloe vera exhibit characteristics of inflammatory modulators, reducing the differentiation and contraction of myofibroblasts, and are essential in the initial phases of burn wound healing.¹⁵⁰ Wheat-derived exosomes have been shown to enhance the proliferation and migration of endothelial, epithelial, and dermal fibroblast cells, as well as to facilitate the formation of tubular structures in endothelial cells, indicating their potential therapeutic application in wound healing.¹⁵¹ Similarly, exosomes derived from Dendrobium have demonstrated efficacy in suppressing IL-1β expression and expediting the repair of skin wound tissues.¹⁵² Collectively, these findings suggest that plant-derived exosomes could represent an effective and environmentally friendly therapeutic strategy for wound healing.

Currently, the primary routes of exosome administration include oral gavage, direct injection, and topical application to wounds. However, free exosomes may rapidly disperse within the body or at wound sites, potentially diminishing their therapeutic efficacy. To preserve the biological activity of exosomes and regulate their effective concentration during treatment, researchers have developed modified exosomes and engineered delivery systems.¹⁵³ Such delivery systems have been extensively utilized in exosome-facilitated wound healing (Table 5). Hydrogels, which consist of a three-dimensional polymer network that mimics the extracellular matrix, offer high water content, excellent biocompatibility, and plasticity. By modifying the network structure and cross-linking density of hydrogels, as well as their degradability, the release rate and duration of exosomes can be precisely controlled. This modulation facilitates improved adaptation to complex wound environments, thereby enhancing the biological activity and therapeutic efficacy of exosomes.¹⁵⁴ Delayed wound healing is primarily attributed to bacterial infection, immune response, and inflammatory response. Exosomes have the capacity to transport immunomodulatory factors, anti-inflammatory agents, and antimicrobial compounds, enabling them to modulate systemic immune responses or specifically target damaged tissues, thereby augmenting their tissue regeneration capabilities.^155,156

Table 5 The Role of Engineered Exosomes in Wound Healing

Diabetic Wounds

Diabetic wounds represent a category of chronic wound diseases. Chronic wounds often become arrested in the inflammatory phase, leading to compromised angiogenesis and postponed re-epithelialization.¹²³ The pathogenesis of diabetic wounds is associated with chronic bacterial infection, oxidative stress, inflammation, and angiogenic impairment.^168–170 Consequently, diabetic wounds necessitate more effective and diversified therapeutic strategies.

Analogous to the treatment of common wounds, stem cell-derived exosomes(SC-Exos) play a crucial role in addressing diabetic wounds. A significant challenge in treating diabetic wounds is angiogenic impairment. BMSC-Exos promote the proliferation, migration, and tubule formation of vascular ECs and simultaneously upregulate the expression of VEGF.^171,172 The PI3K/AKT signaling pathway plays a vital role in modulating cell proliferation and migration. In diabetic wounds, BMSC-Exos activate this pathway, which in turn enhances angiogenesis and facilitates wound healing.^172–174 Human urine stem cell-derived exosomes (USC-Exos) promote endothelial cell angiogenesis by highly expressing deleted in malignant brain tumors 1.¹⁷⁵ Vascular ECs are highly heterogeneous, with CD31^hiEMCN^hi ECs promoting angiogenesis¹⁷⁶ MSC-Exos induce the formation of CD31^hiEMCN^hi vessels in skin regeneration and promote diabetic wound healing.¹⁷⁷ In patients with diabetic ulcers, cellular Ca²⁺ homeostasis is disrupted, and TRPC6 can mediate Ca²⁺ influx. MSC-Exos facilitate the restoration of TRPC6 and mitochondrial function by delivering the transcription factor SP2 and the deubiquitinase USP9, thereby contributing to the healing of diabetic wounds.¹⁷⁸ Autophagy plays a critical role in the removal of damaged mitochondria through various pathways, mitigating skin cell dysfunction induced by high-glucose conditions.¹⁷⁹ ADSC-Exos improve skin wound healing in diabetic mice through the promotion of epidermal autophagy and acceleration of re-epithelialization.¹⁸⁰ Furthermore, iPSC-Exos demonstrate reduced donor variability and exhibit significant therapeutic potential in diabetic wounds by modulating immune cell infiltration and exerting anti-inflammatory and pro-angiogenic effects.¹⁸¹

In addition to SC-Exos, exosomes from various other cellular sources or body fluids have also demonstrated significant therapeutic potential in diabetic wound healing. Sphingosine-1-phosphate, a key regulator of vascular homeostasis and angiogenesis, is enriched in platelet-rich plasma-derived exosomes (PRP-Exos). These exosomes enhance angiogenesis in diabetic wounds by modulating the S1PR1/AKT/FN1 signaling pathway.¹⁸² Hyperglycemia causes vascular dysfunction in diabetic wounds by increasing inflammatory factors and reactive oxygen species.¹⁸³ Macrophages help reduce inflammation through chemotaxis and phagocytosis.¹⁸⁴ Macrophage-derived exosomes loaded with curcumin mitigates oxidative stress and inflammation induced by high glucose, thereby facilitating the proliferation, migration, and angiogenesis of HUVECs.¹⁸⁵ Exosomes from adipose tissue macrophages adjust miR-222-3p levels, influencing macrophage polarization and speeding up diabetic wound healing.¹⁸⁶ Interestingly, plant-derived exosomes promote macrophage polarization and enhance diabetic ulcer wound healing, showing promise for glycolytic reprogramming in these ulcers.^187,188

Analogous to the use of exosomes in the treatment of common wounds, engineered materials combined with exosomes have been extensively employed in addressing diabetic wounds, including multifunctional hydrogels, smart microneedles, protein patches, and multifunctional bio-hybrid nanorobotic platforms (Table 6). These engineered exosomes exhibit enhanced therapeutic efficacy at diabetic wound sites, offering more advantageous strategies for the application of exosomes in diabetic wound treatment.

Table 6 The Role of Engineered Exosomes in Diabetic Wounds

Scars

Following skin injury, the wound healing process often culminates in scar formation, which can be classified into four types: mature scars, immature scars, hypertrophic scars, and keloids.²⁰⁶ Scar formation is linked to metabolic dysfunction of connective tissue during the wound healing process, as well as the overproduction of activated fibroblasts and various components of the ECM.²⁰⁷ Exosomes are instrumental in scar management through mediating cell-to-cell communication.

Hypertrophic scars represent a category of fibroproliferative disorders that arise from surgical wounds or burns. In the course of wound healing, the prolonged persistence of myofibroblasts leads to excessive collagen accumulation, which ultimately results in the development of hypertrophic scars.²⁰⁸ ADSC-Exos ameliorate hypertrophic scarring by inhibiting collagen deposition and the transdifferentiation of fibroblasts into myofibroblasts, specifically delivering miR-125b-5p and miR-192-5p to suppress Smad signaling.^208,209 MSC-Exos mitigate hypertrophic scarring by suppressing fibroblast proliferation through the TNFSF-13/HSPG2 signaling pathway.²¹⁰ Additionally, exosomes derived from Lactobacillus delbrueckii can inhibit the expression of collagen I/III and α-SMA in fibroblasts, thereby suppressing the formation of hypertrophic scars in scleroderma mouse models.²¹¹ Additionally, engineered exosomes have been employed in the treatment of hypertrophic scars. Exosomes functionalized with miR-141-3p and incorporated into soluble microneedle arrays can modulate Smad expression, thereby enhancing the distribution of fibroblasts and the alignment of collagen fibers within hypertrophic scar tissue.¹¹⁸ These exosomes, particularly MSC-Exos, offer a promising therapeutic strategy for hypertrophic scars.

Skin Aging

Skin aging is affected by a combination of intrinsic, time-related factors and extrinsic, environmental factors. As skin ages, it undergoes structural, cellular, and molecular changes, including the buildup of senescent cells.²¹² Intrinsic aging leads to skin thinning due to reduced cell proliferation and changes in dermal components, with a decrease in ECM components like collagen and elastin causing fine lines. Additionally, the skin’s ability to repair itself diminishes, making it more susceptible to oxidative stress.^212–214 Extrinsic aging, primarily caused by UV radiation, smoking, and pollution, results in impaired keratinocyte differentiation, reduced collagen, loss of melanocytes.²¹⁵ Exosomes, especially those from stem cells, have shown anti-aging benefits by restoring skin functions and repairing damage through mechanisms like reducing oxidative stress, lowering MMPs, boosting collagen and elastin production, and enhancing cellular communication.^117,216

Photoaging represents a major contributor to extrinsic skin aging, and several studies have reported the efficacy of exosomes in addressing skin photoaging. For instance, needle-free administration of exosomes sourced from human dermal fibroblast spheroids has been demonstrated to ameliorate UVB-induced photoaging by augmenting type I procollagen expression and dermal collagen deposition while concurrently reducing MMP-1 levels.²¹⁷ Furthermore, exosome-like nanovesicles derived from Phellinus linteus, containing miR-CM1, have been shown to inhibit the expression of Mical2 in HaCaT cells through cross-species regulation, thereby reducing ROS levels and attenuating UV-induced skin aging.²¹⁸ Nanovesicles from dermal papilla MSCs combat photoaging by reducing cell cycle arrest, cellular senescence, and macrophage infiltration, while enhancing cell proliferation, ECM production, and antioxidant enzyme activity.²¹⁹ Cow’s milk exosomes (MK-Exos) aid fibroblast migration and restore collagen expression after UV exposure.²²⁰ Plant-derived exosomes offer antioxidant and anti-inflammatory benefits against skin photoaging. Exosome-like nanovesicles from olive leaf in a hydrogel deliver miR168a-5p to inhibit the NF-κB pathway, reducing inflammation and promoting skin repair after UV damage.²²¹ Exosome-like nanoparticles from ginseng roots protect skin from UV and oxidative stress by inhibiting AP-1 signaling and reducing senescence and inflammation markers.²²² Apple-derived exosomes boost type I collagen and lower MMPs by downregulating the NF-κB pathway, aiding in skin aging.²²³

Similarly, Engineered nanovesicles from human iPSCs improve aging signs in dermal fibroblasts by reducing SA-β-Gal activity and inhibiting p53 and p21.²²⁴ In addition, Combining exosomes with bioactive substances enhances their anti-aging effects. Co-administering hydrolyzed collagen oligopeptides and SC-Exos boosts cell migration and proliferation, reduces ROS production, and inhibits senescence-related genes, enhancing skin’s anti-aging abilities.²²⁵

Flap Regeneration

A flap, consisting of skin and subcutaneous fat with its own blood supply, is used in wound repair, organ reconstruction, or cosmetic procedures. Flap regeneration, the process of restoring blood flow and function post-transplantation, can be hindered by insufficient blood supply causing necrosis.²²⁶ SC-Exos improve flap regeneration due to their regenerative properties, with studies showing BMSC-Exos enhance flap survival after ischemia by reducing oxidative stress, inflammation, and apoptosis.^227,228 Similarly, ADSC-Exos enhance neovascularization and reduce inflammation and apoptosis in skin grafts after ischemia-reperfusion injury.²²⁹ Moreover, Curcumin-loaded ADSC-Exos boost antioxidant and anti-inflammatory effects in flap regeneration.²³⁰ Exosomes from human dental pulp stem cells (hDPSC-Exos) enhance HUVEC proliferation, migration, and lumen formation via the PI3K/AKT pathway, improving flap survival.²³¹ miRNAs in exosomes are crucial for flap regeneration, with hypoxia-treated BMSC-Exos carrying miR-421-3p targeting the mTOR/ULK1/FUNDC1 axis to activate autophagy and support flap survival after ischemia-reperfusion injury.¹¹⁹ ADSC-Exos treated with FGF1 deliver miR-183-5p, targeting GPR137 via the PI3K/Akt/mTOR pathway to reduce oxidative stress and endothelial cell apoptosis, enhancing ischemic flap survival.²³² Beyond stem cells, M2 macrophages exhibit angiogenic potential during tissue repair. M2-derived exosomes facilitate angiogenesis and improve flap survival via the HIF-1AN/HIF-1α/VEGFA axis.²³³ Consequently, exosomes represent a significant therapeutic approach for flap regeneration.

Hair Regeneration

Alopecia, both scarring and non-scarring, affects the hair growth cycle, often shortening the anagen phase and extending the telogen phase due to various factors.^234,235 Exosomes from different cell types have shown potential in promoting hair growth. These cell types include stem cells,²³⁶ keratinocytes,²³⁷ dermal papilla cells,²³⁸ and macrophages.²³⁹

Dermal papilla cells (DPCs) function as the signaling hub within hair follicles, orchestrating hair formation and cycling through paracrine mechanisms.²⁴⁰ Exosomes derived from DPCs (DPC-Exos) enhance intercellular communication and serve as a crucial factor in the treatment of alopecia. DPC-Exos can activate LEF1, thereby regulating the proliferation of hair follicle stem cells.²⁴¹ Moreover, miR-218-5p and miR-181a-5p, which are conveyed by DPC-Exos, target the Wnt/β-catenin signaling pathway,^120,242 while miR-140-5p targets the BMP/TGF-β signaling pathway, thus promoting hair follicle development.²⁴³ Engineered DPC-Exo hydrogels have been explored as a therapeutic strategy for alopecia, aiming to achieve more sustained and comprehensive therapeutic outcome.²⁴⁰ Additionally, reNcell-derived nanovesicles (ReN-NV) and MK-Exos, which exhibit stem cell-like properties, can activate the Wnt/β-catenin pathway to enhance DPC proliferation and expedite the transition of the hair follicle cycle.^244,245 Exosomes derived from fibroblasts increase the expression of PCNA, pAKT, pERK, and VEGF receptor-2 (VEGFR2) in DPCs, thereby promoting their proliferation.²⁴⁶

Androgenetic alopecia (AGA) is a non-cicatricial hair loss disorder attributed to elevated levels of androgens. Recent advancements have seen the application of various SC-Exos in the therapeutic management of AGA. iPSC-Exos have been shown to ameliorate AGA by modulating growth factors and cytokines, as well as activating the androgen receptor (AR)-associated Wnt/β-catenin signaling pathway.²⁴⁷ ADSC-Exos, which carry miR-122-5p, target the TGF-β/SMAD3 axis to facilitate hair follicle regeneration in AGA.²⁴⁸ Additionally, hUCMSC-Exos enhance the stemness of hair follicle stem cells via the RAS/ERK pathway, thereby promoting hair proliferation in AGA mouse models.²⁴⁹ Moreover, the combination of SC-Exos with various hair loss treatment agents can yield a multifaceted synergistic effect in the management of AGA.^250,251 In contrast, alopecia areata, an autoimmune-mediated condition, results from immune attacks on hair follicles.²⁵² In this context, hMSC-Exos have demonstrated efficacy in promoting hair regeneration and hair shaft elongation in hair follicles of imiquimod-induced alopecia areata mice.²⁵³ Collectively, these exosomes offer a comprehensive therapeutic strategy for addressing hair loss.

Therapeutic Role of Exosomes in Skin Cancer

Malignant melanoma (MM) is a skin cancer. Upon exposure to external radiation, such as UV light, the skin initiates a DNA damage response, leading to the secretion of melanocyte-stimulating hormone (MSH) by keratinocytes. MSH subsequently binds to the melanocortin 1 receptor (MC1R) on melanocytes, stimulating melanin production. The metastasis of melanoma is primarily driven by genetic mutations and modifications within the tumor microenvironment, which are characterized by increased immunogenicity and the infiltration of immune cells into the tumor.^254,255 Exosomes, which mediate intercellular communication, have emerged as important players in the diagnosis and treatment of skin cancer. Specifically, miRNAs present in exosomes derived from MM cells, contribute to tumor immune evasion and represent potential therapeutic targets.²⁵⁶ Furthermore, exosomes isolated from the lymphatic drainage of melanoma patients post-lymph node dissection contain proteins that are enriched and analogous to those associated with melanoma progression. Evaluating surrogate markers indicative of tumor progression within circulating extracellular vesicles could provide a robust non-invasive approach.²⁵⁷ Conversely, exosomes originating from MM cells have been implicated in the modulation of MM treatment. Research indicates that WNT5A stimulates the release of MM cell-derived exosomes, which contain immunomodulatory and pro-angiogenic proteins.²⁵⁸ Furthermore, exosomes carrying PD-L1, secreted by MM cells, facilitate the polarization of M2 macrophages, thereby enhancing resistance to therapies targeting programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1).²⁵⁹

In addition to cancer cell-derived exosomes, those derived from normal cells and plants also contribute to MM treatment. Exosomes derived from NK cells have demonstrated the ability to suppress the proliferation of MM cells.²⁶⁰ Similarly, adipose stem cell-derived exosomes inhibit the progression of skin cancer through the miR-199a-5p/SOX4 pathway.²⁶¹ Moreover, grapefruit-derived microvesicles and nanovesicles demonstrate a distinct metabolomic profile and exhibit anti-MM activity in the A375 human melanoma cell line.²⁶²

In addition to their diagnostic and therapeutic roles, exosomes have the potential to function as carriers for cancer therapeutic agents, specifically targeting MM cells. This facilitates the development of targeted drug delivery systems that offer synergistic enhancement and reduced toxicity. Nanovesicles derived from aloe vera, when loaded with indocyanine green (ICG), demonstrate efficient uptake by MM cells over prolonged periods, resulting in more effective inhibition of melanoma growth compared to free ICG.²⁶³ Furthermore, hUCMSC-Exos complexed with the cyclic peptide arginine-glycine-aspartic acid (cRGD) and encapsulating triptolide (TP) exhibit tumor-targeting capabilities. This formulation not only extends the half-life of TP but also significantly inhibits MM growth and prolongs the survival of mice bearing MM.²⁶⁴

Clinical Trials of Exosomes in Dermatological Conditions

Numerous case studies on exosome therapy for dermatological conditions have progressed to the stage of clinical research. These studies primarily focus on MSC-EXOs, plasma-derived exosomes, and include one clinical investigation involving plant-derived exosomes. Among these, MSC-EXOs are the most extensively utilized, aligning with foundational research findings. They have been employed in the treatment of conditions such as hair loss, psoriasis, skin aging, diabetic foot ulcers, melanoma, melasma, and dry eye syndrome, as outlined in the accompanying (Table 7). These clinical trials not only explore the application of exosomes as therapeutic agents for skin conditions but also investigate their potential as biomarkers. This dual functionality—as therapeutic agents and biomarkers—has been validated at the clinical trial level. Unfortunately, as of now, no exosome-based treatments for skin diseases have received approval for market release as medicinal products.

Table 7 Clinical Trials of Exosomes in Skin Diseases

Limitations and Future Prospects of Exosomes in Skin Therapy

Despite significant advancements in fundamental research on exosomes within the field of dermatology in recent years, numerous challenges remain concerning their clinical application as therapeutic agents. Firstly, exosomes originate from a wide array of sources, resulting in compositional variations between those derived from different cell types. Even among exosomes from the same cell type, variations in composition are observed at different stages of cellular growth.¹¹⁶ The nucleic acids, proteins, and lipids within exosomes constitute a highly complex mixture. Although exosomes exhibit promising therapeutic potential across various diseases, the specific therapeutic components have yet to be clearly identified. Research has predominantly focused on microRNAs, with limited studies exploring the detailed composition and mechanisms of action of proteins and lipids. Therefore, future research should prioritize elucidating the therapeutic constituents of exosomes and their specific mechanisms of action. 2) Researchers have devised a range of methodologies for exosome isolation, grounded in principles such as density, size, and immunoreactivity. Nevertheless, each method is accompanied by distinct limitations. For example, differential ultracentrifugation, the most frequently utilized technique, requires expensive equipment and skilled personnel. Size-exclusion chromatography is prone to equipment blockage, whereas immunocapture methods are restricted to isolating specific subsets of exosomes. Furthermore, the exosome isolation and purification process is complex and time-consuming, with operator variability potentially resulting in inconsistencies in the composition of isolated exosomes.^10,265 These inconsistencies hinder the precise identification of exosomes and subsequent experimental analyses. Therefore, the development of cost-effective, scalable, and reliable methods for exosome isolation is crucial for advancing their application in the medical field. 3) The harvested exosomes necessitate long-term storage at −80°C, as their biological activity is only preserved for approximately one week when stored at 4°C. Nevertheless, storage at −80°C is not without its drawbacks, as it adversely affects the stability of exosomes, with degradation observed even after extended storage periods of up to two years. This presents considerable challenges for the storage and transportation of exosomes. Although exosome lyophilization techniques have been developed to facilitate stable preservation at room temperature, there is a lack of sufficient experimental evidence to ascertain whether lyophilization affects their biological activity.²⁶⁶ Consequently, there is an urgent need for more convenient, durable, and stable preservation methods in exosome research. 4) Due to the ambiguous composition of exosomes, particularly the immunogenicity associated with cell-derived exosomes, may result in significant heterogeneity between different donors and recipients. While studies suggest that plant-derived exosomes exhibit lower immunogenicity and enhanced safety profiles, their application in the treatment of skin diseases remains relatively unexplored. Additionally, the identification of plant exosomes continues to pose a significant challenge. The therapeutic application of exosomes in disease management faces several challenges.²⁶⁷ Establishing standardized protocols for the identification of plant-derived exosomes, in conjunction with fundamental research and clinical applications in dermatology, is of paramount importance for future investigations. 5) Currently, there are over a hundred instances of exosomes being evaluated in clinical trials across various disciplines, including orthopaedics (NCT05060107), neurosurgery (NCT03384433), plastic surgery (NCT02565264), and ophthalmology (NCT05413148), with the majority still in the preclinical research phase.²⁶⁸ Despite extensive foundational research on exosome therapies for dermatological conditions, only a limited number of studies have advanced to clinical trials. Future research efforts should focus on translating basic scientific findings into clinical applications and developing safe and effective exosome formulations specifically designed for dermatological therapies. Although there are inherent challenges in the medical application of exosomes, particularly in the treatment of skin diseases, we propose that interdisciplinary advancements in medicine, bioengineering, nanotechnology, and related fields will facilitate significant progress in dermatological therapeutics. This advancement is expected to result in the development of safer, more effective, and varied therapeutic modalities for a wide spectrum of human diseases.

Conclusion

In recent years, exosomes have been extensively utilized across various domains of medical treatment, including cardiovascular diseases, immune disorders, degenerative diseases, inflammation, aging, and regenerative medicine. This is attributed to their diverse origins, favorable biocompatibility, and capacity to transport nucleic acids, proteins, lipids, and other components involved in intercellular communication. Notably, the phospholipid bilayer structure of exosomes confers exceptional biocompatibility with the skin, enhancing their absorption. This review consolidates recent studies on the utilization of exosomes as biomarkers, therapeutic agents, and drug delivery systems in dermatological disorders. It offers a comprehensive analysis of the therapeutic potential of exosomes in autoimmune skin disorders, such as SLE, SC, psoriasis, and vitiligo, as well as in skin regenerative conditions, including wound healing, skin aging, hypertrophic scarring, flap regeneration, and hair regeneration. Furthermore, exosomes demonstrate promising therapeutic roles in the treatment of skin cancers. These results offer compelling therapeutic approaches for managing skin diseases and establish a strong basis for the advancement of exosome-based therapies in dermatology.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was supported by Jilin Province Changbai Yingcai-Young Postdoctoral Program.

Disclosure

The authors declare that they have no known competing financial interests or personal relationships.

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