Exosomes in Dermatology

Annabel Shen, BS¹; Fyona Okundia, MD²; Stephen K. Tyring, MD, PhD^1,2
1Department of Dermatology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
²Center for Clinical Studies, Houston, TX, USA

Conflicts of interest: Annabel Shen, Fyona Okundia, and Stephen Tyring declare that they have no conflict of interest.
Funding sources: This article has no funding source.

ABSTRACT
Exosomes are nanosized extracellular vesicles increasingly recognized as regulators of cutaneous biology with direct clinical relevance. In dermatology, they influence keratinocyte and fibroblast proliferation, pigmentation pathways, and immune modulation in disorders such as atopic dermatitis and cutaneous lupus. Their strongest evidence lies in wound healing, where exosomes accelerate closure by dampening proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, matrix metalloproteinase-9), enhancing angiogenesis through vascular endothelial growth factor signaling, and improving collagen deposition and scar quality. Early studies also support their role in regenerative skin care, including reversal of photoaging, improved elasticity, and stimulation of hair follicle growth. Although current use is limited to cosmetic applications without United States Food and Drug Administration (FDA) approval, international experience suggests therapeutic potential in chronic wounds, inflammatory dermatoses, and pigmentation disorders. For clinicians, exosomes represent a novel biologic platform that may soon complement established therapies, underscoring the importance of ongoing translational research and regulatory clarity.

Keywords: exosomes, extracellular vesicles, wound healing, pigmentation, melanocyte, regeneration

Introduction

Exosomes are small, single-membrane extracellular vesicles, typically 30-200 nm in diameter.¹ They are formed via budding from the plasma membrane and endosomal compartments, and they function to transport internal cargo such as lipids, proteins, nucleic acids, and glycoconjugates to recipient cells via receptor-mediated endocytosis.² Initially regarded as cellular waste products, exosomes are now recognized as bioactive messengers involved in regulating immune responses, tissue repair, angiogenesis, and inflammation across diverse organ systems.^3,4

The use of exosomes has been well characterized in certain medical specialties like neurology and oncology, however, the relevance of exosomes in dermatology remains comparatively underexplored. Accumulating evidence suggests that exosomes influence a wide array of cutaneous processes. These include stimulation of neoangiogenesis, reversal of fibroblast senescence and keratinocyte atrophy, modulation of oxidative stress, and promotion of extracellular matrix (ECM) synthesis.⁵ Skin-derived exosomes may contribute not only to local tissue homeostasis and repair but also to systemic signaling with implications for inflammatory dermatoses, chronic wounds, and photoaging.

Emerging studies have shown potential application in atopic dermatitis (AD), psoriasis, and cutaneous lupus, where exosomes may modulate immune driven inflammation.

Despite growing interest, the regulatory landscape surrounding exosome use remains nascent. In the United States, human-derived exosomes are currently permitted only for cosmetic use and lack FDA approval for therapeutic indications.⁶ In the United Kingdom and other regions, regulations restrict use to plant-derived exosome like nanoparticles (PELNs). While regulations in the United States and Europe are strict, countries like South Korea, Taiwan, and Brazil have adopted more moderate frameworks that support clinical development while still building regulatory infrastructure. The absence of standardized guidelines and approval pathways highlights the need for continued research and regulatory oversight.⁶

In this review, we explore the biology, functional roles, and clinical implications of exosomes in dermatology, emphasizing their potential benefit in inflammation, pigmentation, wound healing, and regenerative skin care. We also discuss emerging applications in aesthetic dermatology and barriers to clinical translation.

Exosomes in Inflammatory Skin Diseases

Emerging research highlights the role of exosomes in the pathogenesis of chronic inflammatory skin diseases such as psoriasis, AD, and systemic autoimmune conditions.

In psoriasis, keratinocyte-derived exosomes are enriched in pro-inflammatory microRNAs (e.g., miR-21, miR-203) that activate dendritic cells and T cells, amplifying interleukin (IL)-17 and tumor necrosis factor (TNF)-alpha–driven pathways.⁷ Another study also confirmed this finding with psoriasis serum-derived exosomes increasing pro-inflammatory cytokines and oxidative stress-related factors Nox2 and Nox4 expression. However, the same study also showed that exosomes from adipose-derived stem cells (ADSCs) reduced this inflammatory state.⁸

In AD, fibroblast-derived exosomes have shown promise in attenuating inflammation and restoring the skin barrier. One study determined a fibroblast-derived exosomal concentration of 1×10^4 particles/ml that increased proteins filaggrin (FLG), loricrin (LOR), involucrin (IVL), and hyaluronan synthase 1 (HAS1) that are usually reduced in AD, without harming the cells.⁹ ADSC-exosomes have also been shown to boost production of ceramides, reduce water loss, and lower levels of inflammatory molecules in AD.¹⁰ Clinical trials using mesenchymal stem cell–derived exosomes administered via subcutaneous or intravenous routes have demonstrated significant clinical improvement in AD without reported adverse events.¹¹

Exosome dysregulation has also been observed in systemic autoimmune diseases. In systemic lupus erythematosus (SLE), exosomal biomarkers such as NEAT1, GAS5, S100A4, BPI, ApoE, miR-124, and Hsa_circ_0000479 are being explored for diagnosis and prognosis, particularly in lupus nephritis.¹² In scleroderma, exosomes derived from diseased fibroblasts promote collagen I and fibronectin overproduction in healthy fibroblasts, contributing to fibrotic remodeling. Preclinical use of umbilical cord mesenchymal stem cells (UCMSC) exosomes has been shown to inhibit fibroblast proliferation and reduce skin ulcer severity in animal models.^13,14

Exosomes in Pigmentation and Melanocyte Biology

Skin pigmentation depends on finely tuned communication between melanocytes and keratinocytes. Ultraviolet (UV) radiation has been shown to trigger the release of keratinocyte exosomes and induce pigmentation.¹⁵ After UV radiation exposure, melanocyte-derived exosomes stimulate keratinocytes to engage in intercellular signaling. Melanocyte-derived exosomes contain enzymes critical for melanogenesis, such as tyrosinase and transient receptor potential channel 1 (TRP-1), as well as pigment-associated microRNAs that influence melanin production in recipient cells.¹⁶ Dysregulation of this exosomal signaling axis may contribute to various pigmentary conditions such as vitiligo.

Vitiligo is an autoimmune depigmenting disorder, and exosomes have been implicated in epidermal melanocyte destruction. Exosomes isolated from patients with vitiligo were found to impair melanogenesis and reduce the protein expression of enzymes such as tyrosinase, tyrosinase-related protein-2, and microphthalmia-associated transcription factor in melanogenesis.¹⁷ These effects are thought to be mediated by cytotoxic components within the exosomes such as anti-melanocyte antibodies or immunemodulating loss.

Conversely, exosomes also hold therapeutic potential in vitiligo. Specifically, they can serve as delivery vehicles for microRNAs that help regulate immune responses, oxidative stress, and the function of keratinocytes and melanocytes. Many of these microRNAs act on multiple pathways simultaneously, offering a multifaceted approach in melanocyte survival.^17,18

Exosomes in Wound Healing and Skin Regeneration

Exosomes are increasingly recognized as active contributors to skin regeneration. In wound healing, they participate in nearly all phases.

Immediately upon injury, immune cells such as neutrophils and macrophages will release inflammatory mediators; this is also known as the inflammation phase. In instances such as chronic wounds or patients with diabetes, this phase is exaggerated and prolonged. In the inflammation phase, exosomes inhibit the inflammatory signaling pathway by delivering regulatory microRNAs, such as miR-181c and miR146a, and proteins that inhibit nuclear factor-kB activation. This decreases the secretion of TNF-alpha and IL-6.¹⁹ At the same time, they also promote a shift in macrophage polarization from a proinflammatory M1 to a prohealing M2 phenotype.²⁰

In the proliferation phase, exosomes enhanced wound size reduction through endothelial cell and fibroblast activation, including factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), and miR-126 and miR-210.^21,22 Keratinocyte-derived exosomes further accelerate re-epithelialization by promoting keratinocyte migration and survival.²³

In the remodeling phase, exosomes promote favorable wound healing outcomes by altering the ratio of matrix metalloproteinases to tissue inhibitors of metalloproteinases. Mechanistically, this is through the delivery of miR-21 which activates the PI3K/AKT intracellular signaling pathway to enhance fibroblast survival and collagen synthesis. It also downregulates transforming growth factor (TGF)-βI to prevent fibrosis and scarring.²⁴

Beyond traditional wound healing, exosomes are also being investigated for their role in aesthetic skin rejuvenation. Preclinical and early clinical studies suggest that topical or injected exosome formulations improve skin texture, elasticity, hydration, and pigmentation.^27,28 In a randomized split-face study, adipose-derived stem cell exosomes (ADSC-exos) applied before microneedling led to greater reductions in wrinkles, pigmentation, and improved elasticity compared to controls.²⁹ Additional trials using placental MSC–derived exosomes (PMSC-exos) demonstrated improvements in vascularity, pore size, and skin tone with no adverse events.^15,30 Topical exosomes have also been shown to shorten recovery time following fractional laser procedures.³¹

In hair restoration, exosomes derived from dermal papilla cells (DPCs) show promise in reversing aging-associated alopecia.³² These vesicles activate Wnt/β-catenin signaling, a key pathway in hair follicle cycling and regeneration. Exosomes from various sources, including DPCs, ADSCs, and bone mesenchymal stem cells, are being explored for their ability to promote follicular growth and counteract miniaturization, with early studies supporting their use in androgenetic alopecia and age-related thinning.³²

Exosomes in Cutaneous Oncology

Exosomes are increasingly recognized as active participants in the development, progression, and immune modulation of skin cancers. By carrying oncogenic proteins, regulatory RNAs, and growth factors, tumor-derived exosomes influence not only the local tumor microenvironment but also distant tissues. Tumor-derived exosomes facilitate immune escape, angiogenesis, invasion, and treatment resistance.

In melanoma, exosomes play a central role in shaping the tumor’s aggressive behavior. They promote immune suppression and facilitate pre-metastatic niche formation by altering distant lymphatic and stromal environments.³³ Exosomes also mediate communication between tumor cells and fibroblasts, enhancing epithelial–mesenchymal transition and invasive potential.³⁴ Given melanoma’s high mortality rate and rising incidence, exosomes are being actively investigated as noninvasive biomarkers to support early detection, prognosis, and monitoring of treatment response. Circulating melanoma-derived exosomes, which retain the molecular signature of their parent cells, have been proposed as “liquid biopsies” with diagnostic and predictive potential.³³ While current findings are largely based on animal models and in vitro systems, efforts are underway to define melanoma-specific exosomal signatures in human studies.

In squamous cell carcinoma, exosomes derived from mutated keratinocytes have been linked to enhanced cellular proliferation, vascular remodeling, and transcriptional dysregulation. These vesicles appear to reinforce tumor expansion and may support immune evasion by discharging interleukin, TGF-beta, and VEGF.³⁵ Basal cell carcinoma has received comparatively less attention in exosome research but is presumed to involve similar vesicle-mediated modulation of local immune and stromal responses.

In mycosis fungoides, the most common form of cutaneous T-cell lymphoma, exosomes are being explored as potential diagnostic and prognostic tools. Notably, miRNAs such as miR-155 and miR- 1246 are overexpressed in patient-derived exosomes.³⁶ This suggests exosomes play a role in disease activity and have the potential to be a therapeutic target.

Current Limitations and Clinical Integration

Exosome based therapies, while promising, still face several significant challenges that hinder progress in clinical translation.

One major issue is the heterogeneity of exosomes. Lack of standardization protocols for isolation and purification make it difficult to isolate exosomes.³⁷ In addition, other components such as lipoproteins and chylomicrons from biological fluids have size overlap with exosomes, which further complicate the purification process.^38,39

Moreover, there is no standard method for dosing or treatment modality for exosomes. Exosomes inherently have a short half-life. Studies have shown that intravenously administered exosomes have a half-life of 2 hours in blood circulation.⁴⁰ With intravenous injection, the short half-life is due to exosomes rapidly being sequestered by macrophages in the liver, lungs, and spleen. For oral administration, although easy and convenient, is altered by intestinal microflora and enzymatic activity. Intranasal and inhalation administration has shown to be most effective.⁴¹ This mode of delivery avoids the intestinal and hepatic metabolism of exosomes and can also cross the blood-brain-barrier. However, intranasal administration is still dependent on breathing patterns and mucociliary clearance.⁴²

In addition, exosomes have a poor zeta potential. Zeta potential measures the stability of colloidal dispersion of a particle. A high zeta potential indicates a stable colloidal dispersion because the strong electrostatic repulsion between particles prevent aggregation between them. In contrast, a low zeta potential means that the particles are less stable and can aggregate easily.⁴³ Exosomes have poor zeta potential and will flocculate before delivery to the correct location. This varies under different pH, temperature, and buffer conditions.^43,44

In addition to the fundamental characteristic of exosomes, the absence of a true “control” exosomes in experimental studies makes it difficult to measure therapeutic efficacy. This is due to the lack of comparison with a molecule with a similar pharmacokinetic profile as exosomes.

From a clinical standpoint, exosomes are still considered biologics and require rigorous standardization protocols. Despite preliminary guidelines from the International Society for Extracellular Vesicles (ISEV), exosome-based therapies still have not been adopted into practice.^40,45 This could be due to several factors, one of which is conflicting views on the storage of exosomes. While -80°C is often cited for long-term storage, some studies suggest that 4°C may be optimal for short-term preservation.⁴⁶ However, many clinical facilities may not have reliable -80°C freezers, necessitating alternative storage strategies. In addition, fluctuations in temperature during transportation are another cause for concern.⁴⁷

Collectively, these issues underscore the need for standardization on isolation, purification, dosing, storage, and pharmacologic characterization of exosomes to ensure efficacy and safety of exosome-based therapies.³⁷

Conclusion

Exosomes are increasingly recognized as key players in skin health and disease, functioning as potent messengers between epidermal, dermal, and immune compartments. From regulating pigmentation to promoting wound healing and contributing to inflammatory and malignant processes, exosomes reflect the dynamic cellular environment of the skin.

For dermatologists, these vesicles represent a promising frontier as biomarkers of disease activity and potential therapeutic agents themselves. As research expands, integrating exosome-based diagnostics and interventions may reshape how we understand and manage a multitude of dermatologic conditions.