Exosomes: A Comprehensive Review for the Practicing Dermatologist

J Clin Aesthet Dermatol. 2025;18(4):33–40.

by Rami H. Mahmoud, BS; Erik Peterson, MD; Evangelos V. Badiavas, MD; Michael Kaminer, MD; and Ariel E. Eber, MD

Mr. Mahmoud, Drs. Peterson, Badiavas, and Eber are with the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery at the University of Miami Miller School of Medicine in Miami, Florida. Dr. Kaminer is with the Department of Dermatology at Yale School of Medicine in New Haven, Connecticut; the Department of Dermatology at The Warren Alpert Medical School of Brown University in Providence, Rhode Island; and Skincare Physicians in Chestnut Hill, Massachusetts.

FUNDING: No funding was provided for this article.

DISCLOSURES: The authors declare no conflicts of interest relevant to the content of this article.

ABSTRACT: This clinical review examines what is known about exosomes and their applicability to aesthetic dermatology. Exosomes are extracellular vesicles with crucial roles in intercellular communication. Their biogenesis is complex and not completely understood, but they are generally formed intracellularly in the endosomal compartment of a cell or through direct plasma membrane release. Several mechanisms of exosome uptake have been described and are dependent on the molecular characteristics of the recipient cell and exosome membrane. Furthermore, there are a multitude of exosome isolation and characterization techniques, each with their own potential advantages and disadvantages. Exosomes have demonstrated promise in preclinical models across various domains of aesthetic dermatology, including as anti-aging and anti-inflammatory therapies and as therapeutics for wound healing, scar reduction, and hair regeneration. However, clinical studies are lacking, and there are substantial safety concerns, such as the potential risk of infections, unwanted inflammatory response, and promotion of malignancy. Further research is needed to develop more precise analytical techniques to better understand the composition of exosomes, their safety profiles, and their potential applications to patient care.

Keywords: Exosomes, aesthetic dermatology, anti-aging, skin rejuvenation, wound healing, scar reduction, hair regeneration, cosmetic dermatology

Exosomes are a type of extracellular vesicle that play an important role in intercellular communication. Their effects are believed to be mediated through their cargo, which reflects the constituents of their cell of origin.¹ Exosomes are taken up by recipient cells where their contents may influence cellular function. They have been implicated to participate in the pathogenesis of several maladies, including cardiovascular disease, autoimmune/inflammatory disorders, neurological conditions, and in the promotion of various cancers.¹ Nevertheless, they also show promising therapeutic potential.¹ In dermatology, exosomes have shown activity in wound healing, scar remodeling, hair regeneration, and more.^2–6 Yet, research regarding safety, efficacy, and treatment regiments are lacking, as are standardization in purification and isolation techniques. As such, the current direct-to-consumer landscape of exosome therapeutics may place patients at undue risk. Therefore, further studies are warranted to help clarify the role of exosomes as therapeutics and promote patient safety.⁴ In this review, we explore what is known and what remains to be studied about exosomes and their applications to aesthetic dermatology. 

Exosome Characteristics, Biogenesis, and Composition

Molecular composition. Exosomes are nano-sized extracellular vesicles of endosomal origin with an average diameter of roughly 100nm, generally ranging from 40 to 160nm.^1,4 They have a plasma-membrane derived phospholipid bilayer structure and contain cytosolic components from their cell of origin.^1,4,7 Exosome cargo is varied and complex and is dependent on cell type and local environment.^4,7,8 Content spans from nucleic acid material to lipids, peptides, and proteins.^4,8 Nucleic acid content may include DNA, messenger RNAs, microRNAs, and circular and long noncoding RNAs.^1,4 Similarly, protein and lipid content is exceptionally diverse and may include enzymes (eg, ATPase, phosphoglycerate kinase 1, and glyceraldehyde 3 phosphate dehydrogenase), membrane transport proteins (annexins, GTPases), ligands and receptors, transcription factors, heat shock proteins (HSP70, HSP90), biogenesis-related proteins (tumor susceptibility gene 101 [TSG101], ALG-2 interacting protein X [ALIX]), transmembrane proteins (CD9, CD63, CD81, CD82), and MHC-1 and II.^1,4,9 Tetraspanins CD63 and CD81 are markers of the endosomal pathway and are particularly robust markers for exosome detection.^7,10 Other exosome markers include CD9, TSG101, ALIX, ceramide, and flotillin.^1,4

Formation and release mechanisms. While the formation of exosomes can vary among different cell types and due metabolic/microenvironmental conditions, they classically begin with the formation of early endosomes via endocytosis through the plasma membrane. These early endosomes undergo further invagination within the larger endosome to form smaller membrane bound structures called late sorting endosomes (LSEs). Through interactions with the endoplasmic reticulum, golgi and lysosomes, and likely other cellular processes, the LSEs modified into structures called intraluminal vesicles (ILVs). Through further processing, the ILVs give rise to multivesicular bodies (MVBs), which are membrane bound intracellular collections of what will become future exosomes.¹ MVBs may then fuse with lysosomes and go down the degradation pathway or follow the pathway for release.¹¹ Those destined for release are transported to the plasma membrane via cytoskeletal and microtubule networks, where they are docked by MVB docking proteins on the intracellular plasma membrane. Subsequently, exocytosis ensues, resulting in the release of exosomes.¹ 

Alternatively, exosome release may occur via an inducible pathway, via specific cell surface receptors and cell types, such as B and T lymphocytes, and/or initiated by cellular stress (ie, hypoxia, DNA damage, heat shock).^7,12 There is evidence to suggest that exosome release is facilitated by the Rab GTPase pathway and this delivery is regulated by calcium channels, cellular pH, and endosomal sorting complexes required for transport (ESCRTs).¹² The mechanisms of cargo sorting are also not well understood but may also involve ESCRTs and the syndecan-syntenin-ALIX pathway.^11,13,14

Role of exosome cargo in cell-to-cell communication (uptake mechanisms).Exosomes are key mediators of intercellular communication. This is carried out through a number of possible mechanisms, including soluble and juxtacrine signaling, exosome fusion, phagocytosis, receptor and raft-mediated endocytosis, and pinocytosis.^15–17 

Soluble and juxtacrine signaling. Soluble signaling is initiated by alternative splicing or proteolytic cleavage of exosome surface ligands, which releases soluble ligands that can then bind to receptors on target cells.^15,17 Signaling may also be evoked through a juxtacrine mechanism, whereby there is juxtaposition of the exosome and target cell ligands and receptors.¹⁵ Downstream signal transduction then produces a cellular response. 

Fusion. Fusion occurs when an exosome merges with the plasma membrane of a cell, leading to a direct release of contents intracellularly.^15,18 The mechanism of fusion is not fully understood but may be mediated by SNARE and Rab proteins.¹⁹ 

Phagocytosis. Cellular uptake of exosomes through phagocytosis is mediated by actin, phosphatidylinositol 3-kinase (PI3K), phospholipace C, and dynamin2.^15,18,19 Phagocytosis is a sequential process characterized by cell membrane deformation, encircling incoming material to form a phagosome that ultimately directs endocytosed cargo to lysosomes.¹⁹ This pathway of uptake is commonly observed in macrophages, dendritic cells, and other professional phagocytes.^15,19 

Clathrin- and caveolin-mediated endocytosis. Actin, PI3K, and dynamin2 also have importance in clathrin-mediated endocytosis, a stepwise endocytic pathway beginning with the formation of cell membrane clathrin-coated vesicles, containing an assembly of transmembrane receptors and ligands. These vesicles internalize the recipient exosomes where they are uncoated and fused with endosomes for processing and transport.^15,18,19 Endocytosis may similarly occur through a caveolin-mediated mechanism, although this is not as well described.¹⁹ Similar to clathrin-mediated endocytosis, this pathway begins with the protein facilitated vesicle formation at the recipient cell membrane and involves dynamin2 as a key mediator. Here, caveolin, an integral membrane protein, is recruited and creates a cell membrane invagination, supporting the uptake and internalization of extracellular substances.¹⁹ Caveolin-1 in particular has a positive impact on exosome uptake in epithelial cells.¹⁹ 

Lipid raft-mediated endocytosis. Lipid rafts are microdomains in the plasma membrane that are enriched with sphingolipids and cholesterol.^18,19 These domains help organize clathrin- and caveolin-mediated endocytosis and also support an independent internalization process via flotillin proteins.^18,19 Notably, lipid rafts have been associated with viral particle uptake.¹⁹

Pinocytosis. Macropinocytosis is another means of exosome uptake. This process is driven by actin lamellipodia or ruffled plasma membrane extensions, which internalize extracellular materials as they fuse back to the cell membrane, creating macropinosomes.^18,19 This pathway is cholesterol-dependent and is mediated by rac1 GTPase, actin and Na+/H+ exchangers.^18,19 The macropinosome is subsequently internalized and fuses with a lysosome for recycling or degradation.¹⁹ Micropinocytosis has also been reported but with limited data.¹⁹ Ultimately, these various uptake mechanisms add complexity to our understanding of exosomal communication.

Key points

• Exosomes are nano-sized extracellular vesicles that carry a diverse cargo, including proteins, lipids, and genetic material.
• Exosomes have a complex biogenesis that is not completely understood, but they are generally formed in the endosomal compartment of the cell or via direct plasma membrane release.
• Exosomes mediate intercellular communication via a number of characterized uptake mechanisms, including soluble and juxtacrine signaling, fusion, phagocytosis, receptor- and raft-mediated endocytosis, and pinocytosis.

Isolation and Characterization of Exosomes

Isolation techniques. The isolation of exosomes is challenging. A variety of techniques exist, each with unique considerations. Some of the more common techniques include differential ultracentrifugation, ultrafiltration, immunoaffinity capture, precipitation, and size exclusion chromatography.^6,20–22 Blood, urine, and other bodily fluids are typically used for diagnostic approaches whereas cell culture medium or fluids from cell suspensions are more common sources for product development.²⁰

Differential ultracentrifugation. Differential ultracentrifugation is often considered the gold standard isolation technique. This process involves sequential separation based on size and density. It is widely used and results in a relatively high exosome purity.²⁰ Despite its many attributes, there are several potential pitfalls. Ultracentrifugation is time consuming, limited by expensive instrumentation, can be subject to contamination with lipoproteins, and may result in damage to exosomes.^20,21

Tangential flow filtration. Tangential flow filtration (TFF) is an isolation technique that leverages parallel flow dynamics to reduce clogging potential. In this technique, particles are moved parallel across a membrane surface.²⁰ This is in contrast to dead-end filtration techniques where fluid flows perpendicularly to the filter membrane.²⁰ TFF may be relatively more cost and time effective than ultracentrifugation and surpasses ultracentrifugation in its potential to isolate greater yields of small extracellular vesicles.^20,23 

Ultrafiltration. Ultrafiltration is often used with other techniques and involves consecutive stages of size-based fluid filtration, allowing for the gradual removal of sample particles.²² It is simple, highly efficient, and relatively inexpensive, but is limited by lower exosome purity, especially when used alone.²⁰

Immunoaffinity capture. Immunoaffinity capture (IA) utilizes antibodies that correspond to exosome surface proteins for separation.^6,21 Exosome surface markers, CD9, CD63, and CD81, are commonly targeted.²¹ This technique produces relatively high purity samples and may be used to isolate exosome subpopulations.²⁰ IA can also be integrated with other detection systems for further optimization of purity.²⁰ Despite its utility, it is limited by cost, intermolecular cross reactions, and nanoscale contaminants.²⁰

Precipitation. Precipitation techniques capitalize on altering solubility to settle out exosomes.⁶ This is carried out with the use of a polymer medium, often poly-ethylene glycol.^21,24 Precipitation is a widely used method that is relatively inexpensive and high yield; however, yield purity is often a concern due to concomitant isolation of lipoproteins and other non-exosome particles.²⁰ Furthermore, polymer mediums may influence sample analysis.²⁰

Size exclusion chromatography. Size exclusion chromatography involves a mobile and stationary phase.^21,24 The stationary phase consists of a porous polymer gel, which allows for differential elution of particles, starting with larger material.^21,24 This method is regarded as simple and cost- and time-effective, with relatively high purity results.²⁰ Its use is limited by the need for specialized instruments and nanoscale contaminants.²⁰

Electrospun nanofiber method. The electrospun nanofiber method is an innovative isolation technique that utilizes co-axial core shell nanofibers to capture exosomes.^25,26 These nanofibers are often produced by combining natural and synthetic polymers.²⁵ In a study by Barati et al,²⁶ nanofibers were created utilizing a polycaprolactone core and a thin thermo-sensitive gelatin shell with immobilized anti-CD63 antibodies to capture exosomes. The gelatin layer could be dissolved at a physiologic temperature of 37°C to release the exosomes with minimal contamination. Here, it was shown that over 87 percent of the exosomes in the culture medium could be effectively isolated with this technique.²⁶ This introduces a novel and potentially more efficient and cost-effective isolation approach.

Methods of exosome characterization and analysis. After isolation, exosome samples may be analyzed in several ways to ensure desired outcomes. This may be done through the quantitative and qualitative characterization of proteins, lipids, DNA, and RNA. 

Total exosome count. Total exosome count may be carried out through a number of techniques, including nanoparticle tracking analysis (NTA) and fluorescence correlation spectroscopy (FCS), which are the most commonly used, as well as flow cytometry, dynamic light scattering, resistive pulse sensing, and electron microscopy.^27,28 NTA is based on the detection of the light scatter and Brownian motion of particles.²⁸ This information allows for an estimation of both the number and volume of exosomes in a sample.²⁸ NTA is rapid and requires minimal preparation; however, it relies on a high sample purity.²⁷ FCS similarly takes advantage of Brownian motion.²⁷ A laser is utilized to illuminate a small section of a sample labeled with fluorescent markers, and an estimate of the number and volume of exosomes is computed by analyzing the fluctuating fluorescence intensity of the molecules.^27,28 Dynamic light scattering also takes advantage of fluctuating light intensity, but via light scattering.²⁸ This method is sometimes preferred for its rapid application and high sensitivity; however, samples that are polydisperse or contain heterogenous exosome populations cannot be effectively analyzed.^27,28 Flow cytometry and resistive pulse testing allow for direct quantification.²⁸ In flow cytometry, exosomes are typically attached to labeled beads and detected by their interaction with a laser beam as they flow through a detection cell, whereas, in resistive pulse testing, exosomes are quantified by their passage through a membrane pore.²⁸ Both methods are limited by insensitivity to smaller exosomes.^27,28 Electron microscopy may also be used, but is slower and more labor intensive as it requires manual counting.²⁸

DNA and RNA. DNA and RNA detection used in conjunction with exosome count provide an indicator of exosome purity. These methods are predominantly carried out with PCR, microarray, and next generation sequencing (NGS). Of these techniques, PCR is considered the gold standard due to its high sensitivity and accuracy.²⁷ Digital droplet PCR is a recent development with particularly impressive sensitivity.²⁷ This technique involves encapsulation of sample DNA into droplets that are then analyzed with Poisson statistics.²⁷ PCR does however have limitations in multiplexing capabilities.²⁷ NGS, on the other hand, employs a multiplexed analysis and is effective with small sample inputs.²⁷ This technique is time consuming and is limited by an intrinsic error rate.²⁷ Microarray allows for the analysis of thousands of genes but is biased towards longer sequences, which can affect quantification results.²⁷ It is important to note that exosome genetic material is reflective of the parent cell, so exosomes originating from a virus infected cell will reflect this by containing the corresponding viral RNA.²⁷ This is similarly detectable in micro-RNA profiles of exosomes originating from malignant cells.²⁷

Protein. Protein content is also frequently utilized to determine sample purity. This is often done with a ratio of total protein mass to exosome particle count.²⁷ The most commonly used methods are mass spectrometry and ELISA. Mass spectrometry detects molecules based on ion mass to charge ratios and may be used with proteomics or bioinformatics to allow characterization of exosome proteins.²⁷ This technique has high technical requirements and is not easily accessible.²⁷ ELISA applies immunolabeling and antibody recognition to detect peptides and proteins.²⁷ ELISA is cost-effective and may be used for quantification and exosome profiling via antigen detection but is not as suitable as mass spectrometry for protein analysis of complex samples.²⁷ Western blotting, stimulated emission depletion (STED) microscopy, and surface plasmon resonance microscopy (SPRM) are frequently used qualitative methodologies.²⁷ STED microscopy utilizes two specialized lasers to provide super resolution identification of protein markers through antibody recognition, and SPRM takes advantage of polarized light to allow real-time detection of exosome membrane proteins.²⁷ The challenges with these techniques include limited antibody availability and dependence on the biophysical properties of the sample for accurate analysis, respectively.²⁷ 

Lipids. Exosome membrane composition is another means of vesicle characterization. This is most effectively performed via lipid analyses, which include sulfophosphovanilin (SPV) assays, fluorescence microscopy using lipophilic dyes, fourier-transform infrared microscopy (FT-IR), and mass and raman spectroscopy.²⁷ SPV assays capitalize on the reaction of phosphovanillin, carbonium ions, and sulfuric acid to produce a colored compound that may be used for lipid quantification.²⁷ This is a low cost technique, but it is not suitable for samples containing less than 50μg/mL lipid.^27,29 Fluorescence microscopy similarly uses lipophilic dyes to label lipids and compare to reference standards.²⁷ Photobleaching and calibration requirements are limiting factors for this technique.²⁷ FT-IR is a specialized microscopy technique that is advantageous for its low cost, high accuracy, and rapid reproducibility; however, it lacks sensitivity for sterols such as cholesterol.²⁷ Mass and raman spectroscopy are high specificity qualitative techniques that do not require molecular labeling.²⁷ Similar to its implementation for protein analysis, mass spectroscopy may be used to identify and differentiate between lipids.²⁷ Raman spectroscopy employs a high intensity laser to produce photon scattering and measure molecular vibrations and rotation. This technique helps distinguish non-protein membrane markers.²⁷ Both methods require high sample purity.²⁷

Although numerous methodologies exist for exosome characterization, there is no one perfect technique and often, multiple approaches must be utilized for maximal accuracy. These limitations pose a challenge for the clinical use of exosomes, as bioactive compounds may go unidentified.

Key points

• Exosomes are commonly isolated from blood, urine, and cell culture medium via a number of common techniques, which include gold standard differential ultracentrifugation as well as ultrafiltration, immunoaffinity capture, precipitation, and size exclusion chromatography.
• Several quantitative and qualitative analytical techniques may be employed to assess the characteristics and purity of isolated exosome samples.
• Exosome isolation and analytical methodologies have their own significant limitations, which may cause bioactive compounds to go unidentified, and ultimately calls for a signal of caution for their use in patient care.

Roles of Exosomes in Cutaneous Physiology and Rejuvenation

Cutaneous functions of exosomes. As previously discussed, exosomes are essential mediators of intercellular communication. They play a key physiological role in cutaneous functions. The downstream effects of these exchanges are vast and varied, depending on the source of exosome origin and the recipient cells as well as the surrounding microenvironment. 

Epidermal progenitor stem cells (EPSCs) form the basis of a functional epidermis.³⁰ Exosomes derived from EPSCs are involved in cross-talk that facilitates this functionality. This is demonstrated in the restoration of skin appendages, nerves, and vessels as well as collagen reorganization when such exosomes are utilized in defective skin.^31,32 Furthermore, microRNAs contained within EPSC-derived exosomes have shown an ability to reduce TGF-β1 expression in dermal fibroblasts and facilitate wound healing with reduced scar formation.^31,33 The same idea is reflected in dermal papilla stem cell derived exosomes, which have been shown to promote hair follicle stem cell differentiation.^31,34 They also affect the hair cycle, inducing anagen and delaying catagen, thereby promoting hair growth.^31,35 

Keratinocyte-derived exosomes have roles in a wide range of cutaneous functions. Their immunomodulatory activity includes the induction of superantigen-induced proliferation of resting T cells. This mechanism is believed to be carried out via exosome MHC I and II molecules that could interact with T cells.^31,36 Furthermore, a study evaluating keratinocyte exosomes in psoriasis suggests a role in neutrophil activation and enhanced autoinflammation.^31,37 A role in stimulating non-specific immune responses has also been demonstrated.^31,38 Further, keratinocyte-derived exosomes have a substantial effect on fibroblasts.^39–43 They have been shown to upregulate the fibroblast gene FGF-2 in a dose-dependent fashion as well as to stimulate fibroblast function, migration, proliferation, and differentiation to myofibroblasts.^39–42 Cross-talk between keratinocyte-derived exosomes and melanocytes and macrophages contribute to enhanced melanogenesis and wound healing, respectively.³¹ Fibroblast-derived exosomes similarly facilitate wound healing and also have roles in paracrine signaling in skin aging.^31,44,45

A study by Shao et al⁴⁶ on neutrophil-derived exosomes demonstrated enhancement of cutaneous autoinflammation in general pustular psoriasis and an analysis of exosomes in human sweat by Wu et al⁴⁷ supports the physiological importance of exosomes in immune homeostasis.³¹ Other immune cell derived exosomes also have distinct and substantial demonstrated effects on the immune system.⁴⁸ Much research remains to be done on the physiological roles of exosomes in the skin; however, the current literature supports their physiological significance. 

Key points

• Exosomes have diverse and integral roles in cutaneous homeostasis that are dependent on their origin and recipient cells as well as the surrounding microenvironment.
• The roles of exosomes in the skin include regenerative, immunomodulatory, and protective functions.

Exosomes as Therapeutic Agents in Aesthetic Dermatology

There is emerging evidence for the utility of exosomes in aesthetics, particularly for anti-aging, reducing inflammation, cutaneous repair, and hair regeneration. While most exosome harvesting techniques focus on mammalian sources, a range of potential sources exist.⁴⁹ These can be broadly categorized into human and mammalian sources, as well as non-human and non-mammalian sources, including animals, plants, bacteria, fungi, and parasites.⁴⁹ The potential benefits of these exosomes may be related to the specific functions they serve in their original hosts.⁴⁹ For example, exosomes isolated from bee glandular secretions demonstrate anti-bacterial and biofilm-inhibiting effects.⁴⁹ Nevertheless, there is currently insufficient data to confidently determine which sources are most effective for aesthetic outcomes.

Anti-aging therapy. Skin aging is in large part the result of the effects of ultraviolet (UV) radiation over time and the subsequent production of reactive oxygen species (ROS), which induce DNA damage, the upregulation of matrix metalloproteinases (MMP), cellular senescence, the breakdown of collagen, and inflammation.⁵⁰ These molecular changes culminate into the appearance of aged skin by way of wrinkles, pigmentary changes, and overall structural alterations to the skin.⁵⁰ Exosomes have shown the potential to reverse many of these changes.

A study analyzing exosomes derived from human umbilical cord mesenchymal stem cells demonstrated a protective effect on skin cells against UV-induced damage via decreased inflammation and oxidative stress.⁵⁰ This finding is echoed in multiple studies using exosomes from adipose tissue-derived stem cells (ADSC).^51,52,53 In addition to ROS downregulation, ADSC-derived exosomes may also regulate Nrf2 and MAPK pathways, ultimately reducing MMPs, which yields a protective effect on the extracellular matrix (ECM).⁵⁰ Enhanced ECM integrity is also demonstrated through other signaling pathways such as PI3K/Akt.⁵⁴ Furthermore, ADSC-derived exosomes support pro-collagen production I secretion through the activation of TGF-B/Smad pathways.⁵⁰ Mir-1246 is a micro-RNA that is highly prevalent in ADSC-derived exosomes, and in a study on mice, has been shown to combat photoaging by reducing epidermal thickening, collagen fiber loss, and wrinkles.⁵⁰ Another micro-RNA, miR-29b-3p, can be found in bone marrow mesenchymal stem cell (BM-MSC) derived exosomes, and is similarly shown to reduce collagen degradation. MiR-29b-3p also supports fibroblast migration and the reduction of oxidative stress and apoptosis.^50,55 ADSC, BMSC, and induced pluripotent stem cell derived exosomes were shown to reduce MMPs and promote collagen and elastin production, a common effect across exosome populations.^50,56,57 Further investigations are needed to better elucidate these mechanisms of anti-aging. 

Anti-inflammatory treatment. The anti-inflammatory effects of exosomes include the reduced ROS activity discussed. Other anti-inflammatory mechanisms include effects on cytokine expression and epidermal barrier function.^58,59 A study investigating the effects ADSC derived exosomes on AD in Nc/Nga mice, an AD mouse model, found a substantial anti-inflammatory effect.⁵⁸ Specifically, there were improvements in clinical skin severity scores, serum IgE and eosinophil counts, mast cell infiltration, and CD86 and CD206 expression, two markers of inflammatory dendritic epidermal cells.⁵⁸ Moreover, there were statistically significant reductions in the inflammatory cytokines interleukin (IL)-4, IL-23, IL-31, and tumor necrosis factor-a (TNF-a) in lesional skin.⁵⁸ This finding is corroborated in another study utilizing an oxazolone-induced mouse dermatitis model that was treated with subcutaneous injections of ADSC derived exosomes.⁵⁹ The investigators found a dose-dependent and marked decrease in IL-4, IL-5, IL-13, IL-17, TNF-a, and interferon gamma.⁵⁹ There was also a reduction in transepidermal water loss, enhanced stratum corneum hydration, and increased production of ceramides and dihydroceramides. Moreover, electron microscopy showed an enhancement of epidermal lamellar bodies, accompanied by the development of a lamellar layer between the stratum corneum and granulosum.⁵⁹ Deep RNA sequencing of treated lesions supported these findings, demonstrating restored expression of genes related to skin barrier function, lipid metabolism, inflammatory response, and the cell cycle.⁵⁹ One study evaluated exosomes derived from Lactobacillus plantarum, a probiotic that has a role in healthy mucosal immunity and skin barrier function.⁶⁰ The investigators studied the effect of Lactobacillus plantarum-derived exosomes (LEVs) on macrophage polarization and other markers of cutaneous immunity.⁶⁰ LEVs induced in-vitro differentiation of monocytic cells to an anti-inflammatory M2 macrophage phenotype in a human leukemia monocytic cell line.⁶⁰ Furthermore, under conditions favoring inflammatory M1 macrophages, LEVs inhibited HLA-DRa expression, an M1 macrophage surface marker.⁶⁰ Taken together, these studies suggest that exosomes have notable anti-inflammatory characteristics, but further studies are needed to determine how this would translate to patient care. 

Cutaneous repair. Optimized cutaneous repair is essential for optimal aesthetic outcomes. Numerous studies support the ability of exosomes to facilitate this process beyond regulating inflammation.

Multiple pathways are implicated for exosome induced wound healing. In HaCat skin lesion models, ADSC-derived exosomes induced cellular proliferation and migration and inhibited apoptosis, likely through the activation of Wnt/B-catenin signaling.^61,62 In two mouse models evaluating the utility of ADSC-derived exosomes for full-thickness wounds, the PI3K/Akt pathway was implicated in accelerating the wound healing process.^63,64,65 Exosomes similarly enhanced collagen deposition and fibroblast and HaCat cellular migration and proliferation through this pathway, facilitating skin repair with attenuated scar formation.^63,64 This migration is enhanced by fibroblast secretion of keratinocyte-derived growth factors, which stimulates keratinocytes to undergo a partial epithelial mesenchymal transition, promoting proliferation and migration towards the wound center.⁶⁶ Studies on diabetic wounds demonstrate enhanced healing via Nrf2-mediated angiogenesis, reduced oxidative stress related proteins, and increased wound growth factors as well as SIRT1 upregulation, which regulates inflammation and cellular migration in the epidermis.^67,68 A systematic review evaluating the role of exosomes in wound healing in 32 mouse model studies found that 81 percent reported significant improvements in wound closure rates and 50 percent had significantly increased vascularity. This finding was similarly demonstrated in nine rat models. There were also notable increases in collagen deposition and wound bed viability as well as decreased fibrogenesis and flap necrosis.⁶⁹ Although exosome cargo varied, micro-RNAs were likely responsible for much of the therapeutic effects observed.⁶⁹ Remarkably, exosomes improved all phases of wound healing, including inflammation, proliferation, and remodeling.⁶⁹ Moreover, another more comprehensive systematic review analyzing 148 papers on exosomes for wound healing, predominantly in rodent models, found improved reepithelization, angiogenesis, collagen deposition, and reductions in scar formation.⁷⁰ 

Exosomes also have a demonstrated ability to enhance angiogenesis and thus optimize healing. Exosomes may stimulate endothelial cell migration, and angiogenic factors such as angiopoietin-2 and endothelin have been identified in exosome cargo.^71,72 Multiple pathways are implicated in exosome-induced angiogenesis. Exosome activation of Nrf2 has been shown to contribute to increased angiogenesis in diabetic wounds in rats and improve endothelial senescence.^67,73 MicroRNAs and proteins like DMBT1 protein, miR-21, miR-31, and miR-125a have also been demonstrated to have a role in optimizing angiogenesis.⁶⁶ Other implicated mechanisms include the PI3K/AKT, AKT/eNOS, and Wnt4/B-catenin signaling pathways.⁶⁶ Enhanced angiogenesis is similarly demonstrated in studies evaluating exosomes for flap repair.^74,75,76

Exosome therapy has been shown to reduce scar formation in various models. The mechanism of action by which this is achieved is multifaceted. One study found that ADSC-derived exosomes significantly reduced scar formation in mouse models via reconstruction of the extracellular matrix. This is achieved through regulation of dermal fibroblast differentiation, promoting reduced fibrotic phenotypes, increased TGF-B3, an antifibrotic, and regulation of type III collagen/type I collagen and MMP-3/tissue inhibitor of metalloproteinases-1 ratios.^69,77 Another study also demonstrates ADSC exosomes optimizing fibroblast characteristics for wound healing, with increased type I and III collagen secretion in early stages of healing and reduced secretion in later healing stages, thus reducing scar formation.⁷⁸ Moreover, exosome microRNAs may prevent myofibroblast differentiation through reduced TGF-B1 expression, allowing for more orderly healing.³² Ultimately, exosomes enhance the wound environment to promote an accelerated and organized healing process.

Hair regeneration. Exosome therapy also supported hair growth in several in-vitro and mouse models and in a clinical study by Gupta et al.⁷⁹ In this retrospective study, 39 patients (27 men, 12 women) with androgenetic alopecia were treated with ADSC-derived exosomes once weekly for 12 weeks.⁸⁰ The results showed statistically significant improvements in hair thickness and density compared to pretreatment, and there were no reported adverse reactions aside from the discomfort of needling during treatments.⁸⁰ The study was limited by the lack of controls and inability to exclude spontaneous hair regrowth.^80,79 Similarly, a study evaluating extracellular vesicle treatment in 22 female and nine male patients with early stage alopecia or in remission from previous treatments showed that 64.5 percent of patients had increased hair growth. However, given that the treatment consisted of a mixture of extracellular vesicles and was delivered in varying dosage schemes, these results cannot solely be attributed to the exosome component.^79,81 Proposed mechanisms of enhanced hair regeneration include paracrine regulation of dermal papilla cells, accelerated telogen to anagen transition via B-catenin pathway activation and increased fibroblast growth factor, and microRNA hair cycle regulation.⁷⁹ Further research is needed to characterize the role of exosomes in hair regeneration. There is currently an ongoing, open label, single-arm study looking at the effects of placental mesenchymal cell-derived exosomes in patients with alopecia (NCT05658094).⁷⁹

Key points

• In preclinical models, exosomes show an anti-aging effect by reducing inflammation, oxidative stress, and MMPs and promoting elastin and collagen production.
• Exosomes have multimodal anti-inflammatory effects via reduction of inflammatory cells and cytokines, enhanced skin barrier function, and the modulation of gene expression in favor of a regulated inflammatory response.
• Exosomes promote accelerated and enhanced wound healing through improved reepithelization, angiogenesis, collagen deposition, and fibroblast characteristics that optimize for repair.
• Exosomes may also promote hair growth via paracrine regulation of dermal papilla cells, accelerated telogen to anagen transition via B-catenin pathway activation and increased fibroblast growth factor, and microRNA hair cycle regulation. 

Safety and regulatory considerations 

Exosomes show great therapeutic potential, but a number of safety and regulatory considerations limit their use. Since exosome therapy is cell-free, it is often marketed as a safer alternative to stem cell treatments.⁷⁹ However, the limitations in current isolation and profiling techniques make it difficult to assess exosome contents and compare products.⁷⁹ This poses significant safety concerns as it is difficult to determine precisely what patients are receiving. Improperly prepared exosomes can carry viral proteins and microbes such as mycoplasma that may cause infection as well as other cellular contents that may trigger immune reactions.^79,82,83 There are currently no approved exosome products by the United States Food and Drug Administration and alerts have been issued against their use.⁷⁹ These risks may be minimized with special care in the manufacturing process with appropriate oversight. While efforts have been made to standardize research protocols, there remains a lack of standardized manufacturing procedures.⁷⁹ Additionally, more data and carefully conducted clinical studies are needed to establish standards for dosing and administration.

Key points

• Exosomes are often marketed as safe, well-understood, cell-free therapies; however, the limitations in their isolation and profiling techniques pose significant safety concerns, and there are currently no approved exosome products by the United States Food and Drug Administration.
• Infective or immunoreactive exosome cargo may go unidentified and lead to patient harm.

Conclusion

Exosome biogenesis is complex, which is reflected in the diversity of exosome cargo and the diversity of potential downstream effects. Their role in intercellular communication is paramount to proper physiological functions. A number of isolation and characterization techniques exist, each with their own advantages and disadvantages. Techniques are often combined to optimize for specificity and purity; nevertheless, there is no perfect method and significant concerns exist regarding inadvertent patient exposure to exosome pathogens and immunogenic compounds. There is growing evidence in support of the use of exosomes in aesthetic dermatology, although much of the existing research is based in preclinical models. Further investigations focused on safety are needed, both to protect patients and enable greater confidence in clinical research. Additionally, future research is needed to refine existing isolation and characterization techniques to optimize for safety and efficacy.

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