Exosomes are nanosized extracellular vesicles, approximately 30–150 nm in size,1–4 derived from the endosomal pathway and secreted by several cell types, including stem cells, keratinocytes, fibroblasts, human and animal immune cells, and also by plant cells.5 They consist of a lipid bilayer replete with encapsulated surface proteins, isolating a biologically active cargo, including proteins, DNA, messenger RNA, microRNA (miRNA), transcription factors, membrane trafficking proteins, antigen-presenting proteins, other peptides, metabolites, and lipids.3,4

They were first reported in 1983 by Johnstone et al. and initially called “cellular garbage carriers”.3,6 In the 1990s, it was discovered that exosomes play a vital role in intercellular communication and immune function, as they express characteristics of the cell of origin, acting as paracrine molecules that interact with the extracellular matrix (ECM) and adjacent cells.3

Exosomes obtained from the same cell type can be highly variable based on the characteristics of the cell and its microenvironment, with different sizes, contents and functions in target or recipient cells.4,7 Given their differences, exosomes are very heterogeneous in structure and function.4 Thus, their effects on recipient cells depend on their content and the different receptors on the cell surface.1

In recent years, exosomes have emerged as a promising treatment for the delivery of nucleic acid-based therapeutics due to their inherent biocompatibility, ability to cross physiological barriers and low immunogenicity. Because they are naturally generated by cells in the human body, they are believed to result in reduced inflammatory responses.5 Moreover, as an alternative to the use of regenerative cell therapy (the use of living cells, such as stem cells, to repair or replace damaged tissues), exosomes would theoretically have several advantages, including stability, low toxicity, biocompatibility, and reduced immune rejection and risk of tumorigenesis, as their use does not involve living cells.8

This review aims to independently address the recent great interest in the use of exosomes in Dermatology, based on the most recent published articles and research, providing a comprehensive summary of their real role in the healing process, scar treatment, skin rejuvenation, hair regeneration, skin neoplasms, inflammatory diseases, autoimmune diseases, acne, melasma, and other hyperpigmentation disorders, as well as discussing biosafety, regulatory issues, products available in the Brazilian market, irregular use, and future prospects. It is expected, therefore, to provide a greater understanding of the action mechanisms and possible current and future clinical applications of exosomes in Dermatology.

Studies show that exosomes can be obtained from cells, tissues, or body fluids of almost all mammalian species. These sources include stem cells, cancer cells, immune cells, hair follicle stem cells (HFSCs), and human dermal fibroblasts (HDFs); saliva, blood, urine8 and platelets are also considered sources for exosome isolation.1 They demonstrate molecular transport capacity with biocompatibility, making them promising agents for intercellular and interspecies communication.6 Mesenchymal stem cells (MSCs) are pluripotent stem cells that originate from adult stem cells and have the capacity for self-renewal and self-repair, as well as the ability to differentiate into multiple functional cells under certain conditions.4 MSCs can be obtained from several sources, including adipose tissue derived stem cells (ADSCs), placental mesenchymal stromal cells (PMSCs), umbilical cord mesenchymal stem cells (UCMSCs), and bone marrow stem cells (BMSCs). Exosomes obtained from these cells are called ADSC-exos, PMSC-exos, UCMSC-exos, and BMSC-exos.8

Plant-derived exosomes are called plant-derived exosome-like nanoparticles (PELNs) and represent an attractive alternative due to their theoretical biosafety. PELNs have been reported to have regenerative, anti-inflammatory, and low immunogenic properties.3 In a recent literature review, PELNs were evaluated as promising substitutes for human exosomes due to their similarity in structure and function and were described as potential therapeutic agents for diseases of the digestive, respiratory, neurological, vascular, genitourinary, endocrine, and musculoskeletal systems. Their origin includes several sources, such as flowers, ginger, grapes, broccoli, asparagus, curcuma, lemon, grapefruit, garlic, soybeans, mushrooms, tomatoes, pears, and strawberries.6,9

Some in vitro and animal studies have also evaluated the effects of exosome-like nanovesicles from Phellinus linteus, a medicinal fungus known for its antitumor and anti-inflammatory properties, and Lactobacillus plantarum, a bacterium capable of performing lactic fermentation.5,10 Other exosomes derived from bacteria found in the human intestinal microbiota have also been reported.11

The potential theoretical benefits of using exosomes in clinical practice also depend on the standardization of isolation methods. Techniques derived from ultracentrifugation are currently considered the reference method. However, other methods have been developed and include isolation by ultrafiltration, immunoaffinity and precipitation. The difficulty of these techniques lies in the exclusive isolation of exosomes, without the presence of other ECM components. The combination of techniques is described to ensure the isolation of pure exosomes in the sample; however, it increases costs and the need for more advanced technical training.4

After isolation, due to the variation in the final yield of exosomes, an analysis is necessary to characterize their purity and concentration. Electron microscopy provides morphological information, allowing the observation of structures bound to the exosome membrane. Techniques such as dynamic light scattering and nanoparticle tracking measure their size variation and concentration. Immunological methods, including flow cytometry and western blot, use specific markers to detect exosomes, which commonly express tetraspanins (CD9, CD63, CD81) and heat shock proteins (HSP70, HSP90). Mass spectrometry allows the identification and quantification of their molecular components, such as proteins, nucleic acids and lipids, and the quantitative reverse transcription polymerase chain reaction confirms and quantifies the RNA of exosomes.4,5,8

Given the ability of exosomes to mediate cellular communication and the potential therapeutic applications based on their composition, researchers have begun to explore their role in Medicine, as part of a still unrecognized area called regenerative Medicine.5 The source from which exosomes are isolated is of critical importance regarding their functions and, therefore, clinical use.

Studies in the last decade have discovered functions of exosomes in cell survival, proliferation, migration, differentiation and senescence, immunomodulation, angiogenesis, and wound healing, as well as potential biomarkers of neoplastic and autoimmune diseases.11

They have recently begun to be explored for use in Dermatology due to their positive effects on healing in in vitro studies and in murine models, through the promotion of cell migration, ECM reconstruction, and angiogenesis.4 In the context of skin diseases, the discovery that exosomes modulate communication between skin cells and their microenvironment is believed to possibly explain the complex pathogenesis of chronic inflammatory and autoimmune dermatoses and, therefore, research has targeted them as promising for diagnosis and treatment.12

In cosmiatry, several studies investigate exosomes for aesthetic purposes and cell regeneration, but most studies are still in the preclinical phase. Despite the plethora of studies developed in the last decade, few researchers have published promising preclinical results, with studies in humans.4 Therefore, more well-designed clinical studies, mainly randomized ones, controlled with a vehicle group, are still required to justify, with efficacy and safety, the use of exosomes and their variations.

Healing is a complex process that comprises distinct and overlapping phases.13 It is known that the presence of inflammation is crucial for skin regeneration. However, persistent inflammation is not beneficial, and the degree of inflammation has a significant impact on the entire process. The onset and disappearance of the inflammatory reaction are key to determining the quality and timing of the formation of regenerated tissue or scar. Studies show that, during the healing of skin wounds, stem cells have the ability to reduce inflammation, accelerate the proliferation phase, and help in tissue remodeling, acting through paracrine mechanisms, and releasing growth factors and exosomes.8

In recent years, exosomes have emerged as a promising treatment to improve wound healing due to their unique characteristics. Their diverse composition theoretically allows the regulation of multiple cell processes involved in wound healing, including inflammation, angiogenesis, cell proliferation, and ECM remodeling.5

The effects of skin aging are one of the most common reasons for dermatological consultation. Internal and external factors contribute to skin aging, including ultraviolet radiation (UVR), pollution, and smoking. Photodamage, in particular, produces changes in the ECM, including a decrease in collagen and elastic fibers, leading to the clinical appearance of wrinkles and changes in skin firmness and texture. Due to their ability to modulate cell communication and fibroblast functions, exosomes have gained much attention in recent years for their potential therapeutic usefulness in skin rejuvenation.23

Hair loss is one of the obvious phenotypes associated with aging. It is known that aging-associated alopecia is linked to follicular quiescence and hair miniaturization.8 In normal hair, growth occurs at the level of the hair follicle as a continuous three-phase cycle: anagen (active growth), catagen (transition and involution) and telogen (rest). Dermal papilla cells (DPCs), responsible for hair follicle development, are known to release several growth factors, communicating with epithelial cells, germ cells and stem cells. These, in turn, are responsible for normal hair growth and proliferation during a new hair cycle. Given the critical role that DPCs play in the hair follicle and hair cycle, they have been used as a source of exosomes, as they upregulate Wnt/β-catenin signaling, a key cellular pathway involved in hair regulation, regeneration and morphogenesis. Exosomes derived from ADSCs, BMSCs, keratinocytes and other MSCs have also been studied.4,6,32

Exosome therapy is considered by many authors as a cell-free method; therefore, a therapy correlated with lower risks of tumorigenicity and immunogenicity, and reduced potential for uncontrolled cell differentiation and cell proliferation when compared to stem cell therapy.7 However, proteins, metabolites and nucleic acids delivered by exosomes to recipient cells effectively alter their biological response, potentially promoting or inhibiting diseases.11

Exosomes can, for example, limit or promote viral infections. Exosomal cargoes can suppress infection by limiting viral replication or increasing antiviral immunity, but they can also promote viral replication after hijacking the exosome biogenesis machinery. These can serve as a pseudoenvelope that improves viral entry, increasing its infectivity. The similarities in size, density, molecular charge, and use of common components to harness cell proteins and vesicle trafficking machinery between enveloped retroviruses, particularly HIV 1 and 2 and exosomes support this idea. Similarly, exosomes originating from immune cells and neoplastic cells release cargoes that can influence the immune system activity in the target cell, stimulating or suppressing its proliferation and function. Exogenous doses of supraphysiological levels of exosomes in mice have been associated with neoplastic induction and progression.11

Only a few clinical studies with allogeneic exosomes, in their methods, stated that infectious screening of the donor and the final product was performed, which included blood typing and Rh factor, research on viral diseases, and sexually transmitted infections.22,23,29,30

Furthermore, there is no consensus/standardization or current regulation on safe extraction, purification, quantification, concentration methods, dose, and posology, which makes it difficult to conduct multicenter clinical trials with a sufficient sample of patients.23

Regarding plant-derived exosomes, more studies are needed to ensure their safe application. A comprehensive understanding of their toxicological aspects, biodegradability and clearance dynamics is necessary.

In Europe and the United States, the use of cosmetics based on products derived from humans is prohibited, as there is the possibility of transmission of viral or prion diseases. In December 2019, the FDA issued a safety notice regarding the use of exosomes following multiple reports of unspecified serious adverse events in patients in Nebraska who were treated with unapproved exosome-containing products.56

Although several in vitro, animal, and basic clinical studies have described the potential benefits of exosomes, the FDA has not yet approved exosomes for use as topical, injectable, or intravenous treatments. However, in the United States, six companies produce and supply products with exosomes for clinical use, all of which are of human origin, without specifying their source.3

In Brazil, the National Health Surveillance Agency (ANVISA, Agência Nacional de Vigilância Sanitária) authorizes the use of exosomes of non-human origin in the group of grade 2 cosmetics, which means that the products must be for external use, that is, they can only be applied to the skin, with an intact epidermis, therefore not allowing their use by injection or as drug delivery. The presentation in sterile vials, however, encourages their use by injection or as “drug delivery” after procedures that cause disruption of the skin barrier, such as microneedling or fractional lasers.23,57

The combination of allogeneic exosomes derived mainly from adult human stem cells, with over-the-counter moisturizers and serums is a growing trend in the global market. The quantity, purity and safety of the exosomes in these products are undefined since there is no regulation or post-marketing surveillance.23

Up until this revision, In Brazil, the products registered by ANVISA as cosmetics include Inno-Exoma®Exo-skin by INNOAESTHETICS, marketed by Suprema Marcas, and ASCE plus SRLV (for the skin), HLRV (for hair) and ILRV (intimate products) developed by BENEV Inc. in partnership with ExoCoBio.

The commercial product Inno-Exoma® Exo-skin was developed using NARBEX (Non-Animal Regenerative Bioengineering Exosome) technology which utilizes bioengineering to mimic cell-derived exosomes. Since it is considered a bioidentical product the company -calls it exosome-like or synthetic exosomes. It is presented in a sterile vial, and each box contains a 10 mL vial of lyophilized exosomes, associated with a complex of amino acids and peptides, mannitol and hyaluronic acid, accompanied by a 2 mL vial of saline solution for dilution. There are, as of now, no published clinical studies on this product.

ASCE Plus products are exosomes derived from the Rosa damascena plant, unlike the exosomes derived from mesenchymal cells marketed by ExoCoBio in other countries, such as South Korea. It is presented in a sterile vial, and the box sold in Brazil contains a 20 mL vial of exosomes, containing a complex of amino acids and peptides and other active ingredients such as ascorbic acid, retinol, nicotinamide and thiamine, as well as a 5 mL vial as diluent, which contains water, sodium bicarbonate, sodium chloride, sodium hyaluronate and an amino acid complex. Its use was evaluated in a single case report in the treatment of AGA and poliosis after four monthly sessions of fractional picosecond laser and drug delivery of the product, demonstrating hair growth and repigmentation of white hair, without adverse effects.9 There are no other published studies on this product.

Two systematic reviews published in 2024, included nine studies in Dermatology-: tissue regeneration (1), AD (2), melasma (1), rejuvenation (1), sensitive skin (1), melanin synthesis (1), skin glow (1), and as adjuvant to laser for acne scars (1). The authors highlight the large number of publications (in vitro studies, cell cultures, animal models,)as reviews on perspectives of possible exossomes aesthetic benefits.56,58 However, there is a lack of clinical studies with good methodology and long-term follow-up. Besides, The presence of numerous components in the vials and the associated use of techniques, even minimally invasive ones, such as fractional laser and microneedling, prevent conclusions about the actual benefit of exosomes. There are no conflicts of interest between the authors and any company involved in the commercialization of exosomes and derivatives.

Despite the infinite possibilities for future applications, there are important issues regarding exosomes that need to be elucidated before their use is authorized: 1) Identification of ideal cell sources for specific conditions/diseases; optimization of isolation methods and their characterization; 2) Standardization of large-scale production in compliance with current good manufacturing practice regulations and consideration of regulatory factors; 3) Establishment of dosing regimens (the appropriate amount, but also the required administration frequency); 4) Identification of the most efficient route of administration; 5) Understanding of the biodistribution and elimination of exosomes in vivo; 6) Overcoming the limitations caused by the lack of placebo-controlled studies; 7) Careful assessment of long-term risks and toxicity. All of these considerations are very important, especially since most of these studies involve the use of genetic cargo derived from human stem cells, without having yet established their true efficacy and safety.

Medical doctors and patients appreciate innovation, but they also place great value on safety. Despite the promising preclinical data, it is difficult to extrapolate findings in cell cultures and animal models to the complexity of human physiology. Further studies are needed to understand all the issues related to the use and applicability of exosomes in Medicine and Dermatology. Determining the potential risks and side effects associated with the use of exosomes is essential for their approval and starting their clinical use.

None declared.

Taciana Dal’Forno-Dini: Design and planning of the study; collection of data, or analysis and interpretation of data; drafting and editing of the manuscript or critical review of important intellectual content; collection, analysis and interpretation of data; effective participation in research orientation; critical review of the literature; approval of the final version of the manuscript.

Martina Souilljee Birck: Design and planning of the study; collection of data, or analysis and interpretation of data; drafting and editing of the manuscript or critical review of important intellectual content; collection, analysis and interpretation of data; critical review of the literature; approval of the final version of the manuscript.

Marco Rocha: Design and planning of the study; collection of data, or analysis and interpretation of data; drafting and editing of the manuscript or critical review of important intellectual content; collection, analysis and interpretation of data; effective participation in research orientation; critical review of the literature; approval of the final version of the manuscript.

Edileia Bagatin: Drafting and editing of the manuscript or critical review of important intellectual content; effective participation in research orientation; critical review of the literature; approval of the final version of the manuscript.

All authors approved the final version of this manuscript.