Next Article in Journal
Usage and Behavioral Data of Consumers Using Hair Dye Products Containing 2-Methoxymethyl-P-Phenylenediamine
Previous Article in Journal
26-SNP Panel Aids Guiding Androgenetic Alopecia Therapy and Provides Insight into Mechanisms of Action
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cosmetics
Volume 12
Issue 5
10.3390/cosmetics12050191
cosmetics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Transformative Impact of Extracellular Vesicles on the Cosmetics Industry: A Comprehensive Review

by
Valéria Dal Col
1,
Fábio Fernandes Ribas
1 and
Rodrigo Pinheiro Araldi
2,3,*
1
GEC Cosmetics Enterprise, Vitória 29055-620, ES, Brazil
2
Postgraduate Program in Endocrinology and Metabolism, Paulista School of Medicine, Federal University of São Paulo, São Paulo 04023-062, SP, Brazil
3
BioDecision Analytics, São Paulo 01451-917, SP, Brazil
*
Author to whom correspondence should be addressed.
Cosmetics 2025, 12(5), 191; https://doi.org/10.3390/cosmetics12050191
Submission received: 25 July 2025 / Revised: 20 August 2025 / Accepted: 26 August 2025 / Published: 2 September 2025
(This article belongs to the Section Cosmetic Dermatology)
Browse Figure
Versions Notes

Abstract

Extracellular vesicles (EVs) have gained attention in the cosmetics industry for their role in intercellular communication and tissue regeneration. They transfer bioactive molecules such as proteins, lipids, and nucleic acids, promoting skin repair, rejuvenation, and anti-aging effects. Human mesenchymal stem cell-derived EVs are particularly valued for their ability to enhance collagen production, reduce inflammation, and improve skin texture and hydration. However, their use is prohibited by regulatory agencies. Plant- and bacterial-derived EVs are being explored to meet the demand for innovative cosmetics. Despite their potential, challenges such as regulatory approval, high production costs, and product stability need to be addressed to fully realize the benefits of EV-based cosmetics. This paper examines the mechanisms, benefits, market trends, and prospects of EV-based skincare products, highlighting their transformative impact on the cosmetic industry.

1. Extracellular Vesicles in Cosmetology: The New Global Market Trend

Cosmetics have evolved significantly, transforming from simple beauty enhancers to sophisticated formulations with multiple purposes. Changes in cosmetology are driven by consumer demand for new products, particularly those free from harmful chemicals and synthetic ingredients. The search for these new products based on natural and organic ingredients for skin and hair care is responsible for the expected 6.1% compound annual growth rate (CAGR) from 2025 to 2030 in cosmetic market, which showed a global market size estimated at USD 295.95 billion in 2023 [1].
In an attempt to meet this demand, the global cosmetic global market has sought for innovative trends, including formulations based on (i) probiotics and postbiotics, which can enhance skin health and balance the microbiome [2,3,4], (ii) extracellular vesicles (EVs) from human cells (particularly derived from mesenchymal stromal cells (MSCs)), bacteria and plants, which can serve as vehicle for delivering functional bioactive molecules [5,6,7]; and (iii) devices that enhance product application [8,9,10]. Among these trends, the cosmetic exploration of EV-based formulations stands out, with a projected compound annual growth rate (GAGR) of 28.73% from 2025 to 2030 and showing a global market valued at USD 117.4 million in 2024 [11].
Despite the numerous new products based on exosomes proposed in the last decade (Table 1), few have properly characterized exosomes according to the recommendations of the Minimal Information for Studies of Extracellular Vesicles (MISEVs) guidelines [12]. Moreover, many of these products lack adequate safety and/or efficacy testing [12]. Therefore, this review aims to provide a concise overview of the research, development, and innovation (RDI) of cosmetic formulations based on EVs, focusing on the technical aspects and potential applications of the human-, bacterial-, and plant-derived EVs for skin and hair care.

2. A Brief History of the Extracellular Vesicles

Extracellular vesicles (EVs) are a heterogeneous group of small, lipid bilayer-enclosed particles ranging in diameter from 10 to 10,000 nm. They are produced and secreted by nearly all cell types, including prokaryotes [13,14,15,16,17].
These particles were first reported in 1945 by the biochemist Erwin Chargaff. While studying coagulation, Chargaff observed the presence of “membrane debris” sediments in platelet-free plasma supernatant subjected to high-speed centrifugation [18].
One year later, working together with Rudolph West, Chargaff demonstrated that “the addition of the high-speed sediment to the supernatant plasma brought about a very considerable shortening of the clotting time” [19]. This observation led to the conclusion that “the particulate fraction probably includes, in addition to the thromboplastic agent, a variety of minute breakdown products of blood corpuscles” with high clotting potential [19].
However, the first EV images were recorded in 1967 by Peter Wolf [20]. Using transmission electron microscopy (TEM), Wolf described a “material in minute particulate form, sedimentable by high-speed centrifugation and originating from platelets, but distinguishable from intact platelets”, which he named “platelet dust” [20].
Novel EV images were obtained in 1971 by Neville Crawford, who introduced the term “microparticles” to refer to these particles isolated from platelet-free plasma [21]. Crawford also demonstrated that these microparticles contained lipids and carried adenosine triphosphate (ATP) and contractile proteins, pioneering the description of the presence and coarse structure of such cell-free components [21].
Between the mid-1960s and early 1980s, several studies using TEM described structures consistent with EVs [22]. Among these, Nunez et al. [23] reported the presence of multivesicular bodies (MVBs) close to the apical membrane within the cytoplasm. The authors proposed that “fusion of the outer or limiting membrane of the multivesicular body with the apical plasma membrane might lead to the release of the vesicles contained within the structure into the luminal space”. This finding contributed to the identification of a subtype of nanosized EVs (30–150 nm) known as exosomes.
The discovery of EVs is closely linked to virology. In the 1960s and 1970s, scientists examined biofluids for virus-like particles (VLPs) with the aim of associating viruses not only with infections but also with other diseases such as cancer [24,25]. However, particles identified in patient biofluids from various diseases, including cancer, exhibited unique characteristics that differed from typical VLPs [24,26,27,28]. This observation led to the consensus that these particles were artifacts resulting from the separation process [28].
This consensus changed in 1975, when Dalton studied fractions of filtered and unfiltered fetal bovine serum (FBS) and demonstrated that the sera contained particles similar to those found in epithelial cell lines [29]. Dalton stated that “to call structures with the morphology of normally occurring vesicles of multivesicular bodies and of microvesicles associated with epithelial cells ‘virus-like’ is unwarranted”, effectively ending the era of VLPs [29].
The early 1980s saw significant advances in extracellular vesicle (EV) biology. Using reticulocyte maturation to study membrane trafficking, research groups led by Stahl and Johnstone demonstrated that the transferrin receptor is lost through vesicle release. Stahl’s group published a paper providing transmission electron microscopy (TEM) images showing that these EVs are released from the multivesicular body (MVB) lumen upon fusion with the plasma membrane [30]. In contrast, Johnstone’s group described a novel intracellular sorting and trafficking pathway [31]. These EVs were named exosomes by Rose Johnstone in 1987 [22].
In 1991, Johnstone et al. demonstrated the presence of transferrin and nucleoside transporters on exosomes. They also reported that various cellular stresses induced both the release and internalization of exosomes [32]. From these historical papers, it was observed that there was a massive interest in EV research. This interest was driven from around 1993 with a paper demonstrating an elevated number of microparticles (a subtype of EV) in transient brain ischemia and other infarctions [33] and later confirmed in Crohn’s [34]. At the same time, studies described the physical and biochemical characteristics of EVs [35] and the immunomodulatory properties of EVs [36].
Although previously called “membrane debris”, “platelet dust”, “small particles”, and even “virus-like particles”, and later classified into different subtypes according to their size, marker expression, and biogenesis (Table 2), the MISEV2023 discourages the EV nomenclature for terms related to the biogenesis, like exosomes, microvesicles, and apoptotic bodies [17,37].

3. Exosomes to Extracellular Vesicles: A Nomenclature Change Proposed by MISEV2023 That Directly Impact the EV-Based Cosmetic Market

Hypothetically, exosomes are the most explored subtype of EVs [38], including in cosmetic formulations [12] (Figure 1). But without an orthogonal characterization test to prove the exosomal nature of these vesicles, most formulations may contain other EV subtypes.
Since MISEV2018, the International Society for Extracellular Vesicle (ISEV) has encouraged the use of the generic term EV to avoid the misuse of the term “exosome” (Table 3). Despite this recommendation, which was endorsed in MISEV2023 [17], and the lack of regulatory guidance, the term “exosome” has been strategically coined, especially by the cosmetic industry to refer to EVs.
Considering exosomes are a subtype of EVs, what drives the specific focus on exosomes rather than EVs in cosmetology?
This focus can be justified by the small diameter of the particles (30–200 nm), which confers the capability to cross different tissue barriers, including the skin [5,7]. This is a desired characteristic, since it enables exosomes to be used in topical formulations, serving as nanocarriers for natural active biomolecules and synthetic compounds.
Another reason that justifies the interest in exosomes is their biogenesis. Exosomes are generated from the endosomal compartment and contain phosphatidylserine, phosphatidylcholine, sphingomyelin, ceramides, and cholesterol in their lipid bilayer, ensuring structural integrity [39,40]. The combination of these characteristics with the nanosized diameter ensures the stability of these vesicles for up to 20 months at 4 °C or up to four years at −20 °C [17,41].
In addition, initially it was proposed that exosomes contain evolutionarily conserved surface proteins, such as tetraspanins (CD9, CD63, and CD81), heat shock proteins (HSP60, HSP70, and HSP90), major histocompatibility complex (MHC) class I and II, Alix, and TSG101 that could serve as putative exosomal markers [38]. This led to the idea that, through the immunodetection of these proteins (particularly CD63), it should be possible to distinguish exosomes from other EVs [13,42]. However, MISEV2023 recognized that immunodetection of tetraspanins CD9, CD63, and CD81 does not allow us to ensure exosomal nature of EVs, since other EV subtypes can also express these surface proteins [17].
Furthermore, exosomes count on exclusive sorting mechanisms during their biogenesis that cargo selective biomolecules such as nucleic acids (coding and non-coding RNAs, double- or single-strand DNA), proteins, metabolites, and lipids that make these nanosized vesicles more homogeneous in terms of content than other EVs [38]. This characteristic is particularly beneficial for the RDI of cosmetic products, as formulation homogeneity is a required feature in any product.
The sorting mechanism is part of several coordinated processes involved in exosome biogenesis [38]. This process begins with the formation of multiple intraluminal vesicles (ILVs) within the MVBs. ILVs form by inward budding of the endosome’s limiting membrane, involving sorting-related proteins like the endosomal sorting complex required for transport (ESCRT). During ILV formation, cytosolic components are also captured within these structures [38].
Upon maturation, MVBs are transported to the plasma membrane via the cytoskeleton and microtubules. After fusion with the cell membrane, ILVs are released as exosomes into the extracellular space (secretory pathway). Alternatively, MVBs can fuse with lysosomes or autophagosomes for degradation (degradation pathway). The mechanisms governing these pathways are not fully understood but coexist [14,42].
Upon release into the extracellular space, EVs interact with recipient cells through different mechanisms, such as adhesion to cellular surface receptors (receptor-mediated uptake), endocytosis (phagocytosis), and fusion with the plasma membrane [43]. Transmembrane ligands on the extracellular vesicle (EV) surface can directly bind with receptors in recipient cells through direct interaction [44]. This binding initiates a downstream signaling cascade, resulting in the activation of the target cell [44]. This interaction mainly occurs in immunomodulation and apoptosis [44].
Altogether, these characteristics suggest that exosomes can be additional advantages to other subtypes of EVs. However, obtaining pure exosomal suspensions at a large scale imposes some technical limitations ranging from isolation to characterization. In this context, the central question is the following: Do we need to focus our attention on exosomes, or should we look for formulations based on EV?
Given the lack of regulatory guidelines for EV-based products and the importance of MISEV to provide technical recommendations and guidance on EV-related studies, the answer to this question is clear on MISEV2023, which discouraged the use of “exosome” and strongly suggested the use of the generic term EV.
Moreover, most EVs isolated from cells under physiological conditions have an average diameter of 100 nm [17], which is within the desired size to ensure these vesicles can cross epithelial layers, serving as a vehicle for the delivery of molecules of cosmetic interest.
In this sense, although the sorting mechanism can address specific nucleic acids to the exosomes, in cosmetology, the main purpose of the use of these nanosized vesicles is to explore their potential as a vehicle for the delivery of natural and/or synthetic compounds that are combined with these vesicles in multiple formulations.
In addition, the appropriate replacement of the term “exosome” by EV can be interesting from a manufacturing point of view of these vesicles. This is because, although it is strongly recommended that all EVs be characterized by orthogonal methods [17], the adoption of EV term does not limit the quality control process to the immunodetection of surface markers that, as previously mentioned, are not specific for exosome characterization and can negatively impact batch release, causing significant economic losses.

4. Exploring the EV Biotechnological Applications in Cosmetic Products

Since the first studies showed that EVs facilitate cell-to-cell communication by transferring bioactive molecules [45,46,47,48,49,50,51], these vesicles have been explored as potential carriers of molecules [52,53,54,55]. This is because EVs have all the features sought in a delivery vehicle, which include stability, little or no immunogenicity, biodegradability, low production cost, easy of fabrication, and tolerability [14].
However, EVs are biotechnological products isolated from human cells, bacteria, and plants, each one possessing unique benefits and limitations, as summarized in Table 4. Considering that the EV cargo (nucleic acids, proteins, metabolites, and even lipids) reflects the transcriptomic nature of the origin cells, it is not surprising that human-, plant-, and bacteria-derived EVs can offer different therapeutic and cosmetic opportunities. For this reason, this review provides a concise summary about the cosmetic applications of human-, plant-, and bacteria-derived EVs.

4.1. Human-Derived EVs

Although there are no cosmetic products based on human-derived EVs approved to date, at least 81 clinical trials analyzing the safety and efficacy of human-derived EVs/exosomes for the treatment of several diseases are ongoing worldwide, as data available on ClinicalTrial.gov (accessed on 10 March 2025, Table 5).
EVs can be isolated from various human tissues. However, there are concerns regarding the use of human-derived EVs. These concerns include the potential risk of disease transmission, as EVs can carry virus particles and genetic material (DNA or RNA) of different viruses [56,57,58]. However, this concern can be mitigated through virological analysis of donors, a practice that is already commonly used for the tissues obtained for the isolation of mesenchymal stem/stromal cells (MSCs) for cellular therapy.
For cosmetic purposes, platelet-rich plasma (PRP) can be considered a primary source of EV obtaining [59].
PRP is an autologous treatment that already has multiple applications in dermatology, particularly in the areas of hair restoration, skin rejuvenation, acne scars, dermal augmentation, and striae distensae [60,61]. PRP therapy is a method that uses a centrifugated blood fraction containing a high concentration of platelets in a small volume of plasma [59,60]. The optimal platelet concentration recommended for high-quality PRP treatment in skin diseases is 1–1.5 million platelets/μL [62,63].
Platelets are small blood cell fragments derived from megakaryocytes that play a key role in hemostasis [63]. These fragments carry two types of storage granules: alpha-granules and dense granules [63,64]. Alpha-granules are the most relevant to PRP therapy since they contain multiple growth factors such as vascular endothelial growth factor (VEGF), endothelial cell growth factor (ECGF), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), epidermal growth factor (EGF), platelet-derived angiogenesis factor (PDAF), hepatocyte growth factor (HGF), fibroblast growth factor (FGF), glial cell line-derived neurotrophic factor (GDNF), platelet factor 4 (PF4), interleukin 8 (IL-8), and β-thromboglobulin (or CXCL7) [63]. Dense granules are the second-most abundant granules, and storage of ADP, ATP, calcium, serotonin, and glutamate, which is released after PRP treatment, plays a complementary beneficial effect of this therapy [60,62,63,64].
The mechanism of action (MoA) of PRP has been attributed to the secretion of growth factors and ATP, which begins 10 min after PRP injection [63,64,65]. Combined, these molecules induce multiple responses in cells within the injection site, resulting in cellular proliferation, matrix formation, regulation of inflammation, angiogenesis, osteoid production, collagen synthesis, and the remodeling of novel tissues [63,64,65]. PRP therapy is safe, with few contraindications, limited to patients with critical thrombocytopenia, platelet dysfunction, hemodynamic instability, sepsis, and local infection at the site of PRP administration [63].
However, current studies have provided evidence that EV (“exosomes”) are the main effectors of PRP activity, mediating the intercellular communication process and serving as a vehicle for the delivery of platelet-derived growth factors and other biomolecules, including ATP [66,67,68]. In this regard, Guo et al. [66] provided strong evidence that intra-articular injection of PRP-EVs can significantly promote the repair of articular cartilage defects in murine models. These data make PRP-EVs potential candidates for cosmetic products. Moreover, these EVs can be easily isolated using already well-established protocols based on ultracentrifugation or tangential flow filtration (TFF). Moreover, for being an autologous treatment, PRP-EVs can be considered safety. On the one hand the PRP-EVs use represents a landmark in personalized cosmetology; on the other hand, the use of these vesicles requires the adoption of rigorous protocols to ensure the safety and efficacy of PRP-EV-based treatments.
Alternatively, MSCs emerge as a useful source of EVs obtained on large scale to supply the cosmetic market, which increases yearly. This is because these cells can be easily isolated from different tissues [13,69,70].
MSCs were first described in the 1960s by Soviet scientist Alexander Friedenstein, who demonstrated that bone marrow and other blood-forming organs contain clonogenic progenitor cells that, under in vitro conditions, can give rise to fibroblasts and other mesenchymal cells [71]. Friedenstein also showed that these cells (not belonging to the hematopoietic lineage) could also form bone and cartilage-forming cells [71,72,73,74].
Because of these characteristics, these cells were called “mesenchymal/stromal stem cells” by Prof. Dr. Arnold Caplan in 1991 [75].
In subsequent studies, Haynesworth et al. [76] showed that MSCs express unique surface antigens that could be used to identify and characterize MSC populations. A few years later, Barry et al. [77,78] reported that, using monoclonal antibodies, it would be possible to identify these antigens (CD105 and CD73), allowing the identification of MSC populations. From this moment, MSCs began to be characterized by (i) their capacity for adhesion and proliferation in culture (known since 1966), (ii) expression of the surface markers CD73, CD90, CD105, CD44, and CD124 and (iii) the capacity to differentiate in vitro into mesodermal lineages.
Due to the increased clinical interest in MSCs and the need to establish broad and unambiguous criteria for defining MSCs, the International Society for Cellular Therapy (ISCT) has established minimum criteria for defining MSCs [79]. These criteria include (i) adhesion (to the plastic), (ii) expression of the surface antigens CD105, CD90, and CD73 in more than 95% of the cell population, and CD45, CD19, CD14, CD11b, CD34, CD79α, and HLA-DR limited to a maximum of 2% of the cell population, (iii) ability to differentiate in vitro into osteoblasts, chondrocytes, and adipocytes (multipotency) [79].
The main advantage of these cells as a source of EVs is that they can be cultivated on a large scale [80] and, under specific stress conditions, can produce high amounts of EVs to supply the cosmetic market [81,82,83].
Other relevant aspects that make MSC potential candidates for EV obtaining are the safety and tolerability of these cells, which have been investigated for over 15 years in multiple clinical trials [15,69,84,85,86].
Although MSCs can be isolated from different tissues, as they share transcriptional signatures with their tissue of origin [87,88,89], it is not surprising that the therapeutic potential of MSCs may vary according to their origin and even donors, as recently shown by a comparative transcriptomic analysis among different MSC types by Araldi et al. [70].
Despite the therapeutic potential of MSCs have already been widely demonstrated in different systematic reviews and meta-analyses, the MoA of these cells remains not completely elucidated [13,42,90,91,92].
Based on cumulative evidence showing that, after intravenous transplantation, MSCs migrate and transmigrate across the endothelium to sites of injury/inflammation, where they attach to target tissues (homing) [93,94], and differentiate into specialized cell types [15,16,95,96,97], initially, it was postulated that the therapeutic action of these cells was mediated by the ability of MSCs to replace dead and/or injured cells [96,98].
However, a study involving renal injury induced by injections of toxic doses of glycerol showed that transplanted MSCs remained at the site of injury for a few days, suggesting that the therapeutic benefits of MSCs do not necessarily depend on cell replacement [99]. Confirming this hypothesis, subsequent studies have shown that only 0.1–2.7% of transplanted MSCs are able to attach to the target tissue [100,101,102] and only 1–2% of transplanted MSCs survive for more than a week after systemic administration [98,103,104,105,106,107]. Therefore, given the low percentage of MSCs that attach to the target tissue, the replacement of injured cells by differentiated MSCs (initially postulated as the MoA of MSCs) would not be able to justify the therapeutic benefits of these cells.
In 1996, Haynesworth et al. showed that MSCs secrete a series of growth factors and cytokines that could act in a paracrine manner on recipient cells [108]. This discovery led to the formulation of the theory of paracrine stimulation. However, this theory was only confirmed ten years later, when Takahashi et al. [109] showed that growth factors and cytokines present in the conditioned medium of MSCs can increase the density of blood capillaries and improve cardiac function, reducing the damage caused by acute myocardial infarction in rats. Since then, it has been recognized that the therapeutic effects of MSCs are due to the paracrine action of the biomolecules secreted by these cells [95,96,105,110,111,112,113,114]. Such effects are mediated by cytokines, growth factors, lipids, nucleic acids, ions, and metabolites produced and secreted by these cells, which act in signaling and intercellular communication processes [98,115,116].
As observed in PRP, these biomolecules can be found in free form and contained in EVs secreted by cells [117]. However, the molecules present in free form are easily hydrolyzed or oxidized, while the molecules contained in EVs are less susceptible to degradation [14,42]. This observation has driven the biotechnological interest in exploring the use of EVs in a new therapeutic modality known as cell-free therapy [14,15,42,52,95,118].
However, the MSC production for the large-scale EV obtaining can be limited by the cost of production of these cells, which can make it economically unviable for cosmetic purposes. This is because the productive chain of MSCs requires multiple cell expansion steps and quality control processes to ensure the maintenance of MSC phenotype according to the minimum criteria defined by ISCT. These steps commonly involve an open process (except for MSC production in bioreactors) that also requires extensive microbiological vigilance. These processes represent important challenges for the sterile EV solution obtained for injectable cosmetic products. However, open processes may not represent a problem for obtaining MSC-derived EVs for cosmetic formulation destinated for topic use.

4.2. Plant-Derived EVs

Human-derived EVs have garnered significant interest and have been extensively studied in recent years. Conversely, plant-derived EVs (also known as plant-derived exosome-like nanoparticles—PELNs) have received comparatively less attention and remain under-researched. Although several investigations have highlighted their promising health benefits and drug delivery potential, comprehensive (pre)clinical studies are still limited [119].
Plants survive by defending themselves against biological and non-biological stress or adapting to the environmental conditions through various secondary metabolites, such as alkaloid, flavonoid, polyphenol, terpenoid, and quinone [120]. These secondary metabolites are commonly explored as nutritional supplements or active ingredients in multiple cosmetic formulations [120]. This is because they exert proven beneficial effects on human skin, providing antiaging, moisturizing, whitening, regeneration properties, and nutritional supply [120].
Besides secondary metabolites, plants produce defense against biological and non-biological threats though EV-mediated mechanisms [121,122]. Like human cells, plant cells, cultured in vitro also release EVs containing nucleic acids, proteins, lipids, and substances with protective functions into the growth medium, which can be harvested for pharmaceutical applications [119,123].
As observed with MSC-derived EVs, plant-derived EVs have various bioactive functions according to the plant they are derived from [120]. Exemplifying these differences, it was demonstrated that blueberry-derived EVs increase the survival rate of cells by regulating the expression of genes that affect inflammation and oxidation stress [124]; strawberry-derived EVs were reported to prevent oxidative stress in human MSCs [125]; grape-, grapefruit-, ginger-, and carrot-derived EVs were reported to help maintain intestinal homeostasis owing to their anti-inflammatory functions [126].
Although extensive evidence suggests that plant secondary metabolites are the primary agents responsible for the mechanism of action of plant-derived extracellular vesicles, Woith et al. [119] showed that these metabolites are not actively packaged into EVs but become enriched in the membrane when sufficiently lipophilic. This is because lipophilic compounds were found associated with nanovesicles, whereas more hydrophilic structures were not consistently observed [119]. This evidence reinforces that plant-derived EVs offer additional therapeutic benefits to secondary metabolites that are already extensively used in cosmetic formulations.
Confirming this hypothesis, analyzing the transcriptome of keratinocytes treated for six hours with plant-derived EVs or conventional plant secondary metabolites from different plants, including ginseng (Panax ginseng) and green tea (Camellia sinensis), Cho et al. [120] showed that EVs promoted more expressive transcriptional changes. In the comparative analysis of expression of genes that are known to affect aging, regeneration, skin barrier, and moisturization (MP12, MMP13, NOTCH3, FGF12, HS3ST3A1, LOX, VIM, ELOVL3, and KRTI), the study showed that EVs are more effective than plant secondary metabolites in contributing to maintaining healthy skin [120]. These results demonstrate that plant-derived EVs have the potential to be commercialized as a cosmeceutical product [120].

4.3. Bacterial-Derived EVs

Bacterial-derived EVs are classified into Gram-negative and Gram-positive bacteria-derived EVs. EVs from Gram-negative bacteria contain lipopolysaccharides (LPS) [127], while EVs from Gram-positive bacteria contain lipoteichoic acids (LTA) [128]. These EVs are involved in the communication process between bacteria [129,130]. For this reason, bacterial-derived EVs have been investigated as mediators of drug delivery [131,132,133,134].
Lactiplantibacillus plantarum (previously Lactobacillus plantarum) is a Gram-positive bacterium belonging to the genus Lactiplantibacillus [135]. L. plantarum is found in many fermented products and has been associated with reducing allergic reactions as a probiotic and lowering cholesterol and triglyceride levels [129,136,137,138,139,140]. L. plantarum, which is an aerotolerant Gram-positive bacterium, is also found on the skin, controlling various harmful Gram-positive and Gram-negative bacteria [141,142,143].
In 2022, Kurata et al. [144] showed that L. plantarum-derived EVs (LpEVs) have immunomodulatory properties. These properties were confirmed in 2024 by Gong et al. [145], who showed that LpEVs lead to increased expression of Arg-1 and anti-inflammatory cytokines IL-10 and decreased expression of iNOS and surface marker protein CD86 in RAW 264.7 cells (murine macrophages) exposed to LPS, causing significant morphological changes in these cells. These results demonstrate that LpEVs can suppress inflammatory responses and promote the polarization of macrophages toward the anti-inflammatory M2 phenotype. These findings support the anti-inflammatory activity of L. plantarum-derived EVs [144].
Still in 2022, Jo et al. [129] provided in vitro and clinical evidence that L. plantarum-derived EVs (LpEVs) modulate the mRNA expression of extracellular matrix (ECM), suppressing skin wrinkle formation and pigmentation. These results show that LpEVs offer benefits against skin aging.
Currently, Kang et al. [146] showed that Lactobacillus-derived artificial EVs (LAEs) effectively improve wound healing in fibroblasts, modulating aging-related genes. These results make LAEs a promising alternative to natural EVs for skin rejuvenation and anti-aging.
Exosomes from other species, such as fungi and algae, have also been identified and may possess bioactive properties. However, this review will not explore their use due to the current lack of supportive data demonstrating their efficacy or safety in cosmetic contexts. To date, there is insufficient evidence validating their stability, bioavailability, or dermatological benefits, and no regulatory consensus regarding their safe incorporation into consumer products.

5. Potential Risks and Adverse Effects of Human-, Plant-, and Bacterial-Derived EVs in Cosmetics Applications

The incorporation of EVs into cosmetic formulations has garnered significant interest due to their capacity to modulate cellular communication, promote skin regeneration, and deliver bioactive molecules. However, despite their promising therapeutic potential, the use of exosome, particularly those derived from human, plant, and bacteria, raises important safety considerations that must be critically evaluated.
Human-derived EVs, often isolated from MSCs or other donor tissues, such as plasma, may carry risks related to immunogenicity and pathogen transmission [147,148]. Although purification protocols aim to eliminate contaminants, residual proteins, nucleic acids, or membrane-bound molecules could provoke unintended immune responses or inflammatory reactions, especially when administered intradermally [149,150]. Additionally, donor variability and the lack of standardized manufacturing practices may result in inconsistent bioactivity and safety profiles [151].
Plant-derived EVs are generally considered less immunogenic due to their phylogenetic distance from humans [152,153]. However, they may contain plant-specific secondary metabolites, allergens, or enzymatic compounds that could irritate sensitive skin or trigger allergic reactions upon topical application [120,153]. The stability of these vesicles in human skin environments and their ability to penetrate the epidermal barrier remain poorly understood, raising concerns about their efficacy and long-term safety [154,155].
Bacterial-derived EVs, or outer membrane vesicles (OMVs), pose unique challenges. While some OMVs have demonstrated beneficial effects such as anti-inflammatory or antimicrobial activity [156,157], they may also contain lipopolysaccharides (LPS), peptidoglycans, or other immunostimulatory components capable of inducing strong inflammatory responses [156,157]. Intradermal administration of bacterial EVs could heighten the risk of systemic immune activation or localized adverse reactions, including erythema, edema, or granuloma formation [158,159].
Across all sources, the route of administration significantly influences the risk profile. Topical application generally presents a lower risk due to limited systemic absorption, though compromised skin barriers may increase permeability [160,161]. In contrast, intradermal delivery bypasses the protective epidermal layer, introducing exosomes directly into the dermis, where they may interact with immune cells, vascular structures, and connective tissue—potentially amplifying adverse effects [7,148].

6. Challenges in EV Large-Scale Production for Cosmetic Purposes

Despite the increasing interest in biotechnology exploring EV, many technical challenges can limit the EV applications in cosmeceutical products. The first and most discussed technical challenge is EV isolation.
Although there are several methods for isolating EVs, such as ultracentrifugation (UC), ultrafiltration (UF), precipitation, isolation kits, and several novel techniques such as microfluidic chips (MFC), size-exclusion chromatography (SEC), field-flow fractionation (FFF), hydrostatic filtration dialysis (HFD), and immunoaffinity precipitation (IP) kits [162], each method has pros and cons that can limit their use for EV obtaining for clinical purposes [162]. For this reason, the best choice depends on the intended downstream application, the type of EV (exosome, microvesicle or apoptotic body), and the homogeneity levels desired.
Centrifuge-based methods separate EVs from a solution according to their size, shape, density, and the viscosity of the medium [162]. Thus, the greater the difference in density, the faster they separate [118,162,163].
UC became the gold standard method for EV isolation, especially for clinical purposes [162]. Three different UC-based techniques can be used for EV isolation: differential ultracentrifugation (DUC), density gradient centrifugation (DGC), and rate-zonal centrifugation (RZU) techniques [164,165].
Historically, DUC was the first technique used to isolate EVs [162]. This technique is based on the density, size, and shape of the EVs [164,166,167,168,169]. The main advantage of this technique is that it does not require the addition of any chemical compound that can result in eventual contaminants that can limit the EV clinical application, since the EV-containing solution is directly subjected to high-speed centrifugation (generally higher than 100,000× g (RCF)). However, the development of DUC-based protocols requires expertise in both high-speed centrifugation and EV biology, since the duration (of ultracentrifugation), temperature, and sample dilution are critical factors for the separation efficiency [170,171]. On the one hand, this technique is scalable, being perfectly adequate for large-scale production to attempt clinical demands; on the other hand, it is not adequate for small sample volumes [172,173]. Another important consideration about this technique is that DUC causes the precipitation of various EV subtypes [174].
In this regard, DGC emerges as an alternative technique for reaching higher purification of specific types of EVs [164]. This is because unlike DUC, DGC occurs in an ultracentrifuge tube containing a preconstructed density gradient medium of sucrose or iodixanol (OptiPrep®) [167,174]. Thus, EVs can be separated from proteins [174] and purified according to their density to obtain most homogeneous isolations of exosomes, oncosomes, microvesicles, or apoptotic bodies [175]. However, by requiring longer durations and larger volumes of samples in relation to DUC [176,177], the application of this technique is not indicated for clinical purposes.
Rate-zonal centrifugation (RZC) is an alternative technique to obtain purified populations of exosomes (that represents the focus of study due to their nanosized diameter). In this technique, the sample is added to the top of the ultracentrifugation tube, and through centrifugation, higher-density compounds go through the dense layer more than lighter compounds [162]. Thus, particles with the same density and different diameters (size) can be separated [178], with more extracellular recovery in comparison with DGC [174]. However, this method is laborious and can leave potential contaminants that can limit the clinical use of these vesicles.
An alternative to methods based on centrifugation is precipitation. This method works based on dispersibility alteration. For this, a polymeric water-excluding compound (generally polyethylene glycol—PEG or lectin) is added to the sample. Next, the sample is centrifuged or filtered. The polymer dries the sample and leads to the EV precipitation [163,179]. Although considered a quick and easy method, since it does not require ultracentrifugation, this method does not offer selectivity and quality for clinical purposes. This is because the polymer leads to the precipitation of multiple types of vesicles simultaneously. Moreover, even using immunoaffinity techniques to purify the exosomal population of EVs [14,163,164], the polymer residues represent important contaminants to exosomal suspension that limit its clinical use. For this reason, precipitation should always be followed by centrifugation and filtration to eliminate contaminants [180,181].
Ultrafiltration (UF) is the most employed size-based isolation method. In this method, samples are filtered through membrane filters with different pore sizes that separate the EVs according to their size and molecular weight [164]. Although simple, this method can be limited by EV clogging and trapping in the membrane. For this reason, it is strongly recommended that samples be initially filtered using large pore filters [164,182]. However, filter plugging-related poor efficiency limits the use of this method for large-scale production [164,183,184]. Moreover, UF can also deform the EVs due to the pressure applied during the filtration process [14,42].
Tangential flow filtration (TFF) is a rapid and efficient method for isolating and purifying exosomes from biological fluids. More efficient than high-speed centrifugation-based methods, TFF uses tangential flow to isolate exosomes. Through this method, the media flows parallel to the membrane, making it more suitable for large-scale research applications [185]. The major advantage of this method is that it can be connected to a mechanical system for large volumes, avoiding eventual contamination by working a closed system [185]. Moreover, TFF can be combined with size-exclusion chromatography (SEC) to remove host–cell protein (HCP) and DNA [185]. However, this method is more complex to operate, since it requires precise control of multiple parameters, such as transmembrane pressure, crossflow velocity, and temperature [185].
In this sense, sequential filtration can be alternatively used to simplify this process. In this method, the sample is filtered by different filtration steps. In each step, particles with large-size than the membrane pores are trapped, whereas smaller particles go through it [184]. However, in a similar way to other filtration-based methods, sequential filtration can be limited by filter trapping that leads to yield rate reduction [184,186,187].
Size-exclusion chromatography (SEC) in turn can be used to purify exosomes isolate by TFF or directly employs as a method to isolating these nanoparticles. SEC is a size-based separation method that employes a stationary phase often consisting of gel polymers through which the mobile phase transverses and is eluted [188]. This molecular sieve separates molecules by Stokes radii, leading to the elution of larger particles first, while the smaller molecules navigate through the pores of the resins (Biogel P, Sephadex, Sepharose, or Sephacryl) and are eluted later [188]. Although this method preserves the integrity of exosomes and their cargos, SEC is not applicable for a large-scale isolation [164,188,189].
Immunoaffinity-based methods also been also used for exosome isolation. These methods are based on the recognition of antigens present on the exosomal surface. These antigens are captured by specific antibodies [164,190]. Although simple, this method requires clearance pretreatment to remove cell debris [164]. On the other hand, this method allows us to obtain highly purified exosomes. The low harvest rate imposes limitations on its large-scale employment. Despite this disadvantage, this method has been explored in several magneto-immunoprecipitation commercial kits applicable to scientific purposes [164,191].
In this sense, methods based on micro- and nano-fluidic chips using acoustic, electrophoretic, and electromagnetic technologies can be efficiently used on small samples [164,192].
Thus, to date, DUC is the most appropriate isolation method for large volumes of samples, and TFF is the most promising method for scaling up the exosomal production for clinical purposes.

7. Regulatory Issues

The use of cosmetic products containing allogenic EVs derived from MSCs in moisturizers and serums is a growing trend in the cosmetic global market [7]. However, in Europe and the United States (U.S.), the use of the cosmetic based on products derived from humans is prohibited due to the possibility of transmission of viral or prion diseases [7]. In December 2019, the U.S. Food and Drug Administration (FDA) issued a safety warming regarding the use of exosomes following multiple reports of unspecified serious adverse events in patients in Nebraska treated with unapproved exosome-containing products [193]. Despite this, six companies in U.S. produce and supply exosome-containing products for clinical use, all from human origin, but with no information about their tissue origin [7].
In Brazil, the National Health Surveillance Agency (ANVISA, Agência Nacional de Vigilância Sanitária) authorized the use of exosomes of non-human origin in the group of grade 2 cosmetics [7]. Thus, these exosome-containing products are exclusively authorized for external use and can only be applied to the skin with an intact epidermis [7]. However, the presentation in sterile vials encourages their use by injection procedures that cause disruption of skin barriers, such as microneedling or fractional lasers [7].
The products authorized by ANVISA as cosmetics include Inno-Exoma® Exo-Skin by INNOASTHETICS and marketed by Suprema Marcas, ASCE Plus SRLV (for skin), HLRV (for hair), and ILRV (INTIMATEPRODUCTS) by BENEV Inc. in partnership with Exo-CoBio, GFCCELLTM EXO SCALP Pep9 (for hair) by GFC Life Science Co. (Hwaseong-si, South Korea), EVO EXO ONE HAIR (for hair) by Evopharma Ltd. (Guaxupe, Brazil), Exocoll and exo.reset, both by Valéria Dal Col. The Inno-Exoma® Exo-Skin was developed using NARBEX (Non-Animal Regenerative Bioengineering Exosome) technology and utilizes synthetic exosomes obtained by bioengineering to mimic cell-derived exosomes [7]. Since these synthetic vesicles do not carry biomolecules as observed in EVs secreted by cells, the product is presented in a 10 mL sterile vial containing 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. However, to date, there are no published clinical studies on this product.
ASCE Plus is comprised by exosomes derived from Rosa damascena (plant), unlike the exosomes derived from adipocyte-derived MSCs marked by ExoCoBio in South Korea. The product is presented in a sterile vial containing a complex of amino acids and peptides and other active ingredients, such as ascorbic acids, retinol, nicotinamide, and thiamine, accompanied by a 5 mL vial of diluent containing water, sodium bicarbonate, sodium chloride, sodium hyaluronate, and an amino acid complex. However, there are no published studies demonstrating the safety and efficacy of the product. The only published study by ExoCoBio describes beneficial therapeutics of the product based on MSC-derived EVs (not approved by ANVISA) for the treatment of atopic dermatitis [194].
Exocoll is a treatment protocol designed to reverse and treat signs of facial aging [195]. Using a powerful combination of peptides, NMN, NADH, and exosomes, Exocoll aims to restore skin elasticity, reduce atrophy, maintain bioactive cells and produce collagen, promoting an improvement in the overall appearance of the skin, in addition to enhancing the effects of in-office treatments (https://valeriadalcoll.com.br/exocoll, accessed on 20 May 2025) [195].

8. Perspectives About the Cosmetic Use of EVs

The global market for EV/exosome-based cosmetics is experiencing significant growth, driven by increasing consumer interest in advanced skincare solutions that leverage the regenerative properties of EV. According to the market size and growth projections, it is expected that by 2032, the global EV skincare market reaches USD 809.5 million. However, the production of EV-based cosmetics faces several significant challenges, primarily revolving around safety and efficacy concerns. One of the main issues is the lack of appropriate regulatory guidelines for the industry.
Currently, the use of human-derived EVs in cosmetics is prohibited by regulatory agencies due to the potential risk of viral transmission. This restriction forces industry to rely on plant- and bacterial-derived EVs, which, despite offering various clinical benefits, have limited transcriptional similarities to human cells. This limitation can negatively impact the potential applications of these vesicles, thereby affecting the dynamics of the cosmetic market. The absence of comprehensive regulations that could make the use of allogenic MSCs for large-scale EV production viable further complicates the scenario. Without these regulations, industry cannot fully explore the potential of human-derived EVs, which represent a promising alternative due to their closer resemblance to human cells.
Another critical challenge is ensuring the safety and efficacy of EV-based cosmetics. The risk of viral transmission through human-derived EVs necessitates specific regulations, including virological analyses of cell donors, to guarantee the safety of these products. However, the lack of such regulations means that the industry must consider alternatives like PRP, which is already regulated by sanitary authorities and naturally contains EVs. The autologous administration of EVs in PRP mitigates the risk of viral transmission, making it a suitable alternative for personalized skincare protocols. Nevertheless, the industry still faces the challenge of proving the efficacy of these alternatives in delivering the desired cosmetic benefits. The limited transcriptional similarities between human and non-human EVs may affect their performance, and without robust regulatory guidelines, the industry struggles to establish standardized methods for evaluating the safety and efficacy of these products.
In this regard, the release of the Guideline on Quality, Non-clinical and Clinical Assessment of Extracellular Vesicle Therapy Products by Korea’s National Institute of Food and Drug Safety Evaluation (NIFDS) in September 2024 marks a pivotal moment in the global regulatory landscape for advanced biologics. This document establishes a comprehensive framework for the evaluation of therapies based on EVs, including exosomes derived from human cells, and sets a precedent for international harmonization in this rapidly evolving field.
This guidance is the first of its kind to systematically address the unique challenges posed by EV-based therapeutics. While regulatory agencies such as the EMA, FDA, and Anvisa have issued general recommendations for advanced therapy medicinal products (ATMPs), the NIFDS document is distinguished by its specificity and depth regarding EVs. It provides a blueprint that other regulatory bodies can adapt, fostering consistency in product development, safety evaluation, and clinical translation.
Among the main contributions of the Guideline on Quality, Non-clinical and Clinical Assessment of Extracellular Vesicle Therapy Products are (i) the definition and classification of EVs, positioning exosomes as therapeutic agents, (ii) standardization of quality attributes, including particle size distribution, surface markers, and cargo characterization, (iii) risk-based non-clinical evaluation, tailored to the biological complexity of EVs and, (iv) clinical trial design considerations, including dose rationale, biodistribution, and immunogenicity.
Although the Korea’s 2024 guidance on extracellular vesicle therapy products represents a landmark achievement in the regulation of next-generation biologics, it is not applied for cosmetic products. However, it provides a robust and detailed framework, it not only accelerates the safe development of exosome-based therapies but also serves as a model for global regulatory convergence for cosmetic industry. As the therapeutic promise of EVs continues to unfold, this guidance will be instrumental in shaping the future of EV-based products.

Author Contributions

Conceptualization, writing and review V.D.C., F.F.R. and R.P.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

V.D.C. and F.F.R. the authors are employees of GEC Cosmetics Enterprise. The author R.P.A. was employer of BioDecision Analytics. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. Grand View Research Cosmetics Market Size, Share & Trends Analysis Report By Product (Skin Care, Hair Care), By End-User (Men, Women), By Distribution Channel (Offline, Online), By Region (North America, Europe), And Segment Forecasts, 2024–2030. Available online: https://www.grandviewresearch.com/industry-analysis/cosmetics-market (accessed on 25 August 2025).
  2. Han, J.H.; Kim, H.S. Skin Deep: The Potential of Microbiome Cosmetics. J. Microbiol. 2024, 62, 181–199. [Google Scholar] [CrossRef] [PubMed]
  3. Woolery-Lloyd, H.; Andriessen, A.; Day, D.; Gonzalez, N.; Green, L.; Grice, E.; Henry, M. Review of the Microbiome in Skin Aging and the Effect of a Topical Prebiotic Containing Thermal Spring Water. J. Cosmet. Dermatol. 2023, 22, 96–102. [Google Scholar] [CrossRef] [PubMed]
  4. Lolou, V.; Panayiotidis, M.I. Functional Role of Probiotics and Prebiotics on Skin Health and Disease. Fermentation 2019, 5, 41. [Google Scholar] [CrossRef]
  5. Thakur, A.; Shah, D.; Rai, D.; Parra, D.C.; Pathikonda, S.; Kurilova, S.; Cili, A. Therapeutic Values of Exosomes in Cosmetics, Skin Care, Tissue Regeneration, and Dermatological Diseases. Cosmetics 2023, 10, 65. [Google Scholar] [CrossRef]
  6. Queen, D.; Avram, M.R. Exosomes for Treating Hair Loss: A Review of Clinical Studies. Dermatol. Surg. 2024, 51, 409–415. [Google Scholar] [CrossRef]
  7. Dal’Forno-Dini, T.; Birck, M.S.; Rocha, M.; Bagatin, E. Exploring the Reality of Exosomes in Dermatology. Bras. Dermatol. 2025, 100, 121–130. [Google Scholar] [CrossRef]
  8. Cohen, M.; Austin, E.; Masub, N.; Kurtti, A.; George, C.; Jagdeo, J. Home-Based Devices in Dermatology: A Systematic Review of Safety and Efficacy. Arch. Dermatol. Res. 2022, 314, 239–246. [Google Scholar] [CrossRef]
  9. Scott, J.A.; Banga, A.K. Cosmetic Devices Based on Active Transdermal Technologies. Ther. Deliv. 2015, 6, 1089–1099. [Google Scholar] [CrossRef]
  10. Hamed, R.; Abu Nahia, B.J.; Alkilani, A.Z.; Al-Adhami, Y.; Obaidat, R. Recent Advances in Microneedling-Assisted Cosmetic Applications. Cosmetics 2024, 11, 51. [Google Scholar] [CrossRef]
  11. Grand View Research Exosomes Market Size, Share & Trends Analysis Report by Product & Service (Kits & Reagents, Services), by Workflow (Isolation Methods, Downstream Analysis), by Application, by End-Use, by Region, and Segment Forecasts, 2025–2030. Available online: https://www.grandviewresearch.com/industry-analysis/exosomes-market (accessed on 25 August 2025).
  12. Villarreal-Gómez, L.J.; Origel-Lucio, S.; Hernández-Hernández, D.A.; Pérez-González, G.L. Use of Exosomes for Cosmetics Applications. Cosmetics 2025, 12, 9. [Google Scholar] [CrossRef]
  13. Kerkis, I.; Araldi, R.; Wenceslau, C.; Mendes, T. Advances in Cellular and Cell-Free Therapy Medicinal Products for Huntigton’s Disease Treatment. In From Physiopatology to Treatment of Huntigton’s Disease; InTech: Penang, Malaysia, 2022; pp. 1–27. [Google Scholar]
  14. Da Costa, V.R.; Araldi, R.P.; Vigerelli, H.; D’Ámelio, F.; Mendes, T.B.; Gonzaga, V.; Policíquio, B.; Colozza-Gama, G.A.; Valverde, C.W.; Kerkis, I. Exosomes in the Tumor Microenvironment: From Biology to Clinical Applications. Cells 2021, 10, 2617. [Google Scholar] [CrossRef]
  15. Teixeira, M.R.; Alievi, A.L.; da Costa, V.R.; Dias Pinto, J.R.; Araldi, R.P. Therapeutic Potential of Extracellular Vesicles in Parkinson’s Disease. Explor. Neurosci. 2023, 2, 106–122. [Google Scholar] [CrossRef]
  16. Araldi, R.P.; Delvalle, D.A.; da Costa, V.R.; Alievi, A.L.; Teixeira, M.R.; Dias Pinto, J.R.; Kerkis, I. Exosomes as a Nano-Carrier for Chemotherapeutics: A New Era of Oncology. Cells 2023, 12, 2144. [Google Scholar] [CrossRef]
  17. Welsh, J.A.; Goberdhan, D.C.I.; O’Driscoll, L.; Buzas, E.I.; Blenkiron, C.; Bussolati, B.; Cai, H.; Di Vizio, D.; Driedonks, T.A.P.; Erdbrügger, U.; et al. Minimal Information for Studies of Extracellular Vesicles (MISEV2023): From Basic to Advanced Approaches. J. Extracell. Vesicles 2024, 13, e12404. [Google Scholar] [CrossRef] [PubMed]
  18. Chargaff, E. Cell Structure and the Problem of Blood Coagulation. J. Biol. Chem. 1945, 160, 351–359. [Google Scholar] [CrossRef]
  19. Chargaff, E.; West, R. The Biological Significant of the Thrombopastic Protein of Blood. J. Biol. Chem. 1946, 166, 189–197. [Google Scholar] [CrossRef]
  20. Wolf, P. The Nature and Significance of Platelet Products in Human Plasma. Br. J. Haematol. 1967, 13, 269–288. [Google Scholar] [CrossRef]
  21. Crawford, N. The Presence of Contractile Proteins in Platelet Microparticles Isolated from Human and Animal Platelet-free Plasma. Br. J. Haematol. 1971, 21, 53–69. [Google Scholar] [CrossRef]
  22. Couch, Y.; Buzàs, E.I.; Di Vizio, D.; Gho, Y.S.; Harrison, P.; Hill, A.F.; Lötvall, J.; Raposo, G.; Stahl, P.D.; Théry, C.; et al. A Brief History of Nearly EV-erything—The Rise and Rise of Extracellular Vesicles. J. Extracell. Vesicles 2021, 10, e12144. [Google Scholar] [CrossRef]
  23. Nunez, E.A.; Wallis, J.; Gershon, M.D. Secretory processes in follicular cells of the bat thyroid. III. The occurrence of extracellular vesicles and colloid droplets during arousal from hibernation. Am. J. Anat. 1974, 141, 179–201. [Google Scholar] [CrossRef]
  24. Levine, P.H.; Horoszewicz, J.S.; Grace, J.T.; Chai, L.S.; Ellison, R.R.; Holland, J.F. Relationship between Clinical Status of Leukemic Patients and Virus-like Particles in Their Plasma. Cancer 1967, 20, 1563–1577. [Google Scholar] [CrossRef]
  25. Seman, G.; Gallager, H.S.; Lukeman, J.M.; Dmochowski, L. Studies on the Presence of Particles Resembling RNA Virus Particles in Human Breast Tumors, Pleural Effusions, Their Tissue Cultures, and Milk. Cancer 1971, 28, 1431–1442. [Google Scholar] [CrossRef]
  26. Fawcett, D.W. Electron Microscope Observations on Intracellular Virus-Like Particles Associated with The Cells of The Lucké Renal Adenocarcinoma. J. Cell Biol. 1956, 2, 725–742. [Google Scholar] [CrossRef] [PubMed]
  27. Lunger, P.D.; Lucas, J.C.; Shipkey, F.H. The Ultramorphology of Milk Fractions from Normal and Breast Cancer Patients. A Preliminary Report. Cancer 1964, 17, 549–557. [Google Scholar] [CrossRef] [PubMed]
  28. Prince, A.M.; Adams, W.R. Virus-like Particles in Human Plasma and Serum: Role of Platelet Lysosomes. J. Natl. Cancer Inst. 1966, 37, 153–166. [Google Scholar] [PubMed]
  29. Dalton, A.J. Microvesicles and Vesicles of Multivesicular Bodies Versus “Virus-Like” Particles. J. Natl. Cancer Inst. 1975, 54, 1137–1148. [Google Scholar] [CrossRef]
  30. Harding, C.; Heuser, J.; Stahl, P. Receptor-Mediated Endocytosis of Transferrin and Recycling of the Transferrin Receptor in Rat Reticulocytes. J. Cell Biol. 1983, 97, 329–339. [Google Scholar] [CrossRef]
  31. Pan, B.-T.; Johnstone, R.M. Fate of the Transferrin Receptor during Maturation of Sheep Reticulocytes in Vitro: Selective Externalization of the Receptor. Cell 1983, 33, 967–978. [Google Scholar] [CrossRef]
  32. Johnstone, R.M.; Mathew, A.; Mason, A.B.; Teng, K. Exosome Formation during Maturation of Mammalian and Avian Reticulocytes: Evidence That Exosome Release Is a Major Route for Externalization of Obsolete Membrane Proteins. J. Cell Physiol. 1991, 147, 27–36. [Google Scholar] [CrossRef]
  33. Lee, Y.J.; Jy, W.; Horstman, L.L.; Janania, J.; Reyes, Y.; Kelley, R.E.; Ahn, Y.S. Elevated Platelet Microparticles in Transient Ischemic Attacks, Lacunar Infarcts, and Multiinfarct Dementias. Thromb. Res. 1993, 72, 295–304. [Google Scholar] [CrossRef]
  34. Powell, J.J.; Harvey, R.S.; Thompson, R.P. Microparticles in Crohn’s Disease—Has the Dust Settled? Gut 1996, 39, 340–341. [Google Scholar] [CrossRef]
  35. Johnstone, R.; Bianchini, A.; Teng, K. Reticulocyte Maturation and Exosome Release: Transferrin Receptor Containing Exosomes Shows Multiple Plasma Membrane Functions. Blood 1989, 74, 1844–1851. [Google Scholar] [CrossRef]
  36. Raposo, G.; Nijman, H.W.; Stoorvogel, W.; Liejendekker, R.; Harding, C.V.; Melief, C.J.; Geuze, H.J. B Lymphocytes Secrete Antigen-Presenting Vesicles. J. Exp. Med. 1996, 183, 1161–1172. [Google Scholar] [CrossRef] [PubMed]
  37. Zhang, Y.; Lan, M.; Chen, Y. Minimal Information for Studies of Extracellular Vesicles (MISEV): Ten-Year Evolution (2014–2023). Pharmaceutics 2024, 16, 1394. [Google Scholar] [CrossRef] [PubMed]
  38. Lee, Y.J.; Shin, K.J.; Chae, Y.C. Regulation of Cargo Selection in Exosome Biogenesis and Its Biomedical Applications in Cancer. Exp. Mol. Med. 2024, 56, 877–889. [Google Scholar] [CrossRef] [PubMed]
  39. Di Bella, M.A. Overview and Update on Extracellular Vesicles: Considerations on Exosomes and Their Application in Modern Medicine. Biology 2022, 11, 804. [Google Scholar] [CrossRef]
  40. Skotland, T.; Hessvik, N.P.; Sandvig, K.; Llorente, A. Exosomal Lipid Composition and the Role of Ether Lipids and Phosphoinositides in Exosome Biology. J. Lipid Res. 2019, 60, 9–18. [Google Scholar] [CrossRef]
  41. Kumeda, N.; Ogawa, Y.; Akimoto, Y.; Kawakami, H.; Tsujimoto, M.; Yanoshita, R. Characterization of Membrane Integrity and Morphological Stability of Human Salivary Exosomes. Biol. Pharm. Bull. 2017, 40, 1183–1191. [Google Scholar] [CrossRef]
  42. Araldi, R.P.; D’Amelio, F.; Vigerelli, H.; de Melo, T.C.; Kerkis, I. Stem Cell-Derived Exosomes as Therapeutic Approach for Neurodegenerative Ddsorders: From Biology to Biotechnology. Cells 2020, 9, 2663. [Google Scholar] [CrossRef]
  43. Ogorevc, E.; Kralj-Iglic, V.; Veranic, P. The Role of Extracellular Vesicles in Phenotypic Cancer Transformation. Radiol. Oncol. 2013, 47, 197–205. [Google Scholar] [CrossRef]
  44. Gurung, S.; Perocheau, D.; Touramanidou, L.; Baruteau, J. The Exosome Journey: From Biogenesis to Uptake and Intracellular Signalling. Cell Commun. Signal. 2021, 19, 47. [Google Scholar] [CrossRef]
  45. Liu, S.-L.; Sun, P.; Li, Y.; Liu, S.-S.; Lu, Y. Exosomes as Critical Mediators of Cell-to-Cell Communication in Cancer Pathogenesis and Their Potential Clinical Application. Transl. Cancer Res. 2019, 8, 298–311. [Google Scholar] [CrossRef] [PubMed]
  46. Lee, K.S.; Choi, J.S.; Cho, Y.W. Reprogramming of Cancer Stem Cells into Non-Tumorigenic Cells Using Stem Cell Exosomes for Cancer Therapy. Biochem. Biophys. Res. Commun. 2019, 512, 511–516. [Google Scholar] [CrossRef] [PubMed]
  47. Mittelbrunn, M.; Gutiérrez-Vázquez, C.; Villarroya-Beltri, C.; González, S.; Sánchez-Cabo, F.; González, M.Á.; Bernad, A.; Sánchez-Madrid, F. Unidirectional Transfer of MicroRNA-Loaded Exosomes from T Cells to Antigen-Presenting Cells. Nat. Commun. 2011, 2, 282. [Google Scholar] [CrossRef] [PubMed]
  48. Peak, T.C.; Praharaj, P.P.; Panigrahi, G.K.; Doyle, M.; Su, Y.; Schlaepfer, I.R.; Singh, R.; Vander Griend, D.J.; Alickson, J.; Hemal, A.; et al. Exosomes Secreted by Placental Stem Cells Selectively Inhibit Growth of Aggressive Prostate Cancer Cells. Biochem. Biophys. Res. Commun. 2018, 499, 1004–1010. [Google Scholar] [CrossRef]
  49. Showalter, M.R.; Wancewicz, B.; Fiehn, O.; Archard, J.A.; Clayton, S.; Wagner, J.; Deng, P.; Halmai, J.; Fink, K.D.; Bauer, G.; et al. Primed Mesenchymal Stem Cells Package Exosomes with Metabolites Associated with Immunomodulation. Biochem. Biophys. Res. Commun. 2019, 512, 729–735. [Google Scholar] [CrossRef]
  50. Sato, Y.; Yaguchi, M.; Okuno, Y.; Ishimaru, H.; Sagou, K.; Ozaki, S.; Suzuki, T.; Inagaki, T.; Umeda, M.; Watanabe, T.; et al. Epstein–Barr Virus Tegument Protein BGLF2 in Exosomes Released from Virus-Producing Cells Facilitates de Novo Infection. Cell Commun. Signal. 2022, 20, 95. [Google Scholar] [CrossRef]
  51. Lee, M.; Ban, J.-J.; Kim, K.Y.; Jeon, G.S.; Im, W.; Sung, J.-J.; Kim, M. Adipose-Derived Stem Cell Exosomes Alleviate Pathology of Amyotrophic Lateral Sclerosis in Vitro. Biochem. Biophys. Res. Commun. 2016, 479, 434–439. [Google Scholar] [CrossRef]
  52. Maas, S.L.N.; Breakefield, X.O.; Weaver, A.M. Extracellular Vesicles: Unique Intercellular Delivery Vehicles. Trends Cell Biol. 2017, 27, 172–188. [Google Scholar] [CrossRef]
  53. Yuan, Z.; Kolluri, K.K.; Gowers, K.H.C.; Janes, S.M. TRAIL Delivery by MSC-Derived Extracellular Vesicles Is an Effective Anticancer Therapy. J. Extracell. Vesicles 2017, 6, 1265291. [Google Scholar] [CrossRef]
  54. Mukhopadhya, A.; Tsiapalis, D.; McNamee, N.; Talbot, B.; O’Driscoll, L. Doxorubicin Loading into Milk and Mesenchymal Stem Cells’ Extracellular Vesicles as Drug Delivery Vehicles. Pharmaceutics 2023, 15, 718. [Google Scholar] [CrossRef]
  55. Haney, M.J.; Zhao, Y.; Jin, Y.S.; Li, S.M.; Bago, J.R.; Klyachko, N.L.; Kabanov, A.V.; Batrakova, E.V. Macrophage-Derived Extracellular Vesicles as Drug Delivery Systems for Triple Negative Breast Cancer (TNBC) Therapy. J. Neuroimmune Pharmacol. 2020, 15, 487–500. [Google Scholar] [CrossRef]
  56. Alkhilaiwi, F.; Yuan, H. Detection of HPV RNA in Extracellular Vesicles from Neuroendocrine Cervical Cancer Cells. Viruses 2022, 14, 2226. [Google Scholar] [CrossRef]
  57. Kouroumalis, E.; Tsomidis, I.; Voumvouraki, A. Extracellular Vesicles in Viral Liver Diseases. Viruses 2024, 16, 1785. [Google Scholar] [CrossRef]
  58. Zhao, M.; Nanbo, A.; Sun, L.; Lin, Z. Extracellular Vesicles in Epstein-Barr Virus’ Life Cycle and Pathogenesis. Microorganisms 2019, 7, 48. [Google Scholar] [CrossRef] [PubMed]
  59. Gupta, A.K.; Wang, T.; Rapaport, J.A.; Talukder, M. Therapeutic Potential of Extracellular Vesicles (Exosomes) Derived From Platelet-Rich Plasma: A Literature Review. J. Cosmet. Dermatol. 2025, 24, e16709. [Google Scholar] [CrossRef] [PubMed]
  60. Hesseler, M.J.; Shyam, N. Platelet-Rich Plasma and Its Utility in Medical Dermatology: A Systematic Review. J. Am. Acad. Dermatol. 2019, 81, 834–846. [Google Scholar] [CrossRef] [PubMed]
  61. Sakata, R.; Reddi, A.H. Platelet-Rich Plasma Modulates Actions on Articular Cartilage Lubrication and Regeneration. Tissue Eng. Part. B Rev. 2016, 22, 408–419. [Google Scholar] [CrossRef]
  62. Dashore, S.; Chouhan, K.; Nanda, S.; Sharma, A. Preparation of Platelet-Rich Plasma: National IADVL PRP Taskforce Recommendations. Indian. Dermatol. Online J. 2021, 12, 12. [Google Scholar] [CrossRef]
  63. Vladulescu, D.; Scurtu, L.G.; Simionescu, A.A.; Scurtu, F.; Popescu, M.I.; Simionescu, O. Platelet-Rich Plasma (PRP) in Dermatology: Cellular and Molecular Mechanisms of Action. Biomedicines 2023, 12, 7. [Google Scholar] [CrossRef]
  64. Heijnen, H.; van der Sluijs, P. Platelet secretory behaviour: As diverse as the granules … or not? J. Thromb. Haemost. 2015, 13, 2141–2151. [Google Scholar] [CrossRef]
  65. Hesseler, M.J.; Shyam, N. Platelet-Rich Plasma and Its Utility in the Treatment of Acne Scars: A Systematic Review. J. Am. Acad. Dermatol. 2019, 80, 1730–1745. [Google Scholar] [CrossRef]
  66. Guo, S.-C.; Tao, S.-C.; Yin, W.-J.; Qi, X.; Yuan, T.; Zhang, C.-Q. Exosomes Derived from Platelet-Rich Plasma Promote the Re-Epithelization of Chronic Cutaneous Wounds via Activation of YAP in a Diabetic Rat Model. Theranostics 2017, 7, 81–96. [Google Scholar] [CrossRef]
  67. Torreggiani, E.; Perut, F.; Roncuzzi, L.; Zini, N.; Baglìo, S.; Baldini, N. Exosomes: Novel Effectors of Human Platelet Lysate Activity. Eur. Cell Mater. 2014, 28, 137–151. [Google Scholar] [CrossRef]
  68. Iyer, S.R.; Scheiber, A.L.; Yarowsky, P.; Henn, R.F.; Otsuru, S.; Lovering, R.M. Exosomes Isolated From Platelet-Rich Plasma and Mesenchymal Stem Cells Promote Recovery of Function After Muscle Injury. Am. J. Sports Med. 2020, 48, 2277–2286. [Google Scholar] [CrossRef]
  69. Kerkis, I.; Valverde Wenceslau, C.; Pinheiro Araldi, R. Stem Cells from Dental Pulp of Deciduous Teeth: Twenty Years of Experience. In Recent Update on Mesenchymal Stem Cells; IntechOpen: London, UK, 2024. [Google Scholar]
  70. Araldi, R.P.; Viana, M.; Colozza-Gama, G.A.; Dias-Pinto, J.R.; Ankol, L.; Valverde, C.W.; Perlson, E.; Kerkis, I. Unique Transcriptional Signatures Observed in Stem Cells from the Dental Pulp of Deciduous Teeth Produced on a Large Scale. Pharmacologia 2023, 14, 72–95. [Google Scholar] [CrossRef]
  71. Friedenstein, A.J.; Piatetzky-Shapiro, I.I.; Petrakova, K. Osteogenesis in Transplants of Bone Marrow Cells. J. Embryol. Exp. Morphol. 1966, 16, 381–390. [Google Scholar] [CrossRef] [PubMed]
  72. Friedenstein, A.J.; Chailakhjan, R.K.; Lalykina, K.S. The Development of Fibroblast Colonies in Monolayer Cultures of Guinea-Pig Bone Marrow and Spleen Cells. Cell Prolif. 1970, 3, 393–403. [Google Scholar] [CrossRef]
  73. Friedenstein, A.J.; Chailakhyan, R.K.; Gerasimov, U. V Bone Marrow Osteogenic Stem Cells: In Vitro Cultivation and Transplantation in Diffusion Chambers. Cell Prolif. 1987, 20, 263–272. [Google Scholar] [CrossRef] [PubMed]
  74. Friedenstein, A.J.; Chailakhyan, R.K.; Latsinik, N.V.; Panasyuk, A.F.; Keiliss-Borok, I.V. Stromal Cells Responsible for Transferring the Microenvironment of the Hemopoietic Tissues. Transplantation 1974, 17, 331–340. [Google Scholar] [CrossRef]
  75. Caplan, A.I. Mesenchymal Stem Cells. J. Orthop. Res. 1991, 9, 641–650. [Google Scholar] [CrossRef] [PubMed]
  76. Haynesworth, S.E.; Barer, M.A.; Caplan, A.I. Cell Surface Antigens on Human Marrow-Derived Mesenchymal Cells Are Detected by Monoclonal Antibodies. Bone 1992, 13, 69–80. [Google Scholar] [CrossRef] [PubMed]
  77. Barry, F.P.; Boynton, R.E.; Haynesworth, S.; Murphy, J.M.; Zaia, J. The Monoclonal Antibody SH-2, Raised against Human Mesenchymal Stem Cells, Recognizes an Epitope on Endoglin (CD105). Biochem. Biophys. Res. Commun. 1999, 265, 134–139. [Google Scholar] [CrossRef] [PubMed]
  78. Barry, F.; Boynton, R.; Murphy, M.; Zaia, J. The SH-3 and SH-4 Antibodies Recognize Distinct Epitopes on CD73 from Human Mesenchymal Stem Cells. Biochem. Biophys. Res. Commun. 2001, 289, 519–524. [Google Scholar] [CrossRef]
  79. Dominici, M.; Le Blanc, K.; Mueller, I.; Slaper-Cortenbach, I.; Marini, F.; Krause, D.; Deans, R.; Keating, A.; Prockop, D.; Horwitz, E. Minimal Criteria for Defining Multipotent Mesenchymal Stromal Cells. Int. Soc. Cell. Ther. Position. Statement. Cytotherapy 2006, 8, 315–317. [Google Scholar] [CrossRef]
  80. Lizier, N.F.; Kerkis, A.; Gomes, C.M.; Hebling, J.; Oliveira, C.F.; Caplan, A.I.; Kerkis, I. Scaling-up of Dental Pulp Stem Cells Isolated from Multiple Niches. PLoS ONE 2012, 7, e39885. [Google Scholar] [CrossRef]
  81. Qu, Q.; Fu, B.; Long, Y.; Liu, Z.-Y.; Tian, X.-H. Current Strategies for Promoting the Large-Scale Production of Exosomes. Curr. Neuropharmacol. 2023, 21, 1964–1979. [Google Scholar] [CrossRef]
  82. Almouh, M.; Pakravan, K.; Ghazimoradi, M.H.; Motamed, R.; Bakhshinejad, B.; Hassan, Z.M.; Babashah, S. Exosomes Released by Oxidative Stress-Induced Mesenchymal Stem Cells Promote Murine Mammary Tumor Progression through Activating the STAT3 Signaling Pathway. Mol. Cell Biochem. 2024, 479, 3375–3391. [Google Scholar] [CrossRef]
  83. Feng, Z.-Y.; Zhang, Q.-Y.; Tan, J.; Xie, H.-Q. Techniques for Increasing the Yield of Stem Cell-Derived Exosomes: What Factors May Be Involved? Sci. China Life Sci. 2022, 65, 1325–1341. [Google Scholar] [CrossRef]
  84. Lee, H.; Cho, H.-J.; Han, Y.; Lee, S.H. Mid- to Long-Term Efficacy and Safety of Stem Cell Therapy for Acute Myocardial Infarction: A Systematic Review and Meta-Analysis. Stem Cell Res. Ther. 2024, 15, 290. [Google Scholar] [CrossRef]
  85. Hoang, D.M.; Pham, P.T.; Bach, T.Q.; Ngo, A.T.L.; Nguyen, Q.T.; Phan, T.T.K.; Nguyen, G.H.; Le, P.T.T.; Hoang, V.T.; Forsyth, N.R.; et al. Stem Cell-Based Therapy for Human Diseases. Signal Transduct. Target. Ther. 2022, 7, 272. [Google Scholar] [CrossRef]
  86. Wang, Y.; Yi, H.; Song, Y. The Safety of MSC Therapy over the Past 15 Years: A Meta-Analysis. Stem Cell Res. Ther. 2021, 12, 545. [Google Scholar] [CrossRef] [PubMed]
  87. Brooke, G.; Tong, H.; Levesque, J.-P.; Atkinson, K. Molecular Trafficking Mechanisms of Multipotent Mesenchymal Stem Cells Derived from Human Bone Marrow and Placenta. Stem Cells Dev. 2008, 17, 929–940. [Google Scholar] [CrossRef] [PubMed]
  88. Sakai, K.; Yamamoto, A.; Matsubara, K.; Nakamura, S.; Naruse, M.; Yamagata, M.; Sakamoto, K.; Tauchi, R.; Wakao, N.; Imagama, S.; et al. Human Dental Pulp-Derived Stem Cells Promote Locomotor Recovery after Complete Transection of the Rat Spinal Cord by Multiple Neuro-Regenerative Mechanisms. J. Clin. Investig. 2012, 122, 80–90. [Google Scholar] [CrossRef]
  89. Shamir, C.; Venugopal, C.; Dhanushkodi, A. Dental Pulp Stem Cells for Treating Neurodegenerative Diseases. Neural Regen. Res. 2015, 10, 1910–1911. [Google Scholar] [CrossRef] [PubMed]
  90. Hmadcha, A.; Martin-Montalvo, A.; Gauthier, B.R.; Soria, B.; Capilla-Gonzalez, V. Therapeutic Potential of Mesenchymal Stem Cells for Cancer Therapy. Front. Bioeng. Biotechnol. 2020, 8, 43. [Google Scholar] [CrossRef]
  91. Archambault, J.; Moreira, A.; McDaniel, D.; Winter, L.; Sun, L.; Hornsby, P. Therapeutic Potential of Mesenchymal Stromal Cells for Hypoxic Ischemic Encephalopathy: A Systematic Review and Meta-Analysis of Preclinical Studies. PLoS ONE 2017, 12, e0189895. [Google Scholar] [CrossRef]
  92. Cai, Z.; Liu, D.; Yang, Y.; Xie, W.; He, M.; Yu, D.; Wu, Y.; Wang, X.; Xiao, W.; Li, Y. The Role and Therapeutic Potential of Stem Cells in Skeletal Muscle in Sarcopenia. Stem Cell Res. Ther. 2022, 13, 28. [Google Scholar] [CrossRef]
  93. Guo, M.; Yin, Z.; Chen, F.; Lei, P. Mesenchymal Stem Cell-Derived Exosome: A Promising Alternative in the Therapy of Alzheimer’s Disease. Alzheimers Res. Ther. 2020, 12, 109. [Google Scholar] [CrossRef]
  94. de Souza, C.F.; de Napoli, P.; Han, S.W.; de Lima, V.C.; Carvalho, A.C.d.C. Células-tronco mesenquimais: Células ideais para a regeneração cardíaca? Rev. Bras. De Cardiol. Invasiva 2010, 18, 344–353. [Google Scholar] [CrossRef][Green Version]
  95. Baek, G.; Choi, H.; Kim, Y.; Lee, H.C.; Choi, C. Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapeutics and as a Drug Delivery Platform. Stem Cells Transl. Med. 2019, 8, 880–886. [Google Scholar] [CrossRef]
  96. Cheng, L.; Zhang, K.; Wu, S.; Cui, M.; Xu, T. Focus on Mesenchymal Stem Cell-Derived Exosomes: Opportunities and Challenges in Cell-Free Therapy. Stem Cells Int. 2017, 2017, 6305295. [Google Scholar] [CrossRef]
  97. Evangelista, A.; Soares, M.B.P.; Villarreal, C.F. Cell-Free Therapy: A Neuroregenerative Approach to Sensory Neuropathy? Neural Regen. Res. 2019, 14, 1383–1384. [Google Scholar] [CrossRef]
  98. Gomzikova, M.O.; Rizvanov, A.A. Current Trends in Regenerative Medicine: From Cell to Cell-Free Therapy. Bionanoscience 2017, 7, 240–245. [Google Scholar] [CrossRef]
  99. Duffield, J.S.; Park, K.M.; Hsiao, L.-L.; Kelley, V.R.; Scadden, D.T.; Ichimura, T.; Bonventre, J.V. Restoration of Tubular Epithelial Cells during Repair of the Postischemic Kidney Occurs Independently of Bone Marrow-Derived Stem Cells. J. Clin. Investig. 2005, 115, 1743–1755. [Google Scholar] [CrossRef]
  100. Chapel, A.; Bertho, J.M.; Bensidhoum, M.; Fouillard, L.; Young, R.G.; Frick, J.; Demarquay, C.; Cuvelier, F.; Mathieu, E.; Trompier, F.; et al. Mesenchymal Stem Cells Home to Injured Tissues When Co-Infused with Hematopoietic Cells to Treat a Radiation-Induced Multi-Organ Failure Syndrome. J. Gene Med. 2003, 5, 1028–1038. [Google Scholar] [CrossRef]
  101. Devine, S.M.; Cobbs, C.; Jennings, M.; Bartholomew, A.; Hoffman, R. Mesenchymal Stem Cells Distribute to a Wide Range of Tissues Following Systemic Infusion into Nonhuman Primates. Blood 2003, 101, 2999–3001. [Google Scholar] [CrossRef] [PubMed]
  102. Kristocheck, M.; Dias, L.D.; Ghem, C.; Eibel, B.; Kalil, R.A.K.; Markoski, M.M. The Homing of Bone Marrow Stem Cells Is Differentially Activated in Ischemic and Valvular Heart Diseases and Influenced by Beta-Blockers. J. Transl. Med. 2018, 16, 133. [Google Scholar] [CrossRef] [PubMed]
  103. Biancone, L.; Bruno, S.; Deregibus, M.C.; Tetta, C.; Camussi, G. Therapeutic Potential of Mesenchymal Stem Cell-Derived Microvesicles. Nephrol. Dial. Transplant. 2012, 27, 3037–3042. [Google Scholar] [CrossRef]
  104. Eggenhofer, E.; Benseler, V.; Kroemer, A.; Popp, F.C.; Geissler, E.K.; Schlitt, H.J.; Baan, C.C.; Dahlke, M.H.; Hoogduijn, M.J. Mesenchymal Stem Cells Are Short-Lived and Do Not Migrate beyond the Lungs after Intravenous Infusion. Front. Immunol. 2012, 3, 297. [Google Scholar] [CrossRef] [PubMed]
  105. Fujita, Y.; Kadota, T.; Araya, J.; Ochiya, T.; Kuwano, K. Clinical Application of Mesenchymal Stem Cell-Derived Extracellular Vesicle-Based Therapeutics for Inflammatory Lung Diseases. J. Clin. Med. 2018, 7, 355. [Google Scholar] [CrossRef]
  106. Gao, J.; Dennis, J.E.; Muzic, R.F.; Lundberg, M.; Caplan, A.I. The Dynamic in Vivo Distribution of Bone Marrow-Derived Mesenchymal Stem Cells after Infusion. Cells Tissues Organs 2001, 169, 12–20. [Google Scholar] [CrossRef]
  107. Lee, R.H.; Pulin, A.A.; Seo, M.J.; Kota, D.J.; Ylostalo, J.; Larson, B.L.; Semprun-Prieto, L.; Delafontaine, P.; Prockop, D.J. Intravenous HMSCs Improve Myocardial Infarction in Mice Because Cells Embolized in Lung Are Activated to Secrete the Anti-Inflammatory Protein TSG-6. Cell Stem Cell 2009, 5, 54–63. [Google Scholar] [CrossRef]
  108. Haynesworth, S.E.; Baber, M.A.; Caplan, A.I. Cytokine Expression by Human Marrow-Derived Mesenchymal Progenitor Cells in Vitro: Effects of Dexamethasone and IL-1α. J. Cell Physiol. 1996, 166, 585–592. [Google Scholar] [CrossRef]
  109. Takahashi, M.; Li, T.-S.; Suzuki, R.; Kobayashi, T.; Ito, H.; Ikeda, Y.; Matsuzaki, M.; Hamano, K. Cytokines Produced by Bone Marrow Cells Can Contribute to Functional Improvement of the Infarcted Heart by Protecting Cardiomyocytes from Ischemic Injury. Am. J. Physiol. Heart Circ. Physiol. 2006, 291, H886–H893. [Google Scholar] [CrossRef] [PubMed]
  110. Joladarashi, D.; Kishore, R. Mesenchymal Stromal Cell Exosomes in Cardiac Repair. Curr. Cardiol. Rep. 2022, 24, 405–417. [Google Scholar] [CrossRef]
  111. Vizoso, F.J.; Eiro, N.; Cid, S.; Schneider, J.; Perez-Fernandez, R. Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int. J. Mol. Sci. 2017, 18, 1852. [Google Scholar] [CrossRef] [PubMed]
  112. Wendt, S.; Goetzenich, A.; Goettsch, C.; Stoppe, C.; Bleilevens, C.; Kraemer, S.; Benstoem, C. Evaluation of the Cardioprotective Potential of Extracellular Vesicles—A Systematic Review and Meta-Analysis. Sci. Rep. 2018, 8, 15702. [Google Scholar] [CrossRef]
  113. Pishavar, E.; Trentini, M.; Zanotti, F.; Camponogara, F.; Tiengo, E.; Zanolla, I.; Bonora, M.; Zavan, B. Exosomes as Neurological Nanosized Machines. ACS Nanosci. Au 2022, 2, 284–296. [Google Scholar] [CrossRef]
  114. Li, Y.; Fang, B. Neural Stem Cell-Derived Extracellular Vesicles: The Light of Central Nervous System Diseases. Biomed. Pharmacother. 2023, 165, 115092. [Google Scholar] [CrossRef]
  115. Haider, K.H.; Aramini, B. Mircrining the Injured Heart with Stem Cell-Derived Exosomes: An Emerging Strategy of Cell-Free Therapy. Stem Cell Res. Ther. 2020, 11, 23. [Google Scholar] [CrossRef]
  116. Lu, J.; Zhang, Y.; Yang, X.; Zhao, H. Harnessing Exosomes as Cutting-Edge Drug Delivery Systems for Revolutionary Osteoarthritis Therapy. Biomed. Pharmacother. 2023, 165, 115135. [Google Scholar] [CrossRef]
  117. Han, C.; Sun, X.; Liu, L.; Jiang, H.; Shen, Y.; Xu, X.; Li, J.; Zhang, G.; Huang, J.; Lin, Z.; et al. Exosomes and Their Therapeutic Potentials of Stem Cells. Stem Cells Int. 2016, 2016, 7653489. [Google Scholar] [CrossRef]
  118. Bu, H.; He, D.; He, X.; Wang, K. Exosomes: Isolation, Analysis, and Applications in Cancer Detection and Therapy. ChemBioChem 2019, 20, 451–461. [Google Scholar] [CrossRef]
  119. Woith, E.; Guerriero, G.; Hausman, J.-F.; Renaut, J.; Leclercq, C.C.; Weise, C.; Legay, S.; Weng, A.; Melzig, M.F. Plant Extracellular Vesicles and Nanovesicles: Focus on Secondary Metabolites, Proteins and Lipids with Perspectives on Their Potential and Sources. Int. J. Mol. Sci. 2021, 22, 3719. [Google Scholar] [CrossRef] [PubMed]
  120. Cho, J.H.; Hong, Y.D.; Kim, D.; Park, S.J.; Kim, J.S.; Kim, H.-M.; Yoon, E.J.; Cho, J.-S. Confirmation of Plant-Derived Exosomes as Bioactive Substances for Skin Application through Comparative Analysis of Keratinocyte Transcriptome. Appl. Biol. Chem. 2022, 65, 8. [Google Scholar] [CrossRef]
  121. Hessvik, N.P.; Llorente, A. Current Knowledge on Exosome Biogenesis and Release. Cell. Mol. Life Sci. 2018, 75, 193–208. [Google Scholar] [CrossRef] [PubMed]
  122. Schorey, J.S.; Bhatnagar, S. Exosome Function: From Tumor Immunology to Pathogen Biology. Traffic 2008, 9, 871–881. [Google Scholar] [CrossRef]
  123. Hansen, L.L.; Nielsen, M.E. Plant Exosomes: Using an Unconventional Exit to Prevent Pathogen Entry? J. Exp. Bot. 2018, 69, 59–68. [Google Scholar] [CrossRef]
  124. De Robertis, M.; Sarra, A.; D’Oria, V.; Mura, F.; Bordi, F.; Postorino, P.; Fratantonio, D. Blueberry-Derived Exosome-Like Nanoparticles Counter the Response to TNF-α-Induced Change on Gene Expression in EA.Hy926 Cells. Biomolecules 2020, 10, 742. [Google Scholar] [CrossRef]
  125. Perut, F.; Roncuzzi, L.; Avnet, S.; Massa, A.; Zini, N.; Sabbadini, S.; Giampieri, F.; Mezzetti, B.; Baldini, N. Strawberry-Derived Exosome-Like Nanoparticles Prevent Oxidative Stress in Human Mesenchymal Stromal Cells. Biomolecules 2021, 11, 87. [Google Scholar] [CrossRef]
  126. Mu, J.; Zhuang, X.; Wang, Q.; Jiang, H.; Deng, Z.; Wang, B.; Zhang, L.; Kakar, S.; Jun, Y.; Miller, D.; et al. Interspecies Communication between Plant and Mouse Gut Host Cells through Edible Plant Derived Exosome-like Nanoparticles. Mol. Nutr. Food Res. 2014, 58, 1561–1573. [Google Scholar] [CrossRef] [PubMed]
  127. Tulkens, J.; Vergauwen, G.; Van Deun, J.; Geeurickx, E.; Dhondt, B.; Lippens, L.; De Scheerder, M.-A.; Miinalainen, I.; Rappu, P.; De Geest, B.G.; et al. Increased Levels of Systemic LPS-Positive Bacterial Extracellular Vesicles in Patients with Intestinal Barrier Dysfunction. Gut 2020, 69, 191–193. [Google Scholar] [CrossRef] [PubMed]
  128. Matsuguchi, T.; Takagi, A.; Matsuzaki, T.; Nagaoka, M.; Ishikawa, K.; Yokokura, T.; Yoshikai, Y. Lipoteichoic Acids from Lactobacillus Strains Elicit Strong Tumor Necrosis Factor Alpha-Inducing Activities in Macrophages through Toll-Like Receptor 2. Clin. Vaccine Immunol. 2003, 10, 259–266. [Google Scholar] [CrossRef]
  129. Jo, C.S.; Myung, C.H.; Yoon, Y.C.; Ahn, B.H.; Min, J.W.; Seo, W.S.; Lee, D.H.; Kang, H.C.; Heo, Y.H.; Choi, H.; et al. The Effect of Lactobacillus plantarum Extracellular Vesicles from Korean Women in Their 20s on Skin Aging. Curr. Issues Mol. Biol. 2022, 44, 526–540. [Google Scholar] [CrossRef]
  130. Schaar, V.; Uddback, I.; Nordstrom, T.; Riesbeck, K. Group A Streptococci Are Protected from Amoxicillin-Mediated Killing by Vesicles Containing β—Lactamase Derived from Haemophilus Influenzae. J. Antimicrob. Chemother. 2014, 69, 117–120. [Google Scholar] [CrossRef]
  131. Saint-Pol, J.; Gosselet, F.; Duban-Deweer, S.; Pottiez, G.; Karamanos, Y. Targeting and Crossing the Blood-Brain Barrier with Extracellular Vesicles. Cells 2020, 9, 851. [Google Scholar] [CrossRef]
  132. Surman, M.; Drożdż, A.; Stępień, E.; Przybyło, M. Extracellular Vesicles as Drug Delivery Systems—Methods of Production and Potential Therapeutic Applications. Curr. Pharm. Des. 2019, 25, 132–154. [Google Scholar] [CrossRef]
  133. de Jong, B.; Barros, E.R.; Hoenderop, J.G.J.; Rigalli, J.P. Recent Advances in Extracellular Vesicles as Drug Delivery Systems and Their Potential in Precision Medicine. Pharmaceutics 2020, 12, 1006. [Google Scholar] [CrossRef]
  134. Walker, S.; Busatto, S.; Pham, A.; Tian, M.; Suh, A.; Carson, K.; Quintero, A.; Lafrence, M.; Malik, H.; Santana, M.X.; et al. Extracellular Vesicle-Based Drug Delivery Systems for Cancer Treatment. Theranostics 2019, 9, 8001–8017. [Google Scholar] [CrossRef]
  135. Edem, E.E.; Nathaniel, B.U.; Nebo, K.E.; Obisesan, A.O.; Olabiyi, A.A.; Akinluyi, E.T.; Ishola, A.O. Lactobacillus plantarum Mitigates Sexual-Reproductive Deficits by Modulating Insulin Receptor Expression in the Hypothalamic-Pituitary-Testicular Axis of Hyperinsulinemic Mice. Drug Metab. Pers. Ther. 2021, 36, 321–336. [Google Scholar] [CrossRef]
  136. Nguyen, T.D.T.; Kang, J.H.; Lee, M.S. Characterization of Lactobacillus plantarum PH04, a Potential Probiotic Bacterium with Cholesterol-Lowering Effects. Int. J. Food Microbiol. 2007, 113, 358–361. [Google Scholar] [CrossRef]
  137. Zheng, Z.; Cao, F.-W.; Wang, W.; Yu, J.; Chen, C.; Chen, B.; Liu, J.; Firrman, J.; Renye, J.; Ren, D. Probiotic Characteristics of Lactobacillus plantarum E680 and Its Effect on Hypercholesterolemic Mice. BMC Microbiol. 2020, 20, 239. [Google Scholar] [CrossRef]
  138. Prakoeswa, C.R.S.; Herwanto, N.; Prameswari, R.; Astari, L.; Sawitri, S.; Hidayati, A.N.; Indramaya, D.M.; Kusumowidagdo, E.R.; Surono, I.S. Lactobacillus plantarum IS-10506 Supplementation Reduced SCORAD in Children with Atopic Dermatitis. Benef. Microbes 2017, 8, 833–840. [Google Scholar] [CrossRef]
  139. Nagata, Y.; Yoshida, M.; Kitazawa, H.; Araki, E.; Gomyo, T. Improvements in Seasonal Allergic Disease with Lactobacillus plantarum No. 14. Biosci. Biotechnol. Biochem. 2010, 74, 1869–1877. [Google Scholar] [CrossRef] [PubMed]
  140. Wang, J.; Zeng, Y.; Wang, S.; Liu, H.; Zhang, D.; Zhang, W.; Wang, Y.; Ji, H. Swine-Derived Probiotic Lactobacillus plantarum Inhibits Growth and Adhesion of Enterotoxigenic Escherichia Coli and Mediates Host Defense. Front. Microbiol. 2018, 9, 1364. [Google Scholar] [CrossRef] [PubMed]
  141. Dinev, T.; Beev, G.; Tzanova, M.; Denev, S.; Dermendzhieva, D.; Stoyanova, A. Antimicrobial Activity of Lactobacillus plantarum against Pathogenic and Food Spoilage Microorganisms: A Review. Bulg. J. Vet. Med. 2018, 21, 253–268. [Google Scholar] [CrossRef]
  142. Valdéz, J.C.; Peral, M.C.; Rachid, M.; Santana, M.; Perdigón, G. Interference of Lactobacillus plantarum with Pseudomonas Aeruginosa in Vitro and in Infected Burns: The Potential Use of Probiotics in Wound Treatment. Clin. Microbiol. Infect. 2005, 11, 472–479. [Google Scholar] [CrossRef]
  143. Chen, Y.E.; Fischbach, M.A.; Belkaid, Y. Skin Microbiota–Host Interactions. Nature 2018, 553, 427–436. [Google Scholar] [CrossRef]
  144. Kurata, A.; Kiyohara, S.; Imai, T.; Yamasaki-Yashiki, S.; Zaima, N.; Moriyama, T.; Kishimoto, N.; Uegaki, K. Characterization of Extracellular Vesicles from Lactiplantibacillus plantarum. Sci. Rep. 2022, 12, 13330. [Google Scholar] [CrossRef]
  145. Gong, S.; Zeng, R.; Liu, L.; Wang, R.; Xue, M.; Dong, H.; Wu, Z.; Zhang, Y. Extracellular Vesicles from a Novel Lactiplantibacillus plantarum Strain Suppress Inflammation and Promote M2 Macrophage Polarization. Front. Immunol. 2024, 15, 1459213. [Google Scholar] [CrossRef]
  146. Kang, S.; Jeon, S.; Baek, H.; Hwang, S.; Kim, S.; Youn, S.H.; Kim, J.W.; Jun, S.-H.; Kang, N.-G. Lactobacillus-Derived Artificial Extracellular Vesicles for Skin Rejuvenation and Prevention of Photo-Aging. Biomater. Sci. 2025, 13, 2026–2035. [Google Scholar] [CrossRef]
  147. Rajendran Venkataswamy, K. Perspective Chapter: Exosome-Mediated Pathogen Transmission. In Exosomes—Recent Advances From Bench to Bedside; Intech Open: London, UK, 2023. [Google Scholar]
  148. Hazrati, A.; Soudi, S.; Malekpour, K.; Mahmoudi, M.; Rahimi, A.; Hashemi, S.M.; Varma, R.S. Immune Cells-Derived Exosomes Function as a Double-Edged Sword: Role in Disease Progression and Their Therapeutic Applications. Biomark. Res. 2022, 10, 30. [Google Scholar] [CrossRef] [PubMed]
  149. Rai, A.; Fang, H.; Fatmous, M.; Claridge, B.; Poh, Q.H.; Simpson, R.J.; Greening, D.W. A Protocol for Isolation, Purification, Characterization, and Functional Dissection of Exosomes. Methods Mol Biol. 2021, 2261, 105–149. [Google Scholar] [PubMed]
  150. Chen, Y.; Qi, W.; Wang, Z.; Niu, F. Exosome Source Matters: A Comprehensive Review from the Perspective of Diverse Cellular Origins. Pharmaceutics 2025, 17, 147. [Google Scholar] [CrossRef]
  151. Andriolo, G.; Provasi, E.; Lo Cicero, V.; Brambilla, A.; Soncin, S.; Torre, T.; Milano, G.; Biemmi, V.; Vassalli, G.; Turchetto, L.; et al. Exosomes From Human Cardiac Progenitor Cells for Therapeutic Applications: Development of a GMP-Grade Manufacturing Method. Front. Physiol. 2018, 9, 1169. [Google Scholar] [CrossRef]
  152. Langellotto, M.D.; Rassu, G.; Serri, C.; Demartis, S.; Giunchedi, P.; Gavini, E. Plant-Derived Extracellular Vesicles: A Synergetic Combination of a Drug Delivery System and a Source of Natural Bioactive Compounds. Drug Deliv. Transl. Res. 2025, 15, 831–845. [Google Scholar] [CrossRef]
  153. Yazdanpanah, S.; Romano, S.; Valentino, A.; Galderisi, U.; Peluso, G.; Calarco, A. Plant-Derived Exosomes: Carriers and Cargo of Natural Bioactive Compounds: Emerging Functions and Applications in Human Health. Nanomaterials 2025, 15, 1005. [Google Scholar] [CrossRef]
  154. Majewski, G.; Craw, J.; Falla, T. Accelerated Barrier Repair in Human Skin Explants Induced with a Plant-Derived PPAR-α Activating Complex via Cooperative Interactions. Clin. Cosmet. Investig. Dermatol. 2021, 14, 1271–1293. [Google Scholar] [CrossRef]
  155. Yang, G.H.; Lee, Y.B.; Kang, D.; Choi, E.; Nam, Y.; Lee, K.H.; You, H.-J.; Kang, H.J.; An, S.H.; Jeon, H. Overcome the Barriers of the Skin: Exosome Therapy. Biomater. Res. 2021, 25, 22. [Google Scholar] [CrossRef]
  156. Zingl, F.G.; Leitner, D.R.; Thapa, H.B.; Schild, S. Outer Membrane Vesicles as Versatile Tools for Therapeutic Approaches. microLife 2021, 2, uqab006. [Google Scholar] [CrossRef]
  157. Xue, K.; Wang, L.; Liu, J. Bacterial Outer Membrane Vesicles and Their Functionalization as Vehicles for Bioimaging, Diagnosis and Therapy. Mater. Adv. 2022, 3, 7185–7197. [Google Scholar] [CrossRef]
  158. Effah, C.Y.; Ding, X.; Drokow, E.K.; Li, X.; Tong, R.; Sun, T. Bacteria-Derived Extracellular Vesicles: Endogenous Roles, Therapeutic Potentials and Their Biomimetics for the Treatment and Prevention of Sepsis. Front. Immunol. 2024, 15, 1296061. [Google Scholar] [CrossRef]
  159. Lieberman, L.A. Outer Membrane Vesicles: A Bacterial-Derived Vaccination System. Front. Microbiol. 2022, 13, 1029146. [Google Scholar] [CrossRef] [PubMed]
  160. Zhao, L.; Chen, J.; Bai, B.; Song, G.; Zhang, J.; Yu, H.; Huang, S.; Wang, Z.; Lu, G. Topical Drug Delivery Strategies for Enhancing Drug Effectiveness by Skin Barriers, Drug Delivery Systems and Individualized Dosing. Front. Pharmacol. 2024, 14, 1333986. [Google Scholar] [CrossRef] [PubMed]
  161. Chamoun, G.; Forsyth, A.; Kazemeini, S.; Ma, J.; Lam, K.; Kasiri, N.; Frasier, K.M. Systemic Risks of Topical Anesthetics in Barrier-Compromised Dermatologic Patients. Cureus 2025, 17, e84157. [Google Scholar] [CrossRef] [PubMed]
  162. Akbar, A.; Malekian, F.; Baghban, N.; Kodam, S.P.; Ullah, M. Methodologies to Isolate and Purify Clinical Grade Extracellular Vesicles for Medical Applications. Cells 2022, 11, 186. [Google Scholar] [CrossRef]
  163. Li, P.; Kaslan, M.; Lee, S.H.; Yao, J.; Gao, Z. Progress in Exosome Isolation Techniques. Theranostics 2017, 7, 789–804. [Google Scholar] [CrossRef]
  164. Doyle, L.; Wang, M. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells 2019, 8, 727. [Google Scholar] [CrossRef]
  165. Zaborowski, M.P.; Balaj, L.; Breakefield, X.O.; Lai, C.P. Extracellular Vesicles: Composition, Biological Relevance, and Methods of Study. Bioscience 2015, 65, 783–797. [Google Scholar] [CrossRef]
  166. Zarovni, N.; Corrado, A.; Guazzi, P.; Zocco, D.; Lari, E.; Radano, G.; Muhhina, J.; Fondelli, C.; Gavrilova, J.; Chiesi, A. Integrated Isolation and Quantitative Analysis of Exosome Shuttled Proteins and Nucleic Acids Using Immunocapture Approaches. Methods 2015, 87, 46–58. [Google Scholar] [CrossRef]
  167. Zhang, M.; Jin, K.; Gao, L.; Zhang, Z.; Li, F.; Zhou, F.; Zhang, L. Methods and Technologies for Exosome Isolation and Characterization. Small Methods 2018, 2, 1800021. [Google Scholar] [CrossRef]
  168. Muller, L.; Hong, C.-S.; Stolz, D.B.; Watkins, S.C.; Whiteside, T.L. Isolation of Biologically-Active Exosomes from Human Plasma. J. Immunol. Methods 2014, 411, 55–65. [Google Scholar] [CrossRef]
  169. Hiemstra, T.F.; Charles, P.D.; Gracia, T.; Hester, S.S.; Gatto, L.; Al-Lamki, R.; Floto, R.A.; Su, Y.; Skepper, J.N.; Lilley, K.S.; et al. Human Urinary Exosomes as Innate Immune Effectors. J. Am. Soc. Nephrol. 2014, 25, 2017–2027. [Google Scholar] [CrossRef]
  170. Baranyai, T.; Herczeg, K.; Onódi, Z.; Voszka, I.; Módos, K.; Marton, N.; Nagy, G.; Mäger, I.; Wood, M.J.; El Andaloussi, S.; et al. Isolation of Exosomes from Blood Plasma: Qualitative and Quantitative Comparison of Ultracentrifugation and Size Exclusion Chromatography Methods. PLoS ONE 2015, 10, e0145686. [Google Scholar] [CrossRef]
  171. Ullah, M.; Kodam, S.P.; Mu, Q.; Akbar, A. Microbubbles versus Extracellular Vesicles as Therapeutic Cargo for Targeting Drug Delivery. ACS Nano 2021, 15, 3612–3620. [Google Scholar] [CrossRef]
  172. Martins, T.S.; Catita, J.; Rosa, I.M.; Da Cruz e Silva, O.A.B.; Henriques, A.G. Exosome Isolation from Distinct Biofluids Using Precipitation and Column-Based Approaches. PLoS ONE 2018, 13, 1–16. [Google Scholar] [CrossRef] [PubMed]
  173. Serrano-Pertierra, E.; Oliveira-Rodríguez, M.; Rivas, M.; Oliva, P.; Villafani, J.; Navarro, A.; Blanco-López, M.C.; Cernuda-Morollón, E. Characterization of Plasma-Derived Extracellular Vesicles Isolated by Different Methods: A Comparison Study. Bioengineering 2019, 6, 8. [Google Scholar] [CrossRef] [PubMed]
  174. Livshits, M.A.; Khomyakova, E.; Evtushenko, E.G.; Lazarev, V.N.; Kulemin, N.A.; Semina, S.E.; Generozov, E.V.; Govorun, V.M. Isolation of Exosomes by Differential Centrifugation: Theoretical Analysis of a Commonly Used Protocol. Sci. Rep. 2015, 5, 17319. [Google Scholar] [CrossRef] [PubMed]
  175. Taylor, D.D.; Shah, S. Methods of Isolating Extracellular Vesicles Impact Down-Stream Analyses of Their Cargoes. Methods 2015, 87, 3–10. [Google Scholar] [CrossRef]
  176. Salih, M.; Zietse, R.; Hoorn, E.J. Urinary Extracellular Vesicles and the Kidney: Biomarkers and Beyond. Am. J. Physiol. Ren. Physiol. 2014, 306, F1251–F1259. [Google Scholar] [CrossRef]
  177. Van Deun, J.; Mestdagh, P.; Sormunen, R.; Cocquyt, V.; Vermaelen, K.; Vandesompele, J.; Bracke, M.; De Wever, O.; Hendrix, A. The Impact of Disparate Isolation Methods for Extracellular Vesicles on Downstream RNA Profiling. J. Extracell. Vesicles 2014, 3, 24858. [Google Scholar] [CrossRef]
  178. Rikkert, L.G.; Engelaer, M.; Hau, C.M.; Terstappen, L.W.M.M.; Nieuwland, R.; Coumans, F.A.W. Rate Zonal Centrifugation Can Partially Separate Platelets from Platelet-derived Vesicles. Res. Pr. Thromb. Haemost. 2020, 4, 1053–1059. [Google Scholar] [CrossRef] [PubMed]
  179. Ullah, A.; Mabood, N.; Maqbool, M.; Khan, L.; Khan, M.; Ullah, M. SAR-CoV-2 Infection, Emerging New Variants and the Role of Activation Induced Cytidine Deaminase (AID) in Lasting Immunity. Saudi Pharm. J. 2021, 29, 1181–1184. [Google Scholar] [CrossRef] [PubMed]
  180. Carnino, J.M.; Lee, H.; Jin, Y. Isolation and Characterization of Extracellular Vesicles from Broncho-Alveolar Lavage Fluid: A Review and Comparison of Different Methods. Respir. Res. 2019, 20, 240. [Google Scholar] [CrossRef] [PubMed]
  181. Deregibus, M.C.; Figliolini, F.; D’antico, S.; Manzini, P.M.; Pasquino, C.; De Lena, M.; Tetta, C.; Brizzi, M.F.; Camussi, G. Charge-Based Precipitation of Extracellular Vesicles. Int. J. Mol. Med. 2016, 38, 1359–1366. [Google Scholar] [CrossRef]
  182. Liga, A.; Vliegenthart, A.D.B.; Oosthuyzen, W.; Dear, J.W.; Kersaudy-Kerhoas, M. Exosome Isolation: A Microfluidic Road-Map. Lab. Chip 2015, 15, 2388–2394. [Google Scholar] [CrossRef]
  183. Yang, D.; Zhang, W.; Zhang, H.; Zhang, F.; Chen, L.; Ma, L.; Larcher, L.M.; Chen, S.; Liu, N.; Zhao, Q.; et al. Progress, Opportunity, and Perspective on Exosome Isolation—Efforts for Efficient Exosome-Based Theranostics. Theranostics 2020, 10, 3684–3707. [Google Scholar] [CrossRef]
  184. Lobb, R.J.; Becker, M.; Wen Wen, S.; Wong, C.S.F.; Wiegmans, A.P.; Leimgruber, A.; Möller, A. Optimized Exosome Isolation Protocol for Cell Culture Supernatant and Human Plasma. J. Extracell. Vesicles 2015, 4, 27031. [Google Scholar] [CrossRef]
  185. Visan, K.S.; Lobb, R.J.; Ham, S.; Lima, L.G.; Palma, C.; Edna, C.P.Z.; Wu, L.; Gowda, H.; Datta, K.K.; Hartel, G.; et al. Comparative Analysis of Tangential Flow Filtration and Ultracentrifugation, Both Combined with Subsequent Size Exclusion Chromatography, for the Isolation of Small Extracellular Vesicles. J. Extracell. Vesicles 2022, 11, e12266. [Google Scholar] [CrossRef]
  186. Soda, N.; Rehm, B.H.A.; Sonar, P.; Nguyen, N.-T.; Shiddiky, M.J.A. Advanced Liquid Biopsy Technologies for Circulating Biomarker Detection. J. Mater. Chem. B 2019, 7, 6670–6704. [Google Scholar] [CrossRef] [PubMed]
  187. Peterson, M.F.; Otoc, N.; Sethi, J.K.; Gupta, A.; Antes, T.J. Integrated Systems for Exosome Investigation. Methods 2015, 87, 31–45. [Google Scholar] [CrossRef] [PubMed]
  188. Thomas, S.; Kaur, J.; Kamboj, R.; Thangariyal, S.; Yadav, R.; Kumar, K.; Dhania, N.K. Investigate the Efficacy of Size Exclusion Chromatography for the Isolation of Extracellular Vesicles from C. Elegans. J. Chromatogr. B 2024, 1233, 123982. [Google Scholar] [CrossRef] [PubMed]
  189. Stranska, R.; Gysbrechts, L.; Wouters, J.; Vermeersch, P.; Bloch, K.; Dierickx, D.; Andrei, G.; Snoeck, R. Comparison of Membrane Affinity-Based Method with Size-Exclusion Chromatography for Isolation of Exosome-like Vesicles from Human Plasma. J. Transl. Med. 2018, 16, 1. [Google Scholar] [CrossRef]
  190. Cui, Y.; Gao, J.; He, Y.; Jiang, L. Plant Extracellular Vesicles. Protoplasma 2020, 257, 3–12. [Google Scholar] [CrossRef]
  191. Hong, C.S.; Muller, L.; Boyiadzis, M.; Whiteside, T.L. Isolation and Characterization of CD34+ Blast-Derived Exosomes in Acute Myeloid Leukemia. PLoS ONE 2014, 9, e103310. [Google Scholar] [CrossRef]
  192. Lee, K.; Shao, H.; Weissleder, R.; Lee, H. Acoustic Purification of Extracellular Microvesicles. ACS Nano 2015, 9, 2321–2327. [Google Scholar] [CrossRef]
  193. Pinto, H.; Sánchez-Vizcaíno Mengual, E. Exosomes in the Real World of Medical Aesthetics: A Review. Aesthetic Plast. Surg. 2024, 48, 2513–2527. [Google Scholar] [CrossRef]
  194. Cho, B.S.; Kim, J.O.; Ha, D.H.; Yi, Y.W. Exosomes Derived from Human Adipose Tissue-Derived Mesenchymal Stem Cells Alleviate Atopic Dermatitis. Stem Cell Res. Ther. 2018, 9, 187. [Google Scholar] [CrossRef]
  195. Matte, B.F.; Medeiros, H.R.; Dal-Col, V. Exosome-Based Compound Activates Skin’s Keratinocytes and Fibroblasts. Curr. Cosmet. Sci. 2025, 29, 148. [Google Scholar]
Cosmetics 12 00191 g001
Figure 1. Number of publications about extracellular vesicles available on the PubMed database. Graphics clearly show an increased interest in EVs, particularly from 2010 (gray bars). Despite the reduced number of publications about EVs in cosmetology, it is possible to verify an increasing interest in these vesicles since 2020 (blue bars). Graphs obtained using the total number of publications available on the PubMed database until 17 March 2025.
Figure 1. Number of publications about extracellular vesicles available on the PubMed database. Graphics clearly show an increased interest in EVs, particularly from 2010 (gray bars). Despite the reduced number of publications about EVs in cosmetology, it is possible to verify an increasing interest in these vesicles since 2020 (blue bars). Graphs obtained using the total number of publications available on the PubMed database until 17 March 2025.
Cosmetics 12 00191 g001
Table 1. Number of articles published regarding exosomes and exosome-based cosmetic applications from 2014 to 2024.
Table 1. Number of articles published regarding exosomes and exosome-based cosmetic applications from 2014 to 2024.
Exosomes-Based Skin Cosmetics Applications
YearExosomesRegenerationAntiagingHydrationPigmentationWound HealingNanodelivery of MoleculesTotal
20244982262527309315382
20235099171124282285443
20225226151112258305543
2021507511411190275309
202042995414145224480
20193281440292153398
20182573130161102649
20172040000141132095
2016156010013641602
2015112610012051153
2014912000042912
Total36,1738162724143818737,972
Data obtained from Villarreal-Gòmez et al. [12].
Table 2. Extracellular vesicle classification based on biogenesis, cell surface expression, and size.
Table 2. Extracellular vesicle classification based on biogenesis, cell surface expression, and size.
EV CategoryNameSize (nm)MarkersBiogenesis
ExosomesClassical30–200CD63+/CD9+/CD81+MVE
Non-classical30–200CD63+/CD9+/CD81−MVE
MicrovesicleClassical150–1000Annexin A1, ARF6PMS
Oncosomes1000–10,000Annexin A1, ARF6PMS
ARMN40–100ARRDC1, TSG101PMS
ApoptoticApoptotic body1000–5000Annexin V, PSApoptosis
Apoptotic vesicle100–1000Annexin V, P5Apoptosis
AutophagicAutophagic EV40–1000LC3B-PE, p62, dsDNA/histonesAmphisome
StressomeStressed EV40–1000HSP90, HSPsPMS
Damaged EV40–1000CD63+/CD9+/CD81+PMS
Matrix vesiclesMatrix vesicles40–1000Fibronectin, ProteoglycanMatrix binding release
MVE—multivesicular endosome; ARMM—arrestin-domain-containing protein 1 (ARRDC1)-mediated microvesicle; PMS—plasma membrane shedding; Amphisome—Autophagosome–endosome fusion.
Table 3. Changes in EV nomenclature in MISEV in ten years (2014–2024).
Table 3. Changes in EV nomenclature in MISEV in ten years (2014–2024).
MISEV2014Definition: EVs are secreted membrane-enclosed vesicles
Nomenclature: No recommendation
MISEV2018Definition: EVs are particles naturally secreted from cells, defined by a lipid bilayer, and cannot replicate
Nomenclature: Unless the authors do not establish specific markers of subcellular origins, they urged to consider operational terms for EVs subtypes based on their physical characteristics and biological constituents. The authors also suggest the replacement of terms such as “exosomes” and “microvesicles” with descriptions of the conditions or cellular origins
MISEV2023Definition: EV are particles released from cells, delimited by a lipid bilayer, and cannot replicate on their own
Nomenclature: Authors recommended the use of generic term “EV” (as previously suggested in MISEV2018) rather than inconsistently defined and sometimes misleading terms such as exosomes
Table adapted from Zhang et al. [37].
Table 4. Benefits and limitations offered by human-, plant-, and bacterium-derived EVs.
Table 4. Benefits and limitations offered by human-, plant-, and bacterium-derived EVs.
EV SourceBenefitsLimitations
Human-derived-Can be isolated from plasma and MSCs
-High potential for therapeutic and cosmetic applications due to their similarity to human cells		-Regulatory restrictions in many regions due to potential disease transmission
-High production costs and complex quality control processes
Plant-derived-Can be isolated from various plants, each offering unique bioactive functions
-Rich in secondary metabolites with proven skin benefits (anti-aging, moisturizing, etc.)
-Generally considered safe and non-immunogenic		-Limited comprehensive (pre)clinical studies
-Variability in bioactive functions depending on the plant source
-Less transcriptional similarity to human cells, potentially affecting efficacy
Bacterium-derived-Specific strains like Lactiplantibacillus plantarum show anti-inflammatory and anti-aging benefits
-Potential for drug delivery and immunomodulatory properties
-Can be produced on a large scale		-Presence of lipopolysaccharides (LPS) or lipoteichoic acids (LTA) may cause immune reactions
-Limited clinical evidence for cosmetic applications
Table 5. Ongoing clinical trials involving EVs.
Table 5. Ongoing clinical trials involving EVs.
NCT NumberConditions
NCT05658094Hair Loss, Alopecia
NCT06568653Fistula Perianal
NCT04500769Metabolism
NCT05043181Familial Hypercholesterolemia
NCT04529915Lung Cancer
NCT04965961Sports Drug Abuse
NCT04544215Drug-resistant
NCT04969172COVID-19 Disease
NCT02957279Sepsis
NCT05402748Fistula Perianal
NCT06853522Ulcerative Colitis (UC)
NCT02147418Oropharyngeal Cancer
NCT04270006Periodontitis
NCT06138210Acute Ischemic Stroke
NCT05475418Wounds and Injuries
NCT03478410Atrial Fibrillation
NCT05499156Perianal Fistula in Patients With Crohn’s Disease
NCT05871463Decompensated Liver Cirrhosis
NCT06609785Diabetes, Exercise, Lifestyle Intervention
NCT06810869Stable Vitiligo
NCT06072794Premature Ovarian Insufficiency, Diminished Ovarian Reserve
NCT06298682Platelet Thrombus
NCT05616234Exosomes, Connective Tissue, Exercise
NCT04636788Pancreas Adenocarcinoma
NCT04602104Acute Respiratory Distress Syndrome
NCT03985696Lymphoma, B-cell, Aggressive Non-Hodgkin (B-NHL)
NCT06697080Androgenic Alopecia
NCT04657406COVID19
NCT06536712Rectal Cancer
NCT02748369Normal Cellular Metabolism
NCT04747574SARS-CoV-2
NCT06764004Apical Periodontitis
NCT06221787Melasma
NCT05933707Obesity
NCT03392441Diabetes Mellitus
NCT06496451Friedreich Ataxia
NCT06330922Cerebral Palsy, Spastic
NCT04081194New Tumor Diagnostics From Human Plasma Samples
NCT03106246Type1 Diabetes Mellitus
NCT05559177Recurrent or Metastatic Bladder Cancer
NCT04595903COVID-19
NCT06598202Amyotrophic Lateral Sclerosis
NCT05228899COVID-19
NCT04384445COVID-19
NCT06773572Infertility
NCT05375604Advanced Hepatocellular Carcinoma (HCC)
NCT04167722Prostate Cancer
NCT02797834Extracellular Vesicles
NCT06824285Aging
NCT03255408Obstructive Sleep Apnea of Adult
NCT04664738Skin Graft
NCT03854032Oral Cavity Squamous Cell Carcinoma
NCT06615531Intensive Meditation in Novice and Experienced Meditators
NCT06536374Prostate Cancer
NCT04134676Chronic Ulcer
NCT01550523Malignant Glioma of Brain
NCT04924504Diabetes Mellitus, Type
NCT02507583Malignant Glioma
NCT04617405Diabetes Mellitus, Type 2
NCT05937594Neonatal Opioid Withdrawal Syndrome
NCT06821243Squamous Cell Carcinoma of Oropharynx
NCT06319742Stroke, TIA, Stroke-mimics, Stroke Biomarkers
NCT02935816Prostate Cancer
NCT00285805Insulin Resistance
NCT00578240Prostate Cancer
NCT06504485Hepatitis D
NCT00001888Asthma
NCT02653339Rhinitis, Allergic, Perennial
NCT02063464Ovarian Cancer
NCT05624203Myocardial Reperfusion Injury
NCT06633003Spinocerebellar Ataxia
NCT06654167Cognitive Function
NCT03406780Muscular Dystrophies
NCT06652425Cardiovascular System
NCT05575752Cardiovascular System
NCT03459703Obesity
NCT03410030Pancreatic Cancer
NCT04350177Parkinson Disease
NCT06219850Diabetes Mellitus, Type 2
NCT04153539Cardiovascular System
NCT02737267Body Weight Changes
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Col, V.D.; Ribas, F.F.; Araldi, R.P. The Transformative Impact of Extracellular Vesicles on the Cosmetics Industry: A Comprehensive Review. Cosmetics 2025, 12, 191. https://doi.org/10.3390/cosmetics12050191

AMA Style

Col VD, Ribas FF, Araldi RP. The Transformative Impact of Extracellular Vesicles on the Cosmetics Industry: A Comprehensive Review. Cosmetics. 2025; 12(5):191. https://doi.org/10.3390/cosmetics12050191

Chicago/Turabian Style

Col, Valéria Dal, Fábio Fernandes Ribas, and Rodrigo Pinheiro Araldi. 2025. "The Transformative Impact of Extracellular Vesicles on the Cosmetics Industry: A Comprehensive Review" Cosmetics 12, no. 5: 191. https://doi.org/10.3390/cosmetics12050191

APA Style

Col, V. D., Ribas, F. F., & Araldi, R. P. (2025). The Transformative Impact of Extracellular Vesicles on the Cosmetics Industry: A Comprehensive Review. Cosmetics, 12(5), 191. https://doi.org/10.3390/cosmetics12050191

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop