Harnessing the power of stem cell-derived exosomes: a rejuvenating therapeutic for skin and regenerative medicine.

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Learn more: PMC Disclaimer | PMC Copyright Notice 3 Biotech . 2025 May 23;15(6):184. doi: 10.1007/s13205-025-04345-y Harnessing the power of stem cell-derived exosomes: a rejuvenating therapeutic for skin and regenerative medicine Gracy Seth 1 , Siddharth Singh 1 , Geetansh Sharma 1 , Divyesh Suvedi 1 , Dinesh Kumar 1 , Rupak Nagraik 1, 2 , Avinash Sharma 1, 2, ✉ Author information Article notes Copyright and License information 1 Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, Himachal Pradesh 173229 India 2 Department of Biotechnology, Graphic Era (Deemed to Be University), Dehradun, 248002 India ✉ Corresponding author. Received 2024 Dec 9; Accepted 2025 May 4; Issue date 2025 Jun. © King Abdulaziz City for Science and Technology 2025. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. PMC Copyright notice PMCID: PMC12102458  PMID: 40417660 Abstract Exosomes are small extracellular vesicles produced by most cell types and contain proteins, lipids, and nucleic acids (non-coding RNAs, mRNA, and DNA) that can be released by donor cells to influence the function of recipient cells. Skin photoaging is the premature aging of skin structures caused by prolonged exposure to ultraviolet (UV), as demonstrated by depigmentation, roughness, rhytides, elastosis, and precancerous alterations. Exosomes are associated with aging processes such as oxidative damage, inflammation, and senescence. Exosomes’ anti-aging properties have been linked to various in vitro and preclinical investigations. There are still several unanswered questions about the use of MSC exosomes for skin rejuvenation, despite encouraging results. Uncertainty surrounds the precise processes by which exosomes stimulate the creation of collagen, skin tissue via a variety of mechanisms, including reduced matrix metalloproteinase (MMP) expression, increased collagen and elastin production, and modulation of intracellular signaling pathways and intercellular communication. These findings suggest the therapeutic potential of exosomes in skin aging. This review provides information on the molecular mechanisms and consequences of exosome anti-aging. Keywords: Exosomes, Anti-aging, Stem cells, Metalloproteinase, Molecular pathways Introduction Aging and complicated phenotypic changes lead to cellular senescence, which is a major risk factor for the development of several degenerative diseases. Aging is described as a permanent decline in an organism’s physiological functions over time. It is distinguished by nine main hallmarks: stem cell exhaustion, telomere attrition, genomic instability, defective intercellular communication, cellular senescence, mitochondrial malfunction, and altered nutritional sensing (Ha et al. 2020 ). Biology, environment, heredity, and culture play a role in the complex aging process (Wang et al. 2023 ). Extrinsic and intrinsic variables can cause a biologically complicated process of skin aging, which manifests as an individual’s appearance (Muralikumar et al. 2021 ). To gain relevance and scientific excellence, the reviews included in the review were screened based on set inclusion criteria. (1) Peer-reviewed articles and clinical trials published in the English language; (2) stem cell-exosome and exosome therapeutic prospects, especially aging skin and regenerative medicine; (3) in vitro, in vivo, and clinically tested exosome effects; and (4) molecularly informative examinations of exosome function were included among the choice criteria. Weeding out were studies that did not undergo peer-review, those lacking experimental results, or were addressing extracellular vesicles not falling into exosomes. The United Nations has stated that the above-65 years population will rise to 1.5 billion in 2050 from 727 million in 2020, showing a significant demographic change requiring restraint on healthcare and rejuvenation issues regarding aging. In 2019, roughly 9% of the world’s population was 65 years and older, and this figure is estimated to double by 2050, increasing the burden of age-related diseases and the need for novel therapeutic interventions (United Nations 2019 ). Intrinsic structural alterations are inherited and result from physiologic aging (Ernster et al. 1995 ). The most likely ones are DNA damage and repair mechanisms, which result in epigenetic modifications across the genome that cause cell senescence, loss of appropriate cell function, and genomic aberrations. The extrinsic factors that accelerate the aging process and increase the generation of free radicals in cells, tissues, and organs include exposure to poisons and UV radiation. The fundamental cause is elevated oxidative stress, which is arguably the most detrimental factor in aging, and results in cell and extracellular matrix loss (Godic 2019 ). Reduced physiological function and a higher chance of age-related illnesses are the two hallmarks of aging, which is a complicated biological process. Aging is an inevitable process, but there is an increasing interest in creating anti-aging treatments that can impede its progression and enhance the quality of life of senior citizens. The exosomes generated from stem cells represent a promising new avenue for anti-aging therapy (Tienda-Vázquez et al. 2023 ). All cells, including stem cells, release small vesicles known as exosomes. The term “exosome” can be ambiguous and requires clarification. Therefore, it may allude to the “exosome complex,” a proteic (enzyme-mediated) macromolecular apparatus found in eukaryotic and archaeal entities or cells that are involved in the degradation of RNA. Conversely, most eukaryotic cells release an extracellular particle called an “exosome vesicle” from their endosomal compartment. This assessment addressed the latter issue. Exosomes are a form of extracellular vesicles (EV), which are lipid bilayer ellipsoids formed by prokaryotic and eukaryotic cells that cannot replicate. Basic unicellular organisms are included, along with intricate multicellular organisms are included. These structures have been preserved through evolution and are involved in intercellular communication (Casado-Díaz et al. 2020 ). Endocytic membranes are sources of exosomes. They contain biomolecules, such as lipids, proteins, RNAs, and DNAs, which are essential for signaling to target cells and facilitating intercellular communication (Cha et al. 2020 ). They include a range of substances that can be transported to other cells and affect their behavior, such as RNA, lipids, and proteins. When studying the processes by which sheep reticulocytes mature into erythrocytes, Pan and Johnston first discovered exosomes in 1983 (Hade et al. 2021 ). Johnstone later gave them the name “Exosomes” in 1987. Since then, EVs have been isolated from various mammalian cells. Furthermore, they have been detected in other bodily fluids, including serum from the blood (blood plasma lacking coagulation factors), saliva, breast milk, urine, and semen (Yáñez-Mó et al. 2015 ). It is interesting to note that ribonucleic acids (RNA), namely microRNAs (miRNAs), may be present in EV (Valadi et al. 2007 ). Table 1 presents the major characteristics of exosomes in detail. Table 1. Characteristics of exosomes Attribute Description Advantages References Size < 150 nm Essential for distinguishing exosomes from other extracellular vesicles Hade et al. ( 2021) , Yáñez-Mó et al. (2015 ), Valadi et al. ( 2007 ) Identification methods Western blotting, ELISA, flow cytometric analysis, transmission electron microscopy, atomic force microscopy, scanning electron microscopy, and nanoparticle tracking analysis TEM provides high-resolution images. NTA enables size distribution analysis in real-time. ELISA is highly specific and quantitative Yáñez-Mó et al. ( 2015 ) Isolation method Precipitation techniques, mass spectrometry, ultracentrifugation, HPLC, ultrafiltration, sequential filtration, SEC, and microfluidics Ultracentrifugation is a widely used gold standard SEC provides higher purity. Microfluidics allows for rapid and efficient isolation Yáñez-Mó et al. ( 2015 ); Valadi et al. ( 2007 ) State of Storage −20 °C (without influencing the exosomes’ size) Ensures long-term stability of isolated exosomes Valadi et al. ( 2007 ) Markers Tetraspanins, lipid rafts, Rab5b, flotillin, Alix, CD9, CD81, CD63, Hsp60, Hsp70, Hsp90, Tsg101 Essential for confirming exosome identity; widely recognized exosomal markers aid in specificity Yáñez-Mó et al. ( 2015 ), Valadi et al. ( 2007 ) Open in a new tab Cell-to-cell communication is essential for preserving cellular functions and homeostasis in multicellular animals. Direct cell-to-cell contact and transfer of biomolecules are two of the many ways in which intercellular communication can be facilitated. EVs, also called extracellular vesicles, deliver cytosolic lipids, proteins, RNAs, and even DNAs to their target cells. The contents of exosomes supplied to target cells considerably facilitate intercellular communication because they disclose the metabolic state of the donor cells. The exosomes play an important role in cell-to-cell communication and have been associated with the onset and progression of several diseases, including cancer (Bayraktar et al. 2017 ). Many studies have shown exosome-targeted delivery in model glioblastoma; for example, integrins modified exosomes showed enhanced tumor targeting. Moreover, for neurologic disease, RVG peptide-modified exosomes facilitate easier drug transport across the blood–brain barrier. MSC-derived exosomes functionalized with antibodies or aptamers improve their tissue localization in inflammatory diseases in regenerative medicine (Alvarez-Erviti et al. 2011 ). These approaches prove exosomes to be precise drug delivery mechanisms. Based on their size and origin, EVs have traditionally been divided into four categories: (i) endosomal exosomes, which are 50–100 nm in size; (ii) micro-vesicles (MV) from the plasma membrane, which range in size from 20 to 1000 nm; (iii) membrane particles, which are also from the plasma membrane and range in size from 50 to 600 nm; and (iv) apoptotic vesicles, which range in size from 1000 to 5000 nm and are derived from the plasma membrane and endoplasmic reticulum via apoptotic processes (Table 2 ) (Pol et al. 2012 ). Table 2. Characteristics of different types of EVs Feature Exosomes Micro vesicles Apoptotic bodies References Diameter and Shape 50–100 nm, cup shape 20–1000 nm, irregular shape 1–5 μm, heterogeneous shape Pol et al. ( 2012 ) Origin Fusion of multivesicular bodies with cell membrane Outward budding of cell membrane Outward budding of apoptotic cell membrane Pol et al. ( 2012 ) Sedimentation 100,000 g 10,000 g 16,000 Pol et al. ( 2012 ) Protein Markers Heat-shock proteins, annexins, CD63, CD81, CD9, Alix, and Tsg101 Integrins, selectins, CD40, flotillin, CD40, ARF6, VCAMP3 TSP, C3b, histones Pol et al. ( 2012 ) Gradient of Sucrose 1.13–1.19 g/mL 1.04–1.07 g/mL 1.18–1.28 g/mL Pol et al. ( 2012 ) Genetic Material mRNA, DNA, miRNA, non-coding RNA DNA, mRNA, miRNA, non-coding RNA Fragmented DNA, mRNA, miRNA, non-coding RNA Pol et al. ( 2012 ) Lipid content Ceramide Phosphatidylserine Phosphatidylserine Pol et al. ( 2012 ) Open in a new tab As previously mentioned, exosomes, and ectosomes (microparticles-MV) are the only two categories into which other writers have divided them. The latter, which have a diameter of 100–350 nm, are produced from the plasma membrane (Cocucci and Meldolesi 2015 ). Exosomes possess many key features that distinguish them from other extracellular vesicles (EVs), such as micro-vesicles and apoptotic bodies, and defines their possible application in medicine in contrast to larger EVs, such as micro-vesicles are (100–1000 nm), that form by budding directly from the plasma membrane, small -vesicles are (30–150 nm) exosomes that travel through the endosomal pathway that offers more targeted delivery of their contents. The special surface proteins and adhesion molecules of exosomes make them more specifically bind to the recipient cells and cause this site-directed distribution. Furthermore, in contrast to micro-vesicles, whose set of biological components may be less defined, exosomes have a more reproducible and specific composition because the very tightly regulated mechanism of cargo-sorting that leads to their generation (Sędzik et al. 2024 ). These differences render exosomes more potent and less susceptible to off-target effects than other EVs in therapeutic applications. Biogenesis of exosomes The process of exocytosis converts endosomal vesicles into exosomes. Differential selection appears to be at work because several proteins found in the endosome, plasma membrane, and cytoplasm are also found within the exosome (Akers et al. 2013 ). Three steps make up the biogenesis of exosomes: (i) endocytic vesicle creation through plasma membrane invagination; (ii) MVB formation through endosomal membrane budding; and (iii) Exosomes are released when MVB fuses with the plasma membrane (Fig. 1 ) (Pant et al. 2012 ). Fig. 1. Open in a new tab Generating “exosomes,” which are microscopic, nanoscale membrane lipid vesicles. Exosomes are produced by most cell types and range in diameter from 30 to 150 nm. A few phases are involved in the biogenesis of exosomes:(1) Endosome-derived multivesicular bodies (MVBs) merge with the cell membrane after early endosomes go through a series of maturation steps to become late endosomes, and (3) exosomes are released into the extracellular environment by the process of exocytosis Growing data indicate the importance of EVs in controlling normal physiological processes, including immunological modulation, tissue healing, and stem cell maintenance (Mistry et al. 2012 ; Basu and Ludlow 2016 ), and (Chan et al. 2019 ). Some of the biological processes that contribute to extracellular vacuum [EV] include vascular development, the presentation of antigens, death, coagulation process, homeostatic balance of cells, inflammatory disorders, differentiation of cells, and intercellular signaling (Yew et al. 2011 ). In inflammatory conditions, immune cells release soluble substances called mediators and inflammatory cytokines, which can exacerbate the situation. Proinflammatory cytokines, including interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α, are predominantly produced by activated macrophages. Heat, discomfort, redness, swelling, and loss of function are common symptoms of inflammation, an intrinsic immune process that occurs in response to infections, injured cells, or irritants. Owing to their innate immunosuppressive characteristics, mesenchymal stem cells (MSCs) have been shown to lower inflammation and immune responses (Chang et al. 2018 ). MSC-exosomes are an excellent alternative to MSC cell therapy because they are more stable and less immunogenic than the parent cells and have biological properties comparable to those of the parent cells (Börger et al. 2017 ). Several variables may be accountable for high variability in reproducibility of exosome therapeutic effect in several experimental settings. These are differences in the source of exosomes (e.g., MSCs from different tissues), procedures for isolating them, storage conditions, dosage, and administration routes. Additionally, differences in recipient cell or animal models employed in different experiments may also be responsible for variable treatment effects. Standardization of the procedures for isolating and characterizing exosomes, optimization of dosing and delivery strategies for exosomes, and careful watchfulness on experimental conditions will guarantee improved reproducibility. Stem cells, up to the recent past, have been seen to secrete various growth factors, which in turn promote the regeneration of the tissue, such as VEGF, bFGF, and transforming growth factor-β (TGF-β) (Yano et al. 2001 ). A comparison between all the kinds of mature MSCs is described in Table 3 . Moreover, proteomic and lipidomic analysis revealed that exosomes derived from UC-MSC exhibit specific enrichment with neuroprotective proteins and bioactive lipids, suggesting their potential for extremely effective application in neural regeneration and wound healing (Börger et al. 2017 ; Yano et al. 2001 ). Depending on cell source and biological properties, the exosomes isolated from different sources of MSC are of differential yield and therapeutic potentials. In comparison to BM-MSCs and UC-MSCs, AD-MSCs yield more exosomes and hence are ideal for bulk production. BM-MSC-derived exosomes have been studied in detail with regard to their anti-inflammatory activity and possess very high immunomodulatory potential. Increased growth factor and anti-apoptotic protein concentrations in exosomes derived from UC-MSCs enhance their regenerative potential, particularly wound repair and neuroprotection (Wang et al. 2020 ). These differences suggest that the targeted therapeutic application should determine the choice of MSC source. For possible use in tissue regeneration, wound healing, and anti-aging, this review emphasizes the critical functions that stem cell-derived exosomes play in proliferation, migration, and anti-senescence (Cunnane et al. 2018 ). Table 3. Comparison of mature MSCs sourced from various sources MSCs types MSCs markers Sources for MSCs Differentiation Applications Advantages Disadvantages References Bone marrow derived-MSCs MHC-11, CD106, CD90, CD44, and CD105 Bone marrow aspirates Adipocytes Osteoblasts Chondrocytes Cardiomyocytes Hepatocytes Muscles Neuron Embryonic tissues Burns (such as radiation burns and chronic burns), Traumatic brain injury, ischemic stroke, spinal cord injury, etc. ALS, Chronic spinal cord lesions) MSCs from this source are easily available and easy to culture. These cells have a low risk of immune reaction Extraction of these cells is invasive and complicated. There is an extremely high chance of malignant cell contamination with these cells. The proliferative ability of BM-MSCs is limited Maqsood et al. ( 2020 ) Adipose-derived MSCs OCN, OPN, BMP-7, low rate of MHC-11, CD34, CD90, CD44, and CD105 Human subcutaneous lipoaspirate, momentum, peritoneal and inguinal fat pads Adipocytes Osteocytes Chondrocytes Muscle cells Skeletal muscle injuries (e.g., soft tissue augmentation), Cosmetic and application in dermatology (such as alopecia, burns, ulcers, and anti-aging), Cells based therapy (e.g., lipodystrophy, critical limb ischemia) This source results in the isolation of the high amount of stem cells compared to others. On extraction of these cells, the donor feels less pain. AD-MSCs have higher cell viability AD-MSCs cannot be extracted from fat atrophy. Compared to other cells, it is more difficult to cultivate these. Furthermore, in comparison to other cells, these exhibit lower osteogenic potential Maqsood et al. ( 2020 ) Umbilical derived MSCs Adipocytes, chondrocytes Umbilical cord tissues Alkaline phosphate, CD73, CD90, CD105, Tra-1–60, Tra-1–81, SSEA-1 Burns e.g., wound healing, Severe diabetic foot, Atopic Dermatitis UC-MSC benefits include high availability and exist faster in the lungs These cells can be obtained via painless collection procedure. These cells exhibit quicker self–renewal ability This source is not easily accessible in comparison with other cells. For these cells tests are required to know healthy genome Maqsood et al. ( 2020 ) Open in a new tab The molecular components seen in exosomes generated by MSCs include lipid, protein, DNA, and RNA profiles When bone marrow (BM) is transplanted to heterotopic anatomical regions, it can create ectopic bone and marrow de novo. This process is commonly referred to as “mesenchymal stem cells” (MSCs), a term first coined by Caplan in 1991. This understanding is based on classical investigation. Friedenstein and associates originally presented MSCs in 1966. Significant strides have been achieved in the direction of characterizing them since then (Caplan 1991 ). Mesenchymal stromal cells (MSCs) were the term given to them since they could develop from mesoderm into specialized cells (Vodyanik et al. 2010 ). Given the widespread distribution of mesenchymal stem cells in almost all tissues and organs, there is also a prevalent view regarding MSC genesis that these cells come from perivascular cells. Researchers have shown, however, that MSCs can also originate from tissues like the intervertebral disc that lack blood arteries and neurons. Multipotent stem cells or mesenchymal stem cells (MSCs) are necessary for the synthesis and maintenance of skeletal tissues, such as bone, cartilage, and bone marrow fat (Bianco et al. 2008 ). Isolation and characterization Mesenchymal stem cells (MSCs) of different origins, i.e., bone marrow, adipose tissue, umbilical cord, and dental pulp, contain exosomes with different regeneration capacity. BM-MSCs are used for wound healing and tissue regeneration due to their strong anti-inflammatory and immunomodulatory activity. Angiogenic growth factors like VEGF and bFGF are particularly found to be present in high numbers in adipose-derived exosomes (AD-MSCs) responsible for the development of new vessels during the regeneration process. With greater concentrations of anti-apoptotic and neuroprotective molecules, exosomes from the umbilical cord (UC-MSCs) are also promising to be therapeutically used for neurological diseases. The necessity for proper exosome source selection for certain clinical applications is highlighted by their variations in miRNA, protein, and lipid composition that all contribute to their specific therapeutic potentials (Andaloussi et al. 2013 ). The lipid moieties, specifically ceramides and sphingolipids, are of central importance in modulating immune responses, promoting cellular uptake, and stabilizing exosome structure. Growth factors and cytokines are two among the proteins contained in the exosomes that exert a direct role in tissue healing and anti-inflammatory activities. RNAs, e.g., mRNAs and miRNAs, can exert effects on immunity and promote regeneration by modulating gene expression within target cells (Kalluri and LeBleu 2020 ). They all contribute to the therapeutic promise of MSC-derived exosomes. Among the several sources are human bone marrow (BM), adipose tissue (AT), peripheral blood (PB), umbilical cord (UC), synovial fluid, tooth pulp, and endometrial tissues (Eto et al. 2012 ), which have all been used to separate MSCs (Maqsood et al. 2020 ). Even when there are several sources, not all of them are helpful in a clinical setting. The best-characterized and most enriched source of MSCs out of all of them is bone marrow (Lin et al. 2019 ). The most widely used isolation technique is predicated on MSCs’ capacity to cling to plastic culture dishes. Using the centrifugation process, mononuclear cells are thoroughly separated from red blood cells, platelets, and granulocytes to accomplish MSC isolation (Omrani et al. 2024 ). After that, the fraction of cultivated cells exhibits fibroblastic shape. Following 2 to 3 weeks of culture, a single MSC gives rise to each colony. Exosome isolation and characterization procedures vary widely in studies, with implications for comparability and reproducibility of findings. Exosome recovery and purification can be affected by varying centrifugal speed, time, and conditions of the buffers, though ultracentrifugation is also used for exosome isolation. Variation in exosome preparations is still enhanced by additional methods such as polymer-based precipitation and size-exclusion chromatography (Baker et al. 2015 ). This requires the use of standardized protocols for enhancing the reproducibility and translational capability of exosome-related research as well as medicinal therapies is emphasized through these methodological variations. Significant progress has been made in characterizing fully developed MSCs. MSCs are usually characterized using flow cytometric immunophenotyping techniques, which highlight the expression of certain MSC markers (Han et al. 2018 ). Characterizing exosomes entails evaluating their cargo, size, shape, and protein markers. Transmission Electron Microscopy (TEM) is used to visualize the morphology and size of exosomes, which are usually between 30 and 150 nm in size; (2) Nanoparticle tracking analysis (NTA) is used to measure the size distribution and concentration of exosomes in solution; (3) Dynamic light scattering (DLS) is used as an alternative method for measuring size; (4) Western blotting is used to detect the presence of specific exosome marker proteins like CD9, CD63, CD81, and Alix; (5) Flow cytometry, which frequently uses antibody-coated beads, is used to quantify exosomes and evaluate the expression of their surface markers; (6) Proteomic analysis using mass spectrometry is used to determine the protein composition of exosomes; (7) RNA sequencing (RNA-seq) is used to analyze the RNA cargo, including microRNAs (miRNAs); (8) ELISA assays are used to quantify specific proteins within exosomes (Thery et al. 2018 ). It is commonly recognized that MSCs express particular surface markers in addition to having plastic adherence and multilineage differentiation characteristics. Adult MSCs can develop into cells with ectodermal and neuronal characteristics, as well as chondrocytes, osteoblasts, adipocytes, and tendon cells—all of which are characteristics of mesoderm-derived cells (Jabbarpour et al. 2020 ). The characterization of MSCs was first introduced by the International Society of Cellular Therapy (ISCT) in 2006. The expression of exosome surface markers differs according to the type of cell that produced them, which affects their biological roles and targeting abilities. The majority of exosomes include common markers including CD63, CD81, and CD9, however, certain markers are unique to particular cell types. For example, the immunomodulatory qualities of exosomes generated from mesenchymal stem cells (MSCs) are enhanced by their enrichment in CD73 and CD105. While tumor-generated exosomes frequently carry PD-L1, which aids in immune evasion, exosomes originating from neural cells express L1CAM, enabling their function in neuroprotection. The absorption, biodistribution, and therapeutic potential of exosomes are impacted by these surface marker changes (Wu et al. 2022 ). In addition to the previously described surface marker, the MSC surface exhibits several other unique cell chemicals that are available for characterization. A cDNA microarray technique can also be used to characterize the gene expression profile of adult MSCs (Li et al. 2020 ). This procedure allows for the characterization of the signaling pathway and the prediction of targeted genes. But this approach is riskier and more contentious. As of right now, simple surface marker localization for MSC characterization is supported. Exosome isolation methods Exosome isolation is a very important step in their application and characterization. Conventional methods of exosome isolation involve ultracentrifugation, precipitation, mass spectrometry, ultrafiltration, sequential filtration, and size-exclusion chromatography (SEC). Nonetheless, new developments have brought microfluidics-based isolation methods, which provide a more scalable and efficient method of exosome purification. Microfluidic platforms enable label-free, high-throughput separation of exosomes by size, density, and immunoaffinity-based capture with minimal sample loss and reduced processing time (Gao et al. 2023 ). These developments further the reproducibility and scalability of exosome applications in regenerative medicine. With the integration of microfluidics as a second isolation method, scientists are able to increase the efficiency and yield of exosome recovery, further broadening their therapeutic value. Hence, variability in quality when isolating exosomes is thought to impact the methods used for their analysis. Specifically, though ultracentrifugation is not the only method of exosome isolation, it is a widely contested one as it might co-isolate contaminants such as protein aggregates and cellular debris, and this might compromise exosome purity and bioactivity. Although precipitation methods-including PEG-based techniques-yield high information recovery, they suffer from severe problems of purity since they co-precipitate all non-exosomal components. Although SEC guarantees good purity by getting rid of large protein complexes, it gives suboptimal exosome yield. Microfluidics-based techniques show great promise in both purity and efficiency, since they selectively isolate exosomes through biophysical properties with little or no contamination. Such methodological differences may affect exosome cargo composition, stability, and therapeutic efficacy, thus highlighting the need for reference isolation protocols for proper comparison (Katsuda et al. 2013 ). Challenges in scaling production of exosome-based therapies The key challenges faced by scaling exosome-based therapies from lab to large-scale production include the following: difficulties of standardizing the isolation methods, with ultracentrifugation being inefficient for mass production. Also, alternatives, such as tangential flow filtration and size-exclusion chromatography, should be optimized further (Ha et al. 2020b ). In addition, batch-to-batch consistency is another challenge owing to cargo variations in exosomes-proteins, lipids, and nucleic acids-which dramatically affect therapeutic efficacy and reproducibility (Wang et al. 2023 ). Besides, the requirement of fully serum-free and xeno-free culture media is important to satisfy regulatory constraints in this case. Exosome stability is of great importance since freeze–thaw cycles and shifts in pH influence their integrity. Lyophilization and optimized cryopreservation buffers have been suggested as possible strategies to improve their shelf-life. Large-scale production also complies with good manufacturing practices (GMP) to meet FDA and EMA regulations (Allen and Taatjes 2015 ). It is very necessary to cooperate interdisciplinarily and further develop scalable exosome therapies supported by advances in bioreactor-based production, automation, and better characterization. MSC-derived exosomes Extracellular vesicles (EVs), which are crucial for tissue regeneration and immunomodulation, are also secreted by MSC. The molecular components seen in exosomes generated by MSCs include lipid, protein, DNA, and RNA profiles. These exosomes have been found to have high levels of proteins such as CD9, CD63, CD81, TSG101, and Alix, which are important in the biological processes of exosome formation and in membrane transport. Other pro-regenerative factors enriched in these exosomes include VEGF, TGF-β, and FGF. Heat shock proteins (Hsp70, Hsp90) help in responding to stress, whereas integrins and ICAM-1 support the targeted delivery of exosomes to respective cells. Additionally, with respect to lipid composition, MSC-derived exosomes are rich in sphingomyelins, phosphatidylserine, cholesterol, and ceramides, endowing them with stability, the ability to readily fuse with recipient cells, and modulation of intracellular signaling (Cai et al. 2025 ). Exosomes generated from MSCs have a diameter of 100–200 nm (Kang et al. 2020 ). Usually, ultracentrifugation is used to separate exosomes. Another way for isolating exosomes is through filtration. Recent studies have started using computational techniques to forecast exosome therapeutic possibilities, even though the majority of the articles in this review were experimental validation-focused. For instance, exosome cargo (proteins, miRNAs) has been analyzed using machine learning techniques to predict how it will affect target cells and the course of disease (Cai et al. 2025 ). These in silico methods can speed up the development process and assist in prioritizing exosome candidates for certain medicinal uses. Exosomes generated from MSCs have also been shown to be able to access their parent cell’s pleiotropic activities, which include stimulating tissue regeneration (Li et al. 2018 ). The exosomes promote collagen synthesis through multiple important processes. First, they can directly supply fibroblasts with growth factors including connective tissue growth factor (CTGF) and transforming growth factor-beta (TGF-β). The Smad signaling pathway, which is triggered by these growth factors, increases the transcription of collagen genes, including COL1A1 and COL1A2. Second, certain microRNAs (miRNAs), such as miR-29 and miR-21, which target and suppress the expression of genes that prevent collagen formation, like those encoding for matrix metalloproteinases (MMPs), can be transferred by exosomes. The exosomes stop freshly generated collagen from degrading by lowering MMP activity. Third, the Wnt/β-catenin signaling system, which is essential for collagen synthesis and fibroblast proliferation, can be modulated by exosomes (Rasti et al. 2024 ). Finally, exosomes can improve the cellular microenvironment by reducing oxidative stress and inflammation, creating a more favorable condition for collagen synthesis. The therapeutic benefits of exosomes generated from MSCs have been associated with several surface markers, such as adhesion molecules, signaling molecules, and CD29, CD44, CD73, and CD105. Furthermore, distinct patterns of miRNA expression were observed in exosomes produced by MSCs originating from younger and older hosts (Marolt Presen et al. 2019 ). Particularly, miRNA-21 controls the PTEN/AKT pathway to promote cell survival and tissue regeneration (Kalluri and LeBleu 2020 ). miRNA-29 regulates extracellular matrix remodeling through matrix metalloproteinases (MMPs) targeting (Lin et al. 2019 ). In addition, miRNA-126 facilitates angiogenesis through the endothelial cell activation by the PI3K/AKT signaling pathway (Omrani et al. 2024 ). miRNA-146a, through its immunomodulatory potential, suppresses pro-inflammatory cytokines through the NF-κB pathway, thus preventing inflammation and promoting healing of wounds. The miRNA-regulated pathways highlight the mechanistic aspect of exosomal function, thus laying to rest specificity issues in the targeted pathways. miRNAs generated from exosomes are essential for controlling cellular functions such as tissue regeneration, angiogenesis, and inflammation. For instance, miR-29 controls extracellular matrix remodeling and lowers fibrosis, whereas miR-21 is known to increase cell survival, prevent apoptosis, and speed wound healing. Vascular repair depends on miR-126 because it promotes angiogenesis by activating endothelial cell activity. Furthermore, by inhibiting pro-inflammatory cytokines, miR-146a has strong anti-inflammatory effects and aids in immunological regulation. On the other hand, miR-155 affects both pro- and anti-inflammatory pathways, contributing to a dual function in immune responses (Zhou et al. 2025 ). Together, these miRNAs influence the regenerative and immunomodulatory actions of exosomes in a variety of disease types, thereby adding to their therapeutic potential. BM-derived MSCs and exosomes have proven to be beneficial in treating degenerative diseases, including intervertebral disk degeneration (IDD) (Zhu et al. 2020b ), cardiovascular disorders, and liver fibrosis (Rong et al. 2019 ). The incorporation of MSCs in repair has been found to have positive benefits due to paracrine signaling, which involves secreted vesicles like exosomes. Remarkably, several studies suggest that in a variety of injury and illness models, MSC-secreted exosomes can take the role of MSC-based stem cell therapies. To put it briefly, MSC-exosomes can help with stem cell-free regenerative therapy by acting as a clever drug delivery method for exogenous compounds and biomolecules. Furthermore, unlike traditional small molecules, MSC exosomes may accommodate a wide variety of biological molecules and allow them to engage in multiple therapeutic strategies at once (Katsuda et al. 2013 ). Molecular pathways involved in exosome-mediated effects were identified in the referenced studies through a combination of techniques, including: (1) Gene expression profiling (e.g., microarray analysis, RNA sequencing) to identify changes in mRNA expression in recipient cells after exosome treatment; (2) Proteomic analysis (e.g., mass spectrometry) to identify changes in protein expression in recipient cells; (3) Western blotting to confirm changes in the expression and activation of specific proteins involved in signaling pathways; (4) Reporter gene assays to measure the activity of specific transcription factors; (5) Inhibitor studies using specific pathway inhibitors to block the activity of signaling pathways and assess their role in exosome-mediated effects; and (6) Bioinformatics analysis to integrate gene expression, proteomic, and signaling data and identify the key pathways involved (Kharrat et al. 2025 ). Although their modes of action are different, mesenchymal stem cells (MSCs) and the exosomes that are produced from them both have potent immunomodulatory qualities. Direct cell-to-cell contacts and paracrine signaling via secreting cytokines including TGF-β, IL-10, and PGE2 are the main ways whereby MSCs suppress the immune system. Exosomes, on the other hand, mediate immunomodulation by transferring bioactive substances that affect immune cell behavior, such as proteins, lipids, and miRNAs (Yanez-Mo et al. 2015 ). Exosomes, on the other hand, are a possible substitute for cell-free immunotherapy since they have benefits over MSCs in terms of stability, storage, and less carcinogenicity. Although MSC-derived exosomes still have important therapeutic properties, their effectiveness in comparison to live MSCs varies depending on the illness setting, dosage, and delivery route. The exosomes derived from mesenchymal stem cells are considered to be effective in immunomodulation and regenerative capacity, thus, they are very valuable in the treatment of degenerative and inflammatory conditions (Borghesan et al. 2019 ). In contrast, the regenerative potential of iPSC-derived exosomes is believed to be more promising because of their pluripotent nature, thereby potentially offering a wider spectrum of applications in tissue repair. On the other hand, there are safety concerns regarding iPSC-derived exosomes, particularly in respect to possible tumorigenicity. Likewise, exosomes derived from embryonic stem cells contain strongly regenerative properties, but they face ethical concerns similar to those concerning possible carcinogenicity. Given the mentioned differences, choosing an exosome source is determined by certain therapeutic objectives, alongside safety and ethical considerations. Advantages of MSC-exosomes include the following: First because MSC-exosomes merge with target cells directly, they have strong biological effects. Second, MSC-exosomes can be stored and transported at temperatures lower than 70 °C for an extended amount of time because the exosome’s plasma membrane shields its valuable components and is difficult to break down. Third, it is simple to regulate the dosage, timing, route, and concentration of usage. Finally, cell transplantation therapy does not carry the danger of cancer or immunological rejection (Lu et al. 2017 ). Integration of MSC exosome therapies in personalized medicine Personalized medicine refers to a method of delivering therapies to a patient with the utmost regard for genetic and lifestyle factors. MSC-derived exosome therapies represented a modern, less risky, cell-free regenerative approach related to the risks associated with stem cell transplantation. MSC exosomes can be engineered for the delivery of particular miRNAs or proteins for directed therapy. For instance, the exosomes can be modified to load neuroprotective miRNAs for neurodegenerative diseases or pro-angiogenic factors for cardiovascular conditions (Lu et al. 2023 ). The analysis of patient’s exosomal profile may also further elucidate a better customization of therapies. The carrier systems based on biomaterials for exosome delivery seem to enhance the precision of treatment through controlled and sustained release. Nevertheless, fair regarding some challenges like the standardization of isolation methods and patient-specific responses needs to be approached for consideration (Borghesan et al. 2019 ). MSC exosome therapy represents a paradigm shift in regenerative medicine, summoning highly demanded and appropriate treatment modalities for many types of diseases. More clinical studies are required to optimize integration into precision medicine. Applications Anti‐aging effects of MSC‐exosomes EVs or exosomes, in addition to transmitting the senescence phenotype, can relieve or even regenerate senescent cells, depending on the cells from which they arise. In both healthy and sick cells, exosomes mediate paracrine senescence, which is the process by which senescence is transferred from diseased or senescent cells to normal cells. Inhibiting exosome synthesis prevents this paracrine senescence, which is favorably linked with exosome uptake by target cells (Helenius et al. 1996 ). The accumulation of proinflammatory senescent cells and ongoing low-grade inflammation are mostly linked to aging and affect the immune system. Senescent cells secrete immunosuppressive exosomes that mainly function to increase them; nevertheless, the exosomes from these cells also contribute to the spread of senescence into neighboring cells. Moreover, aging is linked to immunological remodeling, which includes both innate and adaptive immunity. “Inflammatory aging,” often called chronic-low grade inflammation, is a prevalent sign of aging (Tutuianu et al. 2021 ). There are still several unanswered questions about the use of MSC exosomes for skin rejuvenation, despite encouraging results. Uncertainty surrounds the precise processes by which exosomes stimulate the creation of collagen, elastin, and skin regeneration (Marofi et al. 2021 ). However, quantitative research has indicated that fibroblasts treated with MSC-exosomes have 2.5-fold higher elastin gene expression than untreated controls and 40% increased migration of fibroblasts, which is essential for skin repair. Therapeutic efficacy is also impacted by differences in donor cell source, exosome isolation procedures, and delivery strategies; however, there are no established guidelines in place. More research is needed to determine long-term safety and any potential negative effects, like fibrosis or unexpected immunological reactions. Before broad clinical use, strong guidelines must be established because there are currently few clinical studies assessing the best doses, treatment plans, and patient-specific responses (Tutuianu et al. 2021 ). Biancone et al. found that MSCs secrete EVs, which alter gene expression, to regulate physiological processes. Additionally, it was observed that older MSCs treated with EV produced by younger MSCs showed upregulated Oct4 and Nanog expression. Transcript factor expression has been observed to be lower in the culturing of young MSCs with EV derived from aged MSCs. This demonstrates that EV affects the mesenchymal stem cells’ ability to self-renew at the genetic level. Donor age has a significant effect on the properties of exosomes and is the most important factor determining their therapeutic value. Research suggests that aged MSC-derived exosomes have different cargo composition, with reduced expression of rejuvenating proteins like Oct4 and Nanog, and impaired angiogenic and anti-inflammatory functions. Moreover, exosomes of old MSCs can transmit “pro-aging” signals that adversely affect recipient cell functions, even reducing their regenerative potency. Exosomes of younger MSCs, on the contrary, have been proved to promote cellular proliferation, migration, and extracellular matrix remodeling, which play key roles in anti-aging and tissue repair (Heyman et al. 2025 ). These results indicate that the donor age should be a critical factor in the optimization of exosome-based therapies for skin rejuvenation and regenerative medicine. Nanovesicles also enhance the signal pathway linked to the proliferation of the mouse mesenchymal stem cells, but they do not control or affect the properties of the mouse MSCs (Jo et al. 2016 ). Subsequently, these vesicles may supply stable MSCs for regenerative medicine and further therapeutic uses (Bayraktar et al. 2017 ). Exosomes generated from aged mesenchymal stem cells (MSCs) may carry different chemical cargo, such as proteins linked to oxidative stress, senescence-associated miRNAs, and pro-inflammatory cytokines, which might accelerate the aging process in recipient cells. According to studies, exosomes from aged MSCs have less capacity for regeneration because they express more senescence markers like p53 and p16 and less pro-repair miRNAs like miR-21 and miR-29 (Jeon et al. 2017 ). These alterations may affect tissue repair, contribute to a pro-inflammatory microenvironment, and affect cellular aging. The effects of donor age on exosome composition and therapeutic efficacy require more investigation. This study suggests that "age-promoting" chemicals present in EVs derived from old MSCs could be the cause of the age-related decrease in stem cells, pluripotency, and self-renewal. Additionally, the development of EV-based therapies is aided by an understanding of the aging process. Effect of MSC-exosomes in wound healing Accelerating wound homeostasis, controlling macrophages’ anti-inflammatory polarity, promoting the growth and migration of vascular endothelial cells and fibroblasts, controlling the cytokine ratio, and remodeling the extracellular matrix are all examples of how EVs contribute to wound healing (Rodrigues et al. 2019 ). By increasing anti-inflammatory cytokines and inhibiting pro-inflammatory cytokines, MSC-exosomes can both regulate inflammation (Li et al. 2022b ). On another note, while MSC-derived exosomes have proved effective in treating a multitude of skin diseases, their effectiveness compared with more conventional treatments would still need to be considered. Conventional skin disease treatments include corticosteroids, immunosuppressants, and biologics, all targeting inflammation and immune modulation. However, they can carry side effects, for instance, skin thinning, systemic immunosuppression, or risk of infections. Clinical studies are now underway to further verify the long-term effectiveness and safety of MSC-exosomes in comparison to other therapies, with some studies already suggesting improved regenerative effects with very few adverse responses (Fakouri et al. 2024 ). This progressive approach may revolutionize the treatment modes of chronic skin diseases with a more sustainable and holistic therapeutic alternative. In contrast, MSC-exosomes provide targeted and more biocompatible options with mechanisms that stimulate tissue regeneration, regulate an immune response, and collagen synthesis, avoiding the adverse effects of prolonged drug treatment. Several studies show that whereas biologics act primarily by inhibiting inflammatory cytokines, exosome therapy helps boost wound healing and cuts down inflammation through miRNA- and protein-mediated pathways (Fakouri et al. 2024 ). MSC-exosomes have proved their potential in wound healing applications in many studies. A study done by Yan et al. (2020) showed that exosomes from iPSCs accelerated second-degree burn wound healing in mice through miR-16-5p-mediated enhanced keratinocyte migration. Similarly, clinical studies have investigated the ADSC-derived exosomes in diabetic foot ulcers, where enhanced angiogenesis was observed via the upregulated expression of VEGF-C (Zhang et al. 2025 ). One case study found that adipose-derived MSC exosomes mitigated ischemia–reperfusion injury in skin flaps by way of expressing IL-6, which highlighted their immunomodulatory properties. Collectively, these findings bolster the growing body of research suggesting MSC-exosomes as therapeutics for chronic and acute wound healing dilemmas. Moreover, instead of giving relief from symptoms alone, MSC-exosomes have shown promise in targeting the root pathophysiology of such conditions as atopic dermatitis and psoriasis, due to their immune-modulating role and ability in promoting skin barrier repair (Pi et al. 2022 ). This contributes to a favorable environment that promotes wound healing. Encourages endothelial cell migration and proliferation, which in turn promotes angiogenesis. This is significant for wound healing since angiogenesis is necessary to get nutrients and oxygen to the wound site (Hu et al. 2019 ). The two primary cell types involved in wound healing, keratinocytes, and fibroblasts, can proliferate and migrate in response to MSC-exosomes. Collagen synthesis is also facilitated, which is necessary for wound closure (Zaim et al. 2012 ). Significant amounts of lnc RNAs and miRNAs are present in EVs. EVs are critical for mediating trauma repair at the miRNA level, as numerous studies have shown. The optimal processes for wound healing necessitate angiogenesis, extracellular matrix deposition, remodeling, and cell migration and proliferation. However, utilizing these cells has drawbacks, including invasive methods in the collecting of MSCs from adult tissues and decreased capacity to proliferate and differentiate after many passages (Goradel et al. 2017 ). Ethical and safety concerns are additional drawbacks of employing ESCs. In light of these drawbacks, induced pluripotent stem cells (iPSCs) may be a preferable option to employing MSCs and ESCs (Zhou et al. 2019 ). MSC-exosomes in promoting angiogenesis Proteins, lipids, and nucleic acids are only a few of the bioactive substances found in MSC exosomes. These molecules can be transported to other cells to mediate a range of biological effects. MSC-exosomes can stimulate angiogenesis in multiple ways. Stimulates endothelial cell migration and proliferation: The endothelium cells that line the inside surface of blood arteries can be stimulated to migrate and proliferate by MSC exosomes. Because it permits the growth and branching out of new blood vessels, this is crucial for angiogenesis (Zou et al. 2019 ). Prevents endothelial cell apoptosis: MSC-exosomes can prevent endothelial cell apoptosis, also known as programmed cell death. The likelihood that there will be sufficient endothelial cells capable of creating new blood vessels increases as a result. Promotes the growth of new blood vessels: MSC-exosomes can promote the growth of new blood vessels by triggering the synthesis of pro-angiogenic molecules such as vascular endothelial growth factor (VEGF). MSC-exosomes have been demonstrated to encourage angiogenesis in a variety of animal models, including models of stroke, myocardial infarction, and peripheral artery disease (Zou et al. 2019 ; Xin et al. 2013 ). Both in vitro and in vivo models are used to assess the pro-angiogenic effects of exosomes. Angiogenesis tests that measure endothelial cell migration, proliferation, and the development of capillary-like structures in vitro include tube formation, wound healing (scratch), and trans-well migration tests. Western blotting or ELISA are used to evaluate important angiogenic indicators as VEGF, bFGF, and angiopoietins. Models like the Matrigel plug experiment, in which mice are implanted with exosome-treated plugs to measure vascularization, are used to study exosome-induced angiogenesis in vivo. Functional blood vessel creation in response to exosome therapy is also assessed using models of ocular neovascularization and hindlimb ischemia (Zhu et al. 2018 ). These methods aid in assessing exosomes’ angiogenic potential for use in regenerative medicine. Clinical trials are currently being conducted to evaluate the safety and efficacy of MSC-exosomes in the treatment of human diseases and conditions with poor angiogenesis (Ma et al. 2020 ). MSC exosomes in regenerative medicine MSC-exosomes have an enormous amount of potential application in regenerative medicine. They can be used to promote tissue regeneration and repair in a variety of diseases and conditions. Exosomes produced from mesenchymal stem cells (MSCs) from various sources, including bone marrow, adipose tissue, umbilical cord, and dental pulp, have been found to have varied regeneration potential. Bone marrow-derived exosomes (BM-MSCs) are useful for tissue regeneration and wound healing because of their potent immunomodulatory and anti-inflammatory properties. Pro-angiogenic factors including VEGF and bFGF are especially abundant in adipose-derived exosomes (AD-MSCs), which promote vascularization during regeneration processes. With a greater concentration of anti-apoptotic and neuroprotective chemicals, umbilical cord-derived exosomes (UC-MSCs) hold promise for treating neurological diseases (Kong et al. 2024 ). The significance of choosing the right exosome source for certain clinical applications is highlighted by the variations in their miRNA, protein, and lipid compositions, which all contribute to their unique therapeutic effects. Also, several clinical trials are investigating the use of MSC-derived exosomes in regenerative medicine, including their potential to treat neurodegenerative conditions like Alzheimer’s and Parkinson’s disease, and their utility for promoting wound healing and orthopedic interventions. Many variables may contribute to substantial heterogeneity in the reproducibility of exosome therapeutic outcomes among multiple experimental models. These would involve differences in the source of exosomes (e.g., MSCs from different tissues), methods of isolation, storage conditions, dose, and delivery routes. It has been shown that MSC exosomes increase angiogenesis and reduce cardiac inflammation, which can improve cardiac function after a heart attack. They have also been shown to protect kidney cells from injury and to promote kidney function in animal models of acute and chronic kidney disease, liver cell regeneration (Tan et al. 2014 ), inflammation reduction (Huang et al. 2017 ), neuron protection, and nerve regeneration in animal models of stroke and spinal cord injury, bone and cartilage regeneration in animal models of osteoarthritis and fracture (Cosenza et al. 2017 ), and so forth. Recent research has indicated that exosomes derived from MSCs possess significant therapeutic potential in the management of Alzheimer’s disease (Perets et al. 2019 ). Through their effects on neuroinflammation, amyloid-beta (Aβ) clearance, and neuronal repair, exosomes are essential in Alzheimer’s disease (AD). It has been demonstrated that neuroprotective miRNAs (such as miR-124 and miR-146a) that control inflammation and lessen tau disease are delivered by exosomes produced from stem cells. Furthermore, by encouraging the breakdown of harmful Aβ aggregates via microglial activation, exosomes aid in their elimination (Jiang et al. 2021 ). They are a viable drug delivery method for AD treatment because of their capacity to pass through the blood–brain barrier. However, more research is necessary to address issues including exosome heterogeneity and possible off-target consequences. These exosomes have also shown neuroprotective effects in models of Parkinson’s disease, such as improving motor functioning and preserving dopaminergic neurons. Although these results are promising, the preclinical data’s robustness varies, and more study is required to completely comprehend the mechanisms at play as well as assess the products’ safety and effectiveness in clinical settings (Sun et al. 2023 ). The accumulation of -βamyloid, which results in abnormal production and excretion of Ab, caused this. Parkinson’s disease was treated with exosomes produced from BM-MSCs following systemic therapy in a rat model (Tatullo et al. 2020 ). By promoting angiogenesis and neurite remodeling, this therapy greatly enhanced functional recovery. Although MSCs and exosomes have a well-established role in regenerative medicine, additional research is necessary to completely comprehend the complex mechanisms underlying exosome regulation in wound healing. Figure 2 depicts the information about the functions of MSCs in detail. Fig. 2. Open in a new tab Function of mesenchymal stem cells Clinical trial outcomes of MSC-derived exosomes Clinical trials have investigated the use of MSC-derived exosomes in neurodegenerative diseases, cardiovascular conditions, wound healing, and regenerative medicine. The established neuroprotective effects of MSC-EVs in neuroinflammation control and enhancing neuronal survival against neurodegenerative diseases such as Alzheimer’s and Parkinson’s have been widely reported (Tatullo et al. 2020 ). On the other hand, for wound healing, they have been reported to help with angiogenesis and healing through inflammatory reduction. In cardiovascular disease, trials have shown that inhibition of myocardial infarction results in reduced infarct size and enhanced heart function (Sanz-Ros et al. 2022 ). Previous studies hinted at the possible use in chronic kidney disease, liver regeneration, and drug delivery and diagnostics in oncology Hu et al. ( 2016 ). The differences in research outcomes may be probably attributed to the source of exosomes and methods of obtaining them, not to mention inter-individual patient variability, suggesting the standardization of protocols is needed. Beyond skin aging: extracellular vesicles in age-related diseases Beyond skin aging: additional applications of exosomes Exosomes have been found to possess potential therapeutic functions beyond skin renewal, such as their significant role in wound healing, angiogenesis, neurological disorders, and organ regeneration. The exosomes in wound healing enhance the repair of tissues by modulating inflammation, triggering fibroblast proliferation, and activating extracellular matrix remodeling. They also promote angiogenesis by delivering pro-angiogenic factors like VEGF and bFGF to endothelial cells, thereby enhancing vascularization in ischemic conditions. In addition to this, exosomes have been explored in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, where they show neuroprotective activity by preventing neuroinflammation and facilitating neuronal regeneration (Sanz-Ros et al. 2022 ). Exosomes in regenerative medicine are involved in repairing tissue in cardiac, renal, and hepatic injuries through immune modulation and cellular differentiation. These multifaceted uses reflect the wide-ranging potential for exosomes as a regenerative therapy in many areas of medicine. Beyond skin aging: extracellular vesicles in age-related diseases Exosomes and extracellular vesicles (EVs) play key roles in age-related diseases that affect neurodegeneration, cardiovascular disease, and metabolic disorders (Perets et al. 2019 ). Neurodegenerative disorders EVs encourage neuronal protection in both Alzheimer’s and Parkinson’s disease through the delivery of miRNAs such as miR-124 and miR-146a, which are involved in inflammation and the clearance of amyloid-beta aggregates. In addition, neurogenesis and synaptic plasticity are promoted, inhibiting disease progression. Cardiovascular diseases Cardiovascular progenitor cell-derived exosomes restore cardiac function by prolonging angiogenesis and reducing oxidative stress. Also, they are capable of supplying such bioactive molecules as Hsp70 and miR-21 that ensure endothelial cell functions and myocardial recovery after HIT. Furthermore, EVs also reduce cardiac fibrosis and orient the immunological responses so that further damaging events are prevented. Metabolic syndromes Exosome secretion from adipose-derived mesenchymal stem cells (AD-MSCs) improves insulin sensitivity and regulates glucose metabolism through the action of miR-29a and miR-126, with a reduction in inflammation occurring in metabolic tissues. Furthermore, they modulate lipid metabolism, thereby preventing obesity-related complications, and promote general metabolic wellbeing. Stem cells derived from adipose Adipose tissue is the most prevalent kind of tissue in the human body Zhao et al. ( 2017 ). The stromal vascular fraction (SVF) and mature adipocytes are the two primary components of adipose tissue. The cells that are left over after SVF adherent culture are known as adipose stem cells (ASC). Adipose-derived stem cells (ADSCs) are a type of mesenchymal stem cell (MSC) that can be obtained from fat or adipose tissue (Tobita et al. 2011 ). MSCs are regarded as multipotent cells because of their ability to differentiate into an extensive variety of unique cell types. Liposuction, excisional biopsy, needle aspiration, and other techniques can be used to separate ADSCs from adipose tissue (Ong and Sugii 2013 ). The method of separating ADSCs from other cells in adipose tissue involves enzymatic digestion and mechanical processing, which is carried out after the tissue has been obtained. The ADSCs can subsequently be grown in culture to promote differentiation into a variety of cell types, including bone, muscle, neuron, and fat cells. Isolation and characterization Human adipose tissue taken from liposuction patients at the affiliated Hospital of Qingdao University was digested with collagenase type 0.075%. Following the complete DMEM halt of the digestion reaction, the solution was centrifuged at 1300 × g for 10 min. The ADMSC solution was transferred to culture dishes and grown in 5% CO2 at 37 °C (Li et al. 2022a ) in low-glucose Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 0.1% 100 U/mL penicillin–streptomycin and 10% fetal bovine serum after being resuspended in a medium containing 15% fetal bovine serum. When the cells achieved 70–80% confluence, they were detached with 0.25% trypsin and sub-cultured. ADMSCs at passage 3 were trypsinized and then resuspended in PBS to achieve a cell density of 1 × 106 cells/mL. After the 200 μL of cell suspension was put into Eppendorf tubes, 5 μL of monoclonal antibody was used to probe the sample for 15 min at 4 °C in the dark (Cao et al. 2020 ). Together with the appropriate isotype control IgG, they included CD34, CD44, CD45, and CD105 antibodies. By centrifuging with 2 mL PBS for 5 min at 1000 rpm, the excess antibodies were eliminated. The ADMSCs were then again suspended in 400 µl of PBS that had 0.5% paraformaldehyde in it. The surface markers of ADMSCs were determined using a flow cytometer (FACS Calibur, Becton–Dickinson, Mountain View, CA, USA) (Wang et al. 2019 ). Identifying and separating exosomes derived from ADMSCs For an entire night, ADMESCs were grown in DMEM (Thermo Fisher Scientific, Waltham, MA, USA) devoid of fetal bovine serum. The cells and detritus were removed from the medium by centrifuging it for 30 min at 2000 g. After generating an exosome precipitate with an Optima MAX-XP benchtop ultracentrifuge (Beckman Coulter, Inc., Chaska, MN, USA), the supernatant was moved to a new test tube and centrifuged at 100,000 g for 1 h at 4 °C (Kou et al. 2022 ). Exosomes were resuspended in 1 × PBS and stored at − 80 °C for further investigations. The exosomes were quantified using the total exosome protein test. The measurement of the total exosome protein was handled using the Western Blot technique. 100 μg of exosomes may often be obtained from 20 ml of culture medium containing 3–5 passes 10 × 9 h ADSC. Using a transmission electron microscope (TEM, FEI, USA), the morphology of the exosomes was investigated. Before being employed for Nano sight tracking analysis, the liquid was filtered through a 0.22-μm filter and put into a new centrifuge tube after the exosomes had been diluted with 1 × PBS (tenfold) (Gurunathan et al. 2019 ). Research demonstrating that exosomes have capacities equivalent to host cells and exhibit no obvious side effects, such as immunogenicity, vascular obstructive risks, or malignant transformation, indicates that exosome-based therapy is significantly safer and more promising for tissue regeneration therapy than direct cell utilization (Sun et al. 2019 ). The exosomes promote angiogenesis, collagen synthesis, cell proliferation, and the restoration of the skin barrier function, all of which contribute to the healing of wounds. To improve cutaneous regeneration by systemic distribution, local administration in conjunction with intravenous injection of h ADSC and h ADSC-exosomes provided extra advantage above either therapy alone (Kokai et al. 2014 ). The way exosomes are administered has a big impact on their cellular absorption, biodistribution, and therapeutic effectiveness. Exosomes can circulate and reach several organs, especially the liver, spleen, and lungs, because of intravenous (IV) injection, which is frequently utilized for systemic distribution. To improve treatment benefits in musculoskeletal and joint disorders, localized delivery techniques like intramuscular (IM) or intra-articular (IA) injections offer larger concentrations at the target site. Given that exosomes can penetrate the blood–brain barrier and directly target the central nervous system, intranasal delivery has demonstrated potential in neurological applications (Lee and Minko 2021 ). Topical treatment also promotes localized tissue repair and is useful for wound healing and skin regeneration. Because various techniques affect exosome stability, bioavailability, and target specificity, the route of delivery is determined by the particular therapeutic use. Applications of ADSC exosomes Skin wound healing ADSC-exosomes can reduce inflammation at the location of the wound, helping to create a more healing environment. Additionally, they can boost the migration and proliferation of fibroblasts and keratinocytes, the two primary cell types involved in the healing of skin wounds. Promoting angiogenesis, which is essential for the healing of wounds, by causing new blood vessels to form where the wound is. By encouraging the more ordered deposition of collagen, ADSC-exosomes can aid in the reduction of scar formation (Yu et al. 2018 ). ADSC-exosomes, an autologous cell-free method, mainly stimulate wound healing mechanisms apart from supplemental maintenance modes of certain conventional therapies. In a nutshell, skin wound healing is an intricate web of responses and exchanges between cells and “mediators” (Fig. 3 ) (Yan et al. 2020 ). Fig. 3. Open in a new tab Effects of ADSC on skin Anti-inflammatory reactions ADSC-exosomes manifest remarkable immunomodulation, in large part through inhibition of T cell activation and promotion of regulatory T cell differentiation, helping to control inflammation through the downregulation of key inflammatory biomarkers, including TNF-α, IL-6, and IL-1β. Studies have demonstrated that miRNA-451a from ADSC-Exosomes allows for M1-to-M2 polarization of macrophages through inhibition of MIF and so acts to dampen inflammatory signaling (Yan et al. 2020 ). Additionally, ADSC-exosomes are involved in the release of immunomodulatory proteins such as RBP-4, which is an important mediator of immune regulation. By perpetuating a balanced inflammatory response, ADSC-exosomes enhance a local microenvironment optimized for tissue regeneration and healing. In addition, ADSC-exosomes impact the NF-κB signaling pathways that curtail chronic inflammation and oxidative stress (Willis et al. 2018 ). The expression of TGF-β and IL-10 in exosomes establishes an anti-inflammatory environment supporting tissue repair (Lo Sicco et al. 2017 ). These combined mechanisms confirmationally indicate that ADSC-exosomes are a versatile tool for the treatment of inflammatory diseases, autoimmune diseases, and wound healing (Eming et al. 2017 ). Regulation of angiogenesis ADSC-exosomes have multiple ways of controlling angiogenesis. These consist of encouraging endothelial cell migration and proliferation. Endothelial cells, which line the inside of blood vessels, are essential for the growth of new blood vessels, increasing the production of pro-angiogenic molecules such as VEGF (vascular endothelial growth factor). The protein VEGF is essential for stimulating the growth of new blood vessels (Zhang et al. 2016 ). Reduction of anti-angiogenic factors (thrombospondin-1, for example) in production. One protein that stops new blood vessel formation is called thrombospondin-1. Within cells lies a network of chemicals, including proteins, known as the extracellular matrix. The extracellular matrix can be altered by ADSC-Exosomes to encourage the growth of new blood vessels (Kranendonk et al. 2014 ). Many animal models have shown that ADSC-exosomes are efficient at promoting angiogenesis. As an illustration, a study discovered that ADSC-exosomes accelerated the healing of wounds in diabetic rats by promoting angiogenesis. Furthermore, ADSC-exosomes are being investigated as a potential treatment for human disorders that include impaired angiogenesis, including coronary artery disease and peripheral artery disease. An example of this is a clinical study that evaluates the efficacy and safety of ADSC-exosomes in the treatment of critical limb ischemia, a condition in which there is a substantial decrease in the blood flow to the legs (Vannella and Wynn 2017 ). Granulation tissue is formed in part by loose connective tissue, macrophages, and newly developing capillaries. Diabetes patients’ high blood sugar levels can upset the delicate balance between artery development and growth. Disturbances in vascular integrity lead to a reduction in capillary density and vascularity in chronic wounds. VEGF, angiopoietin, fibroblast growth factor (FGF), and transforming growth factor (TGF) are prominent angiogenic cytokines in wound angiogenesis. ADSC EXOs are more successful in stimulating angiogenesis in fat grafting because they stimulate the protein kinase A (PKA) signaling pathway and control VEGF/VEGF-R signaling (Long et al. 2022 ). ADSC-EXOs are prevalent in miRNA-125a and miRNA 31, as well as growth factors like VEGF-A and platelet-derived growth factor BB (PDGF BB) that facilitate wound healing. Following their uptake by ADSC-EXOs, vascular endothelial cells (VECs) produce less of the angiogenesis inhibitor Delta-like ligand 4 (DLL4), which promotes the expansion and angiogenesis of VECs (Zhou et al. 2021 ). ADSC-EXOs expressing miRNA-486-5p can accelerate cutaneous wound healing and promote. Additionally, ADSC EXOs inhibit the activation of the anti-angiogenic gene hypoxia-inducible factor-1 (HIF-1) following chronic wound damage (Zhu et al. 2020a ). We suggest that ADSC-EXOs have a major impact on angiogenesis; this is a potential that needs more research. Mesenchymal stem cells of the umbilical cord Umbilical cord mesenchymal stem cells, or UC-MSCs, are stem cells found in the umbilical cord. They are referred to as multipotent because of their capacity to differentiate into a variety of cell types, including bone, cartilage, fat, muscle, and nerve cells. Additionally, UC-MSCs have immunological privilege, which reduces the likelihood that the body will reject them after transplantation. After birth, it is simple to separate UC-MSCs from the umbilical cord and store them in cryobanks for later use (Kim et al. 2017 ). For research and medicinal purposes, they are thus a valuable source of stem cells. Among mesenchymal stem cells (MSCs) formed from various sources, umbilical cord blood-derived MSCs (UCB-MSCs) are believed to be the earliest and most primitive cells UCB-MSCs release a higher concentration of wound-healing factors than other MSCs (Kim et al. 2017 ). Collagen synthesis, fibroblast migration, and proliferation are all accelerated by UCB-MSCs. Moreover, UCB-MSC conditioned media are injected subcutaneously into mice to promote wound healing and re-epithelialization (Kim et al. 2007 ). Among the most widely used techniques to improve skin penetration are bilayer vesicle systems. Although there are a few methods for separating exosomes from umbilical cord mesenchymal stem cells (UC-MSCs), ultracentrifugation is the method that is most frequently employed. To separate exosomes from other components of the supernatant, such as cells, detritus, and proteins, this method includes spinning the cell culture supernatant at high speeds (Mendonca et al. 2025 ). The separated exosomes can be characterized by a variety of methods, such as Western blotting, electron microscopy, and nanoparticle tracking analysis. The exosomes can be used for research, diagnostics, and therapies, among other uses, once they have been separated and characterized. Despite being the most popular technique for isolating exosomes, ultracentrifugation has several drawbacks that may compromise the yield and purity of the exosomes. The possibility of co-isolating protein clumps and non-exosomal vesicles is a significant disadvantage that could reduce the selectivity of the extracted exosome fraction. Furthermore, exosomes may sustain structural damage as a result of the high centrifugal forces (100,000–120,000 × g) used during ultracentrifugation, which could compromise their integrity and biological activity. The procedure is less scalable for clinical applications because it takes a long time and needs specialist equipment. Additionally, ultracentrifugation has a low recovery efficiency and significantly loses sample after several centrifugation steps (Mendonca et al. 2025 ). Alternative exosome isolation methods with higher yields, like size-exclusion chromatography and polymer-based precipitation, have been developed as a result of these constraints and purity. Applications of UCB-MSC Tissue regeneration and repair The unique characteristics and potential therapeutic applications of umbilical cord-derived mesenchymal stem cells, or UC-MSCs, have shown them to hold considerable promise in tissue regeneration and repair. The following are some of the main functions and processes that UC-MSCs use to aid in tissue healing and regeneration. UC-MSCs possess the ability to differentiate into several cell types, such as myocytes (muscle cells), adipocytes (fat cells), chondrocytes (cartilage cells), and osteoblasts (bone cells). They can replace damaged or malfunctioning cells in different tissues thanks to this ability. Numerous bioactive substances, such as growth factors, cytokines, and chemokines, are secreted by UC-MSCs (Pu et al. 2017 ). These elements are necessary for tissue repair because they promote cell division, migration, and proliferation, regulate the immune system, and reduce inflammation at the site of injury. They can control the immune response or immunomodulation. This can be particularly helpful in cases when immune-mediated injury or inflammation impedes tissue repair. UC-MSCs can lessen immune system overreactions and foster an atmosphere that is more favorable for tissue healing (Han et al. 2019 ). Angiogenesis is the process through which new blood vessels form. This is essential for supporting the growth and repair of regenerated tissues by giving them oxygen and nutrients (Kang et al. 2016 ). Through the promotion of the creation of collagen and elastin, two components of the extracellular matrix (ECM), UC-MSCs can affect the ECM. UC-MSCs have lower immunogenicity than other types of stem cells, which lowers the risk of immune rejection when transplanted into patients. This helps in tissue remodeling and structural repair (Doi et al. 2016 ). They also have the potential to protect and regenerate neural tissues, making them a candidate for treating neurological injuries and disorders. Potential clinical uses of UC-MSCs in tissue regeneration and repair are being researched for a wide range of ailments, including but not limited to bone and cartilage repair, cardiovascular disease, wound healing, liver and kidney injuries, and neurological disorders. It is important to keep in mind that while UC-MSCs show great potential, more research and clinical trials are necessary to fully understand their safety and efficacy for specific applications. Immunomodulation One of the main roles of umbilical cord-derived mesenchymal stem cells, or UC-MSCs, is immunomodulation, or the capacity to regulate and modify the immune system. Their immunomodulatory effect, which has important implications for a variety of diseases and treatments, is one of the most important therapeutic properties of UC-MSCs. Natural killer (NK) cells, T cells, and B cells are a few of the immune cells that UC-MSCs can stop from activating and multiplying. In cases of autoimmune illnesses and other disorders where an excessive immune response results in tissue damage, this immuno-suppressive impact is advantageous. The release of chemicals that reduce inflammation, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). By lowering inflammation in inflammatory tissues or at the site of damage, these components help to create an environment that is more conducive to tissue regeneration (Tatullo et al. 2020 ). The differentiation and proliferation of regulatory T cells (Tregs) can be aided by UC-MSCs. Tregs are essential for preserving immunological tolerance and reducing hyperbolic immune reactions (Kim et al. 2017 ). This is particularly crucial in the case of post-transplant graft-versus-host disease (GVHD) and autoimmune disorders, which can control how different cytokines and chemokines are produced by immune cells. In situations when there are cytokine storms or dysregulated immunological responses, this can assist balance the immune response. Immunological tolerance may be induced by UC-MSCs, which is particularly useful when a patient’s immune system needs to be more receptive to organ or tissue transplants. This impacts the development and operation of dendritic cells (DCs) (Kim et al. 2007 ) and antigen-presenting cells essential for triggering immunological responses. The strength and direction of immunological responses can be changed by modifying DCs. A potential treatment for GVHD, a problem that can arise following hematopoietic stem cell transplantation, is UC-MSCs. UC-MSCs may lessen the severity of GVHD by reducing the immune reaction against transplanted cells (Mendonca et al. 2025 ). The immunomodulatory characteristics of UC-MSCs render them a highly promising option for a range of therapeutic uses, such as the management of autoimmune diseases (Luo et al. 2010 ), inflammatory disorders, complications associated with transplantation, and ailments requiring the regulation of excessive inflammation and immune responses. Additional research and clinical trials are required to guarantee their safety and effectiveness. It’s crucial to remember that the precise processes and efficacy of UC-MSC-based immunomodulation may differ based on the clinical setting and the illness being treated (Blazquez et al. 2014 ). Reversing skin aging Studies have looked into the possible advantages of using mesenchymal stem cells obtained from the umbilical cord (UC-MSCs) to treat skin aging. To completely comprehend the effectiveness and safety of these cells, additional research is necessary, thus it is important to keep in mind that this field of study is still in its infancy. Collagen is a protein that gives skin structure, and UC-MSCs have the power to increase the synthesis of this protein. Skin that is drooping and wrinkled due to a decrease in collagen formation as we age. UC-MSCs have the potential to enhance the elasticity and suppleness of skin by inducing the production of collagen. Secret chemicals are rich in antioxidants that can shield skin cells from free radical damage and oxidative stress (Seo et al. 2009 ). Reducing oxidative stress can have anti-aging effects because it is a major factor in skin aging. Aging skin is correlated with persistent inflammation. Because of their anti-inflammatory qualities, UC-MSCs may aid in reducing skin inflammation (Rodrigues et al. 2021 ), giving the skin a more youthful appearance. Skin cell proliferation, including that of fibroblasts and keratinocytes, may be promoted by UC-MSCs (Guo et al. 2019 ). This may help the skin’s dermal and epidermal layers regenerate, possibly resulting in skin that is smoother and looks healthier. It is critical to stress that, despite the potential advantages of UC-MSCs for treating skin aging, research is still ongoing and their use for anti-aging or cosmetic purposes may not yet be generally accessible or approved in many areas. Furthermore, the efficacy and safety of UC-MSC-based therapy for skin aging should be appropriately evaluated through rigorous clinical trials. Depending on several factors, including the specific protocol followed, the patient’s age, skin type, and overall health, the effectiveness of UC-MSC therapy for skin aging may differ from patient to patient. It is advised that you speak with a licensed medical practitioner if you are interested in learning more about UC-MSC-based skin aging treatments. They can offer advice and make sure that any treatments are carried out in a safe and regulated manner. Skin wound healing process The multi-layered tissue that makes up the skin serves as the body’s first line of defense against illnesses like bacteria and radiation that can endanger human life. Because of its expansion, the skin is frequently subjected to a wide range of damages and injuries, which can lead to both acute and chronic wounds. Skin can heal itself, but only to a limited degree, generally speaking. The incidence of skin injuries is very common. For instance, trauma or surgical incisions in the event of acute wounds may be the cause (Shahir et al. 2020 ). Many times, acute or chronic wounds such as severe burns, trauma, or ulcers of different origins cause harm to the skin. These wounds alter how the skin perceives touch, pain, and warmth in addition to destroying the skin’s barrier function (Liu et al. 2021 ). After an injury, cutaneous wound healing is a highly regulated physiological process that repairs the skin’s integrity. Although MSC-derived exosomes have been shown in many research to have anti-inflammatory qualities, not all studies have shown the same results. The results can vary depending on the donor cell source, exosome isolation methods, and experimental settings. According to certain research, pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6 are significantly reduced, while anti-inflammatory markers like IL-10 and TGF-β are increased (Shen et al. 2021 ). Other research, however, suggests that the context-dependent immunomodulatory effects of MSC-derived exosomes rely on a number of variables, including the disease model, dosage, and the milieu in which they are delivered. The three stages of skin wound healing are the proliferative, remodeling, and inflammatory phases (Fig. 4 ) After the injury, the Inflammatory Phase lasts for 4 days, then the Proliferative Phase lasts for up to 21 days, and the Remodeling Phase lasts for over 300 days. (Xin et al. 2020 ). Fig. 4. Open in a new tab Timeline for skin wound healing which depicts the information that after the injury, the inflammatory phase lasts for 4 days, then the proliferative phase lasts for up to 21 days, and the remodeling Phase lasts for over 300 days Stem cell extracellular vesicles (EVs) have the potential to improve all three phases of wound healing because of their capacity to decrease inflammation, encourage cell migration and proliferation, and even diminish scarring (Meng et al. 2023 ). Research to elucidate the processes behind the effects of stem cell extravasation (EVs) on wound healing has traditionally relied on the vertical transfer of microRNAs or proteins to skin cells (Shi et al. 2019 ). Inflammatory phase Since inflammation is the body’s defensive mechanism in response to harmful stimuli, it is advantageous for optimal wound healing that the inflammatory response be prompt and regulated (Hu et al. 2014 ). Skin damage sets off the inflammatory response, which in turn starts the coagulation process. Vascular constriction and a fibrin network are then provided to close the wound and maintain its structural integrity. Apart from preserving equilibrium and repelling external agents, this fibrin net functions as a medium for cellular migration and the build-up of growth factors, including platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and transforming growth factor-beta (TGF-β) (Ferreira and Gomes 2018 ). Within the first 24 h after the injury, white blood cells are drawn to the area and stay there for 2 to 4 days (Bernardo and Fibbe 2013 ). White blood cells create reactive oxygen species (ROS) and proteases to directly kill germs, degrade damaged tissue, and absorb any leftover cell debris. Simultaneously, neutrophils have been seen to release cytokines, such as necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, to intensify the inflammatory response (Fig. 5 ) (Blais et al. 2013 ). Fig. 5. Open in a new tab Neutrophils control infection and promote healing by inducing angiogenesis and fibroblast proliferation via cytokines It has been demonstrated that MSC-derived exosomes affect the production and activity of a number of important cytokines linked to angiogenesis. To encourage endothelial cell migration, proliferation, and tube formation, exosomes, for example, can transport vascular endothelial growth factor (VEGF) straight to target cells. Additionally, they have the ability to alter the levels of other pro-angiogenic factors such angiopoietin-1 (Ang-1) and basic fibroblast growth factor (bFGF). Furthermore, by inhibiting the expression of anti-angiogenic proteins such as thrombospondin-1 (TSP-1), exosomes might indirectly stimulate angiogenesis (Bernardo and Fibbe 2013 ). Proliferative phase After the inflammation begins to subside, the proliferative phase can last for up to 14 to 21 days. It begins 48 h after the incision is formed. When horn cells are induced by the contraction and creation of filaments, this phase results in a little lesion (Liu et al. 2016 ). The hallmarks of this phase include the formation of granulation tissue to replace the temporary wound matrix and the recovery of growth factor and cytokine sources within the vascular network, including transforming growth factor-beta (TGF-beta, including TGF-β1, TGF-β2, and TGF-β3), interleukin (IL), and vascular formation factors (Sugimoto et al. 2016 ). Moreover, using stem cell EVs can improve collagen and elastin deposition. Numerous studies use in vitro models to clarify the molecular processes that might account for stem cell extracellular vesicles’ impacts. Skin fibroblasts play a key role in the healing and regeneration of skin tissue through their involvement in wound contraction, extracellular matrix deposition, tissue remodeling, and other processes (Vahabi et al. 2015 ). To control the proliferation and migration of the receiving cells, MSC-exosomes can internalize and transfer their contents, including proteins and RNAs. It has been demonstrated that MSC exosomes regulate the production of growth factors and genes associated with them, hence regulating fibroblast migration and proliferation (Gantwerker and Hom 2012 ). Consequently, they aid in the production of collagen, which gives wounds structural support for healing ( 2014 ), as well as the formation of granulation tissue. Remodeling phase The extracellular matrix (ECM) is composed of four main chemical types: collagen, non-collagen (fibronectin, laminin), elastin, proteoglycans, and aminoglycans. The synthesis and breakdown of collagen are essential for ECM regeneration. A normal scar is a byproduct of the remodeling and healing process. Conversely, loss of skin function and abnormal myofibroblast-induced collagen production result in severe scarring. The capacity of stem cell extracellular vesicles to reduce scarring is an exciting characteristic. Further reduction in scarring can be achieved by human amniotic stem cell EVs through the control of extracellular matrix deposition. According to Zhao and associates, matrix metalloproteinase-1 (MMP-1) activation may contribute to this (Carmeliet and Jain 2011 ). By injecting adipose-derived MSCs-EVs intravenously, scar size was decreased, fibroblast differentiation into myofibroblasts was prevented, and the ratio of transforming growth factor-β3 (TGF-β3) to TGF-β1 increased (Li et al. 2007 ). Furthermore, by stimulating the extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway, EVs increased the expression of matrix metalloproteinases-3 (MMP3) in skin dermal fibroblasts. This resulted in a high ratio of MMP3 to tissue inhibitor of matrix metalloproteinases-1 (TIMP1), which is also advantageous for the remodeling of the extracellular matrix (Sorg et al. 2017 ). Therapeutic regeneration The goal of the multidisciplinary discipline of regenerative medicine is to aid in the regeneration and repair of damaged tissues and organs. It is the use of biology and tissue engineering to develop effective and useful treatments that promote self-healing and regeneration, or the development of new organs or tissues to preserve, improve, and repair damaged bodies. Organ transplantation is expensive, difficult to find donors, prone to immunological rejection, requires a skilled team, and can be risky during surgery. Regenerative medicine has become a viable alternative (Diegelmann and Evans 2004 ). MSC-Exo-based treatments have problems with immune rejection, tumor differentiation, and cell survival. Exosome therapy offers an alternative to these issues in cell-free therapy. Even after allogeneic delivery, there is very little chance of immunological rejection because of the low concentration of exosome membrane-bound proteins. Furthermore, exosomes do not multiply, ruling out the chance of tumor development (Shabbir et al. 2015 ). Exosomes can deliver active materials into recipient cells to facilitate information transfer across cells. As a result, exosomes can transport medications and biological macromolecules. The exosome membrane contains proteins that have a binding affinity for either an ECM ligand or the target cell membrane. Exosomes can more easily target certain organs or microenvironments when these molecules are connected to membranes. Exosomes’ bilayer membrane can be altered by certain substances to allow for the targeting of cells and organs (Guo and DiPietro 2010 ). The effectiveness of exosome-based treatments is greatly influenced by environmental variables as temperature, oxygen concentrations, and culture conditions. It has been demonstrated that hypoxia increases the pro-angiogenic and anti-inflammatory substances that exosomes carry, hence enhancing their capacity for regeneration. Exosome composition can also be changed by oxidative stress and pH changes, which can impact the stability and bioactivity of exosomes. Exosome absorption and therapeutic efficacy are further influenced by the physiological state of the recipient in vivo, including inflammation, metabolic status, and immunological responses (Carmeliet and Jain 2011 ). For consistent therapeutic results, it is essential to standardize the environmental conditions during exosome manufacturing and storage. Stem cell-derived exosomes’ therapeutic potential in regenerative medicine Many studies have looked into the beneficial therapeutic and protective benefits of MSCs in the field of regenerative medicine. MSC-secreted exosomes and other extracellular vesicles (EVs) are important in preserving and reestablishing tissue microenvironment homeostasis due to the high biochemical potential of their bioactive components, which include proteins and RNAs (Pelizzo et al. 2018 ). Exosomes facilitate several processes that help wounded tissues regenerate, including: (a) they maintain endogenous stem cells through their proliferation, self-regeneration, and differentiation (Elliot et al. 2018 ); (b) they induce regenerative phenotypes by encouraging cell proliferation, angiogenesis, and nerve regeneration (Goradel et al. 2015 ; Marote et al. 2016 ); (c) they mitigate tissue damage and protect cells from apoptosis through a variety of mechanisms (Vader et al. 2016 ); (d) They provide immunomodulatory mediators to wounded tissue, which lowers oxidative stress and regulates the immunological response (Colombo et al. 2014 ; Maumus et al. 2013 ). Consequently, EVs generated by MSCs, especially exosomes, can repair tissue damage and retain their therapeutic efficacy by influencing target molecules and conveying physiologically active molecules, ultimately altering the gene expression and phenotype of damaged recipient cells (Fig. 6 ) (Gradilla et al. 2014 ). Fig. 6. Open in a new tab Diagrammatic illustration of mesenchymal stem cells in regenerative medicine Because of their immunomodulatory qualities and wide range of differentiation potential, mesenchymal stem cells are easily isolated from a variety of organs and make excellent candidates for cell therapy. CD represents the cluster of differentiation; ESCs are embryonic stem cells; iPSCs are induced pluripotent stem cells; DCs are dendritic cells; NK cells are natural killer cells; and MSCs are mesenchymal stem cells. Because of their well-known immunomodulatory and regenerative qualities, MSC-derived exosomes are useful in the treatment of degenerative and inflammatory illnesses. On the other hand, because of their pluripotency, exosomes produced from iPSCs have improved regenerative capacities and may be useful for tissue regeneration and repair. Although ESC-derived exosomes have strong regenerative qualities as well, their clinical use is restricted by potential carcinogenicity and ethical issues (Ranghino et al. 2017 ). As a result, the source of exosomes should be chosen with the particular therapeutic objectives in mind, taking into account the related safety and ethical considerations. MSC-exosomes are being investigated in animal models of myocardial infarction for a range of potential therapeutic applications in regenerative medicine, such as enhancing heart function and reducing infarct size (Bodart-Santos et al. 2019 ). In animal models of Alzheimer’s disease, stroke, and spinal cord injury, shield neurons from damage and promote neural regeneration (Karaoz et al. 2019 ), facilitate muscle and bone healing in animal models of musculoskeletal diseases and fractures, and promote wound healing and reduce inflammation in animal models of skin burns and chronic wounds associated with dermatological diseases. Exosomes preserve the medicinal benefits of the parent cells while averting major issues like unintended gene mutation and potential carcinogenesis associated with MSC treatment (Choi et al. 2022 ). MSCs’ possible off-target effects need to be carefully considered. The non-specific distribution of exosomes may cause these effects by interacting with healthy tissues inadvertently, which could have negative consequences. Furthermore, proteins and RNAs that are carried by exosomes may unintentionally affect gene expression in cells that are not their intended targets, which could interfere with regular biological processes (Vader et al. 2016 ). Before clinical use, it is essential to fully describe the exosome content and create targeted delivery systems to reduce these dangers. Additionally, the therapeutic effects of MSC exosomes may be improved by genetically modifying them to express particular ligands that direct them toward an appropriate target and deliver tiny molecules of medication directly to the target regions as a drug delivery mechanism (Sun et al. 2021 ). Researchers are investigating a number of engineering techniques to improve the targeted delivery of exosome-based medicines. To increase specificity, one method is to alter exosome membranes to express particular ligands or antibodies that identify and attach to target cell receptors. Exosomes, for example, have been designed to exhibit peptides that target neurons, making it easier to transfer therapeutic drugs for neurological purposes across the blood–brain barrier. Loading exosomes with magnetic nanoparticles is an additional tactic that enables external magnetic field direction to the target region (Forsberg et al. 2020 ). Furthermore, artificial exosome-like nanovesicles are being created to resemble natural exosomes, providing cargo loading and surface characteristics that can be altered to improve targeting effectiveness. There are still certain problems that need to be fixed before MSC-exosomes are widely used in regenerative medicine. One challenge is developing efficient and scalable procedures for the synthesis and purification of MSC exosomes. Another difficult task is to comprehend the mechanisms by which MSC exosomes exert their therapeutic effects. The outcomes of several laboratory studies employing various techniques to separate, characterize, and purify MSC exosomes might not always line up. Additionally, MSCs frequently lack the large-scale exosome production capacity needed to have positive therapeutic benefits. The characterization of MSC exosomes in various subpopulations and the precise content characterization of the cargo must be investigated as well, since variability in exosome contents may modify the effect of the intervention on the target tissue (Tenchov et al. 2022 ). All things considered, MSC-exosomes could be a promising new instrument for regenerative medicine. To assess the safety and effectiveness of MSC-exosomes for the treatment of various diseases and ailments, clinical trials are presently being conducted. By modifying immunological responses, the exosome-based inhalation treatment EXO-CD24 has demonstrated encouraging outcomes in the treatment of severe COVID-19. Exosomes are being used in an oncology clinical trial in Australia to detect ovarian cancer early with 94% accuracy. Furthermore, Rion Aesthetics has created plated intense serum, a skincare product made from exosomes that has been shown to improve skin tone and texture (Ha et al. 2020 ). These studies demonstrate the growing use of exosomes in immunotherapy, regenerative medicine, and diagnostics. Economic feasibility of exosome therapies While exosome-based therapies seem to be gaining momentum in clinical translations, economic feasibility continues to be an important aspect in mainstream adoption. The high cost of extraction, purification, and mass manufacture of exosomes present heavy constraints. Traditional methods of ultracentrifugation, although widely used, are expensive and have low yield, which invites the need for scalable and cost-effective alternatives: tangential flow filtration, size-exclusion chromatography, and microfluidics-based isolation techniques (Tenchov et al. 2022 ). In addition, the economic burden of getting regulatory approval for exosome-based products is aggravated as products need to pass through rigorous quality control concerning good manufacturing practices (GMP). By providing support to healing wounds and regenerative medicine, therapeutic MSC-derived exosomes could shorten hospital stays and spare the patient from multiple surgeries. Exosome-based drug delivery systems can lower subsequent doses required and thus the total expense of treatment. Further improvements in scalable bioprocessing and storage conditions will determine the extent of affordability (Lee et al. 2021 ). Although exosome therapies bear high up-front costs, the paradigm shift that they would elicit within regenerative medicine and the continuing technological progress would likely provide a pathway toward cost-effectiveness and broader clinical applicability. Future research should focus on developing more economized production schemes and setting up standard operating protocols to make it more economically viable. Challenges in bringing exosomes-based therapeutic actions The development of medicines based on SC exosomes still faces several obstacles. The scalability of current exosome production techniques remains a significant challenge in translating exosome therapies to clinical applications. Although they are efficient, traditional isolation techniques such as density gradient separation and ultracentrifugation have low yields and cannot be scaled for large-scale production. Other methods, such as size-exclusion chromatography and tangential flow filtration (TFF), are more appropriate for producing clinical-grade exosomes since they are more efficient and have higher purity. Systems based on bioreactors have also been investigated to improve exosome synthesis by cell density enhancement and culture condition optimization (Colao et al. 2018 ). But maintaining sterility, batch-to-batch consistency, and regulatory compliance with good manufacturing practices (GMP) continue to be significant challenges. To produce therapeutic-grade exosomes in a high-yield, economical, and repeatable manner, more developments in purification technologies and standardization procedures are required. Standardized procedures are required for the administration, characterization, and isolation of exosomes. Standardizing separation and characterization techniques, guaranteeing batch-to-batch uniformity, and setting precise safety and efficacy criteria are some of the regulatory hurdles facing the clinical translation of exosome-based therapeutics. Different classifications of exosome-based goods by regulatory bodies like the FDA and EMA create ambiguity in the approval processes. Determining whether exosomes should be regulated as biologics, medications, or cell-free therapy presents additional difficulties. Furthermore, thorough preclinical and clinical validation is necessary to address concerns regarding long-term safety, off-target effects, and possible immunological reactions (Wang et al. 2024 ). For exosome medicines to be advanced into clinical practice, international regulatory frameworks and GMP-compliant manufacturing procedures must be established. Now that there have been so many encouraging in vitro, animal, and preclinical findings in a range of disease models involving various cancer types and age-related disorders, researchers must develop an MSC-exosome therapy that is feasible, repeatable, and risk-free (Petersen et al. 2014 ). Exosomes generated from MSCs have demonstrated promise in several disorders, but their effectiveness in some illnesses is still restricted. Exosomes may play two functions in advanced-stage malignancies, perhaps even aiding in the growth of the tumor. The results in chronic kidney disease have also been mixed, with some studies indicating no benefit. Concerns regarding the long-term efficacy of exosome-based skin rejuvenation treatments in dermatology are raised by the absence of adequate clinical validation (Lener et al. 2015 ). These drawbacks emphasize the necessity of additional study to maximize the uses of MSC-derived exosomes and guarantee reliable therapeutic results. Due to its many advantages, SC-derived EV therapy has become more and more popular as a cell-free treatment (Hamidi et al. 2024 ); yet, it has a few disadvantages as well. (1) The absence of established procedures for EV synthesis, isolation, and purification. Furthermore, there are issues with poor yield and purity, practical challenges, and economic considerations with the present EV production processes (Mendt et al. 2019 ). To enable EVs to be used in clinical settings more widely in the future, a strategy for the stable creation of high-yield EVs is required (Varderidou-Minasian and Lorenowicz 2020 ). 2) The unclear composition of EVs. EVs’ composition can change based on their origins and the conditions of their culture. As of yet, there is no reliable assessment procedure in place for analyzing the particular composition of EVs. (3) There is currently no information available about the molecular characteristics of EVs in vivo or their carcinogenic effects. This treatment strategy carries some risk of toxicosis and immunological rejection. Although MSC-derived exosomes are typically regarded as safe, using them may come with concerns of overstimulation or adverse effects. These include: (1) the potential for off-target effects, where exosomes may affect cells or tissues other than the intended target; (2) the potential for exosomes to trigger an excessive immune response, especially if the recipient is not well-matched to the exosomes; and (3) the rare possibility of tumor growth promotion if exosomes contain oncogenic cargo or stimulate pro-tumorigenic pathways (Meng et al. 2020 ). Besides, the immunogenicity of exosomes is a multi-faceted problem influenced by donor variability, exosomal surface proteins, and recipient immune status. Studies have suggested that exosome surface modifications such as glycosylation patterns and protein expression could make a much larger contribution to their immunological recognition (Yadav et al. 2024 ). In some cases, exosomes coming from an allogeneic source have been reported to trigger pro-inflammatory responses, thus calling for insights into adaptive immune evasion strategies and designing personalized therapeutic regimens. To properly evaluate these hazards and create mitigation plans, more research is required. There are several challenges associated with analyzing the diversity of exosome cargo from various mesenchymal stem cell (MSC) sources. Exosome composition can be affected by differences in donor attributes, including age, health, and genetic background, which can result in inconsistent therapeutic success. Furthermore, as diverse approaches might produce exosomes with differing purity and cargo profiles, the absence of standardized isolation and purification methods makes direct comparisons between research more difficult. Their study is further complicated by the dynamic nature of exosome composition, which can alter in response to cellular states and external factors (Ahn et al. 2022 ). To overcome these obstacles and guarantee repeatability and dependability in MSC-derived exosome research, standardized procedures and thorough characterization methods must be developed. To take this activity to the next level, guidelines regarding more precise isolation and storage are required because there are a lot of variables to consider about the various MSC sources, culture techniques, and EV enrichment processes. Although exosome-based treatments are usually regarded as safe, some safety issues have been noted. Immunogenicity is one possible concern, where exosomes from allogeneic origins could cause unintended immunological reactions. Furthermore, by encouraging angiogenesis and cellular proliferation, exosomes might affect the course of tumors, which raises questions regarding their application in cancer patients. Another danger is contamination during exosome isolation and purification, since lingering cellular components or contaminants may compromise the effectiveness of treatment. Moreover, contradictory effects may result from variations in exosome cargo based on the culture circumstances and donor cell source (Welsh et al. 2024 ). There is currently a lack of long-term safety data, so more study is required to create standardized procedures and legal requirements for clinical applications. The mechanism of action, distribution method, and length of therapeutic therapy in specific diseases are some of the variables that affect the potential of MSC-therapeutic small EVs. Several ethical questions are brought up by the usage of exosomes made from stem cells. These consist of (1) Informed consent: Making sure stem cell donors are completely aware of how their cells will be used to produce exosomes and any possible commercial uses; (2) Safety: to reduce the possibility of negative effects or unforeseen outcomes, the safety of exosome-based therapies should be thoroughly evaluated; (3) Fair access: encouraging fair access to exosome treatments, especially if they turn up to be successful and in great demand; (4) Transparency: encouraging responsible innovation that puts the welfare of patients and the good of society first; and (5) Transparency: preserving transparency in the creation, production, and promotion of exosome products (FDA 2019 ). Furthermore, comprehensive clinical trials are required to verify the long-term safety and efficacy of these medicines. Notwithstanding these difficulties, there is a strong case for continuing study and development of SC-exosomes due to their enormous potential benefits. When we gain a better understanding of the mechanisms of action of SC-exosomes and their interactions with target cells, we should anticipate the development of novel and powerful therapeutic approaches that have the potential to completely transform the field of regenerative medicine (Kuriyama et al. 2021 ). How we manage tissue regeneration, compromised skin integrity, and aging skin could be drastically altered by the therapeutic application of stem cell-produced exosomes. Ethical considerations in exosome-based therapies The use of stem cell-derived exosomes for therapy is a significant ethical concern, primarily in relation to donor consent and commercialization. There should be proper informed consent among donors due to the possibility of using stem cells and their derivatives for purposes other than what they were originally obtained for. This is especially crucial considering the likelihood of secondary or unexpected uses of exosome-based therapies. Furthermore, there are ethical concerns with regard to potential exploitation of donors, particularly in low-income communities where participation can be induced by financial incentive rather than adequate decision-making. Moreover, commercialization of exosome-based products also raises intricate bioethical and legal challenges. An expanding market in regenerative medicine has raised worries regarding fair access to exosome-based treatments due to the costs, which will potentially limit the accessibility to special groups. It is also important to consider the regulatory aspect as classification of exosomes as a biological product or therapeutic agent affects their market dispensation, cost, and avenues for clinical approvals (Ha et al. 2020 ). In addition, the threat of proprietary rights and patents on stem cell-derived exosome technologies can restrict their extensive therapeutic application, limiting innovation and access in medicine (Wang et al. 2023 ). Balancing innovation with ethical accountability requires strict guidelines to safeguard donor rights, provide equitable distribution, and avoid unethical profiteering in regenerative medicine (Muralikumar et al. 2021 ). Limitations of exosome therapies Although the potential of exosomes as therapeutic tools for regenerative medicine and rejuvenation of skin has been encouraging, there are many limitations to consider. A prominent limitation is that there is currently no standard method of isolating and characterizing exosomes. The present approaches like ultracentrifugation, precipitation, and size-exclusion chromatography yield variable purity and yield and impact reproducibility of the therapeutic effect. The exosome uptake mechanism and bioactivity are not well understood, preventing accurate control of their actions. An equally important issue is safety and immunogenicity because stem cell-derived exosomes contain bioactive molecules that can evoke off-target and/or unintended immune reactions. In addition, massive clinical use demands scalable and affordable manufacturing processes, which are still a roadblock in bench-to-bedside translation of exosome-based treatments (King and Perrin 2014 ). Overcoming these challenges is important for exosomes to be established as a standardized and widely used therapeutic strategy. Conclusion The transformational potential of exosomes derived from stem cells in the fields of wound healing, regenerative medicine, skin proliferation, and skin aging represents a paradigm shift in therapeutic methods. This thorough analysis has painstakingly investigated the various facets of exosome-mediated interventions, offering a sophisticated comprehension of their molecular workings and therapeutic applications. As we approach the end of this investigation, it is clear that the field of medicine is about to enter a revolutionary phase in which the complex cargo of exosomes formed from stem cells will be the key to unlocking new and potent therapeutic interventions. Numerous in vitro and in vivo investigations have demonstrated the connection between exosomes and the regulation of MMP expression. Mesenchymal stem cell (MSC)-derived exosomes have been demonstrated to control extracellular matrix remodeling by modifying MMP expression, specifically MMP-1, MMP-2, and MMP-9 (Mashouri et al. 2019 ). The transfer of bioactive molecules, such as miRNAs (e.g., miR-21, miR-29, and miR-181), mediates these effects by downregulating MMP activity to promote tissue regeneration and prevent excessive matrix breakdown. The proteomic studies have also shown important proteins in exosomes that interact with signaling pathways like MAPK and TGF-β to further alter MMP production (Hajialiasgary Najafabadi et al. 2024 ). The effectiveness of SC-exosomes in reversing the indications of skin aging has been exceptionally demonstrated. They additionally stimulate collagen synthesis, reduce oxidative stress, and inhibit matrix metalloproteinases (MMPs) from degrading extracellular matrix (ECM) components. Moreover, SC-exosomes stimulate the migration and proliferation of fibroblasts and keratinocytes, two crucial cell types for maintaining the integrity and functionality of the skin. A more youthful and revitalized appearance is the result of these combined actions, which help to restore the elasticity, firmness, and moisture of the skin. They have an incredible ability to stimulate the growth of skin cells, including keratinocytes, fibroblasts, and melanocytes. They are, therefore, good candidates to encourage hair development and wound healing due to this characteristic. Fibroblasts aid in the production of new granulation tissue, which promotes the healing process, while keratinocytes carry out the process of re-epithelialization, which restores the skin’s outer layer. Skin pigmentation is attributed to melanocytes, and SC-exosomes can help restore skin color and minimize the appearance of uneven pigmentation. They hasten the production of granulation tissue, angiogenesis, and re-epithelialization, which improves skin texture and speeds up wound closure. Re-epithelialization is the process by which keratinocytes proliferate and migrate to cover the exposed surface of a wound. The process of angiogenesis, or the formation of new blood vessels, is necessary to provide oxygen and nourishment to the wound while it heals. Temporary granulation tissue supports the wound’s structure and gets it ready for the creation of scars. Beyond skin uses, SC-exosomes have regenerative potential. Osteogenesis, or the process of making new bone, is aided in bone regeneration by SC-exosomes, which stimulate mesenchymal stem cells (MSCs) to multiply and develop into osteoblasts, or bone-forming cells. Encourage chondrocytes—the cells that create cartilage—to proliferate and differentiate to aid in the process of chondrogenesis, or cartilage creation, in cartilage regeneration. Although SC-exosome-based therapy development is still in its infancy, there are a plethora of potential advantages. These therapies may provide targeted, non-invasive, and efficacious treatments for a variety of skin-related disorders as well as uses in regenerative medicine. We can usher in a new era of regenerative medicine and give patients with a range of crippling illnesses hope by utilizing the regenerative and immunomodulatory characteristics of SC-exosomes. Even if there are still issues to be resolved, such as the requirement for legislative clarity, standardization, and increased accessibility, the potential advantages are too great to be disregarded. Cooperation between researchers, clinicians, and regulatory agencies becomes critical as the scientific community works to understand the intricacies of exosome-mediated medicines. By taking this action, we pave the way for a day when the revolutionary potential of exosomes made from stem cells is fully realized, offering highly effective and state-of-the-art therapies that can drastically transform the fields of regenerative medicine and dermatology. Acknowledgements The authors are thankful to the Shoolini University to provide the appropriate facilities and data to complete this review. Author contributions G.S. and S.S.: formal analysis, conceptualization, designing, writing—original manuscript, writing—review and editing. G.S. and D.S.: conceptualized the manuscript and wrote two sections. D.K., AS and RN: design, validate and supervised the whole manuscript. Funding No funding was received for any assistance. Data availability The data to support the findings for this study are available with the corresponding author upon request. 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