Exosomes, derived from the late endocytic compartment, diffuse easily into intracellular fluids and rapidly fuse with target cells, enhancing their potential for therapeutic delivery. They exhibit exceptional interaction with cellular membranes, which is crucial for efficient drug delivery. Recent in vivo studies have shown that exosomes exhibit specific cell tropism, guiding them to disease-affected tissues and organs56. This targeting ability is a result of both their intrinsic properties and engineered modifications. Exosomes express unique surface proteins that enhance their natural ability to bind to specific cell types, facilitating efficient targeting and drug delivery57.

The lipid bilayer structure of exosomes contributes to their low immunogenicity, allowing prolonged circulation and reducing the risk of immune rejection. Their natural structure also helps maintain integrity, ensuring that they protect their cargo until reaching the target site58, 59, 60. Furthermore, exosomes are biodegradable, reducing long-term toxicity risks compared to synthetic carriers that may persist in the body and cause chronic inflammation61, 62. Genetic modifications can enhance the targeting capabilities of exosomes. Incorporating homing peptides and ligands allows exosomes to be directed to specific organs or tissues, improving therapeutic efficacy59. These modifications can also facilitate on-demand drug release in response to specific stimuli, enhancing precision in drug delivery58. Additionally, surface proteins such as tetraspanins and integrins improve exosomes' natural targeting ability, ensuring efficient delivery to the intended tissues57. Engineered exosomes can also express chemokine receptors to enhance their tropism toward inflamed tissues, which has been demonstrated in treatments for conditions like atherosclerosis63. This ability is further supported by transcytosis, a process enhanced by factors such as inflammation64.

Despite their promise, exosomes' targeting efficiency can be inconsistent, and their production remains challenging. Synthetic alternatives may offer more controlled delivery mechanisms, highlighting the need for further optimization of exosome engineering60. Exosome production involves extensive cell culture and purification processes, which are resource-intensive and time-consuming. Variability in exosome composition requires rigorous quality assessment to ensure therapeutic efficacy65, 66. Additionally, the lack of standardized manufacturing guidelines is a significant barrier67. The regulatory landscape for exosome-based therapies is complex, varying by jurisdiction, and requires comprehensive pharmacokinetic and therapeutic efficacy data, along with toxicology studies and potency assays to ensure safety and efficacy in clinical settings68. Low yield and batch reproducibility further limit their scalability, posing another challenge for widespread clinical application. While the potential of exosomes as therapeutic agents is significant, these challenges must be addressed through ongoing research. Optimization of production methods, improvements in targeting precision, and regulatory advancements are crucial to unlocking the full therapeutic potential of exosomes.

MSC-exos have attracted considerable interest due to their immunomodulatory and regenerative capabilities. They increase Treg production in vivo and in vitro through TGF-α and IFN-γ69.

MSC-exos regulate pattern recognition receptors (PRRs), modulate B-cell activities, polarize macrophages toward anti-inflammatory phenotypes, and fine-tune T-cell activity. These processes orchestrate diverse immunological responses, making MSC-exos valuable for precision medicine and therapeutic interventions70.

MSC-exos primarily induce M2-like macrophage polarization through CD73 activity, which converts AMP to adenosine. This adenosine activates A2A and A2B receptors, triggering AKT/ERK signaling pathways that alleviate inflammation and immune dysfunction71. Furthermore, MSC-exos pre-treated in a diabetic environment (Exo-pre) enhance M2 polarization via miR-486-5p, which targets PIK3R1 and modulates the PI3K/Akt pathway72.

Additionally, miR-150-5p within MSC-exos downregulates the PI3K/Akt/mTOR pathway by targeting Irs1 in recipient macrophages, promoting M2 polarization and inhibiting M1 activation73. They also inhibit LPS-induced inflammatory responses, increase IL-10 and Arg-1 levels, enhance CD206 expression, reduce NF-κB signaling, and stimulate STAT3 activity, further supporting M2 macrophage polarization74. In vivo studies show MSC-derived extracellular vesicles enhance M2 macrophage polarization, providing a novel therapeutic strategy to mitigate inflammatory conditions75.

MSC-exos modulate T-cell activity by decreasing T-cell proliferation and Th1 differentiation while promoting Treg differentiation and restoring the Th17/Treg balance. These effects are mediated through pathways involving TGF-β and autophagy, as demonstrated in studies on primary Sjögren's syndrome76, 77. MSC-exos also promote the generation of IFN-γ⁺/Foxp3⁺ T cells with suppressive capacity and influence Th1 metabolism. Proteins such as p27kip1 and Cdk2 play significant roles in cell cycle arrest and T-cell suppression mediated by MSC-exos78. Moreover, exosomes enriched with CD73 can inhibit T-cell proliferation, modulate T-cell differentiation, and enhance immunosuppressive effects, making them potential therapeutic agents for autoimmune diseases79.

MSC-exos reduce neutrophil infiltration, attenuate NLRP3 inflammasome activation, and suppress the formation of neutrophil extracellular traps (NETs). They achieve this by up-regulating miR-199 in neutrophils, thereby decreasing NETs expression after stimulation80.

Managing wound healing is a complex process involving sequential, overlapping stages, where disruptions can lead to chronic, non-healing wounds. Collagen, a critical component of the ECM in the dermis, provides structural integrity and support to the skin81. In aging skin, collagen type I and elastic fibers become fragmented, causing dermal layer damage and impairing skin elasticity82, 83. Reconstructing the dermal structure can potentially mitigate aging effects and improve wound healing.

Several treatment options have been explored to counteract collagen degradation. Topical agents such as retinoids, alpha-hydroxy acids, and antioxidants stimulate collagen synthesis and inhibit its breakdown, but their effects are often limited and require prolonged use84, 85, 86. Invasive procedures like laser resurfacing, micro-needling, and injectable fillers can improve skin texture and reduce wrinkles. However, these methods carry risks such as scarring and infection84, 87, 88, 89, 90, 91.

Exosomes, nano-sized extracellular vesicles, offer a promising alternative. They can be applied topically or injected into the skin, allowing precise delivery to the dermis while minimizing systemic side effects. Exosomes contain bioactive molecules, including growth factors and cytokines, which promote angiogenesis and tissue remodeling92, 91, 93. Derived from various cell types, exosomes can influence collagen metabolism by breaching the epidermal barrier and interacting with target cells to regulate ECM homeostasis94, 95. MSC-exosomes exhibit remarkable capability in delivering functional molecules, including proteins, lipids, mRNAs, and miRNAs, to recipient cells. Their phospholipid bilayer enables efficient delivery, influencing cellular processes like gene regulation, immune modulation, and tissue repair96, 97, 98, 99. MSC-exosomes can enhance collagen production and reduce breakdown, particularly in fibroblasts, leading to smoother, more elastic skin95, 100, 101, 102, 103. They also address oxidative stress and inflammation, major contributors to skin aging104, 105.

MSC-exosomes are a promising strategy for treating skin disorders characterized by collagen dysregulation. These exosomes regulate collagen synthesis and degradation in fibroblasts by modulating the expression of key genes and pathways. For instance, they enhance the expression of collagen-related genes such as col1a1 while reducing the levels of matrix metalloproteinases (MMPs) and increasing the expression of tissue inhibitors of metalloproteinases (TIMPs), thereby preserving the balance of the ECM100, 106. Furthermore, MSC-exosomes contain miRNAs, such as miR-34b-3p and miR-144-3p, which regulate fibroblast behavior and collagen metabolism through pathways like PI3K/Akt 107, 108, 109.

During the early stages of wound healing, MSC-exosomes enhance type I and III collagen formation, promoting effective tissue regeneration. In later stages, they limit excessive collagen deposition, reducing scar formation. For instance, ADSC-derived exosomes adjust the type III-to-type I collagen ratio, aiding in balanced tissue repair110, 111. Exosomes rich in miR-21-5p and miR-125b-5p suppress TGF-β receptors, preventing myofibroblast differentiation and promoting better skin regeneration112. Additionally, UCB-MSC-exos inhibit collagen I production while encouraging skin cell proliferation and migration, further optimizing wound healing outcomes.

Aging induces significant morphological and functional changes in cutaneous blood vessels, impacting overall skin health and vascular functionality. Structural remodeling includes vascular adventitia thickening and a decrease in the density of skin lymphatic vessels, impairing fluid transport and immune responses113, 114. Functional decline manifests through reduced vasomotor function, increased blood viscosity, and heightened platelet aggregation, compromising vascular health. Furthermore, aging diminishes the ability of blood vessels to respond to stimuli, evidenced by reduced skin blood flow and impaired post-occlusive hyperemia115.

Endothelial dysfunction in aging cutaneous blood vessels is marked by reduced nitric oxide (NO) production, increased oxidative stress, and impaired vasodilation. Aging reduces NO bioavailability due to heightened superoxide anion production, leading to vascular dysfunction116, 117. This dysfunction affects nutrient delivery and waste removal in skin tissues, contributing to skin sagging, dryness, and wrinkle formation, all hallmarks of declining skin health116, 118 . Increased vascular stiffness further exacerbates these conditions, reflecting overall skin aging.

Exosomes, especially those originating from MSCs and endothelial cells, play a key role in angiogenesis. They transport pro-angiogenic factors, including VEGF and bFGF, to target cells, thereby stimulating endothelial cell proliferation, migration, and the formation of blood vessels119, 120. Both in vivo and in vitro studies show that exosomes derived from MSCs promote wound healing and angiogenesis. This is evident in diabetic skin ulcer models, where they accelerate wound closure and the formation of new blood vessels121, 122, 123.

MSC-derived exosomes promote angiogenesis and improve skin health through various molecular pathways. Exosomal miR-126 activates the PI3K/Akt signaling pathway, enhancing VEGF and angiopoietin-1 expression, thereby stimulating endothelial cell proliferation and migration124, 125. Exosomal miR-17-92 further supports angiogenesis by inhibiting ferroptosis and enhancing endothelial cell functions126. MicroRNA-125a, found in adipose-derived MSC exosomes, suppresses the angiogenic inhibitor DLL4, promoting the formation of endothelial tip cells120.

MSC-derived exosomes exhibit anti-aging effects on skin vasculature by regulating angiogenic factors and improving collagen production. These exosomes stimulate dermal fibroblast proliferation, migration, and collagen deposition, facilitating tissue regeneration and wound healing127. Additionally, exosomal Jagged1, derived from HIF-1α-overexpressing MSCs, enhances angiogenesis via Notch signaling activation in endothelial cells, further supporting vascular rejuvenation128.

Figure 1

The beneficial role of MSC-derived exosomes in skin rejuvenation. MSC-derived exosomes are essential in skin treatment due to their superior bioavailability and low immunogenicity. They efficiently penetrate tissues and are safe for therapy. These exosomes also possess immunomodulatory properties, reducing inflammation and promoting immune balance. They stimulate collagen production and prevent its breakdown, thus improving skin texture. Additionally, they promote angiogenesis, addressing vascular changes in aging skin. Exosomes have anti-inflammatory properties, providing protection against inflammation-related damage.