Adipose-derived stem cell exosomes: multifaceted therapeutic applications in regenerative medicine

Abstract

Adipose-derived stem cell exosomes (ADSC-Exos) have emerged as promising cell-free therapeutic agents in regenerative medicine, offering many benefits of stem cell therapy without the risks of cell transplantation. These nanoscale vesicles (30–150 nm) contain bioactive cargo including proteins, microRNAs, and lipids that mediate tissue repair through multiple mechanisms: promoting angiogenesis, modulating inflammation, reducing fibrosis, and activating endogenous regenerative pathways. Recent preclinical studies demonstrate remarkable efficacy across diverse applications, from accelerating chronic wound healing and stimulating skin regeneration to repairing cartilage, bone, and nerve tissues. In cardiovascular applications, ADSC-Exos protect against ischemic damage and improve cardiac function post-infarction. Neurologically, they show potential in stroke recovery, spinal cord injury, and neurodegenerative diseases by crossing the blood-brain barrier and delivering neuroprotective signals. Their potent immunomodulatory properties make them candidates for treating inflammatory and autoimmune conditions. Early clinical trials report encouraging safety profiles and preliminary efficacy in conditions ranging from acne scarring to Alzheimer’s disease. However, significant challenges remain in standardizing isolation methods, ensuring consistent potency, scaling production to clinically relevant quantities, and establishing optimal delivery strategies. This review synthesizes recent advances and limitations in ADSC-Exo research across various clinical applications, examines their underlying mechanisms of action, discusses current translational challenges, and highlights the potential of these versatile nanoparticles to transform regenerative medicine as off-the-shelf, cell-free therapeutics for multiple disease states.

Introduction

Why use ADSC in regenerative medicine

Adipose-derived stem cells (ADSCs) have attracted significant interest in regenerative medicine due to their abundance, ease of harvest, and potent paracrine healing effects^[1]. ADSCs can be obtained in large quantities from lipoaspirates and have multilineage differentiation capacity similar to bone marrow stem cells^[2,3]. However, delivering live stem cells can pose risks including immune rejection, emboli formation, or unwanted differentiation. As a cell-free alternative, the secretome of ADSCs – particularly extracellular vesicles known as exosomes – has gained attention for therapeutic applications^[4]. ADSCs exhibit greater genetic and morphological stability in prolonged culture compared to bone marrow mesenchymal stem cells, alongside enhanced proliferative capacity^[5]. They are better adapted to anoxic conditions and possess advantages in inflammation regulation^[6]. Furthermore, ADSCs have demonstrated significant anti-inflammatory, anti-phagocytic, anti-apoptotic properties, and improved cell viability in the context of anti-atherosclerosis^[7]. Notably, ADSCs exhibit potent immunomodulatory properties alongside low immunogenicity, meaning they can be used allogeneically with a reduced risk of immune rejection^[1]. They actively release anti-inflammatory factors and induce macrophage polarization toward pro-healing phenotypes^[1]. Additionally, ADSCs maintain genetic stability over long-term culture and have high proliferative capacity in vitro^[8], facilitating the expansion of clinically relevant cell numbers. The anti-fibrotic and trophic factors secreted by ADSCs have supported the hepatic and renal regeneration^[9]. They also exhibit superior regenerative capabilities in skeletal muscle^[10], spinal cord injuries^[11,12], and got promising approach against various diseases^[13]. The remarkable versatility of ADSCs – spanning tissue types from heart and brain to skin – underscores their role as a pivotal, all-purpose regenerative cell source in current translational research.

HIGHLIGHTS

• This review examines the therapeutic applications of adipose-derived stem cell exosomes in regenerative medicine, highlighting their benefits over cell transplantation across multiple organ systems.

• ADSC exosomes promote tissue repair through multiple mechanisms including angiogenesis, inflammation modulation, and activation of endogenous regenerative pathways with proven efficacy in preclinical models.

• Despite promising clinical trials showing safety and efficacy, challenges remain in standardizing isolation methods, ensuring consistent potency, and scaling production for clinical applications.

Exosomes among the extracellular vesicles

The International Society for Extracellular Vesicles defines “extracellular vesicles” (EVs) as all non-replicating particles possessing a bilayer lipid membrane that are secreted by cells^[14]. These varied membrane structures differ in biogenesis and dimensions: exosomes (50–150 nm) arise from endosomes, microvesicles (50–1000 nm) bud from plasma membranes, and apoptotic bodies (>1000 nm) are generated following cell death^[15]. All cells continuously release EVs carrying selected biomolecules – proteins, peptides, RNA species, lipids, and DNA fragments – that function locally or travel through circulation to modulate cellular responses at distant sites via paracrine signaling^[16–18]. Figure 1 illustrates these various EV types, the broad spectrum of their applications and the effective exosomal cargo.

Figure 1.

Classification and biogenesis of extracellular vesicles (EVs). This comprehensive diagram illustrates the heterogeneous family of membrane-bound vesicles secreted by cells, depicting their diverse biogenesis pathways and structural characteristics. The central cell shows the formation of exosomes (50–150 nm) through the endocytic pathway, where endocytosed material forms early endosomes that mature into multivesicular bodies (MVBs) containing intraluminal vesicles; these MVBs subsequently fuse with the plasma membrane during exocytosis, releasing exosomes into the extracellular environment. In contrast, microvesicles (50–1000 nm) are shown budding directly from the plasma membrane, while apoptotic bodies (>1000 nm) appear as larger vesicles formed during cell death. The diagram highlights these three main EV classes with distinct origins: exosomes from endosomal compartments, microvesicles from direct membrane budding, and apoptotic bodies from dying cells. A rectangular box emphasizes the “small EVs (sEVs)” category that encompasses vesicles of approximately 50–200 nm in diameter, noting that while exosomes are generally smaller than microvesicles, their size ranges overlap, making size alone insufficient for differentiating between these EV types. Each vesicle type contains cargo molecules such as proteins, peptides, RNA species (including microRNAs, mRNAs, and long noncoding RNAs), lipids, and DNA fragments, demonstrating how EVs carry bioactive chemicals based on their biological origin. The figure also indicates two newly acknowledged EV subtypes, supermeres and exomeres, marked with question marks to suggest their biogenesis pathways remain under investigation. All cell types continuously secrete these diverse EVs, which function as intercellular messengers carrying selected biomolecules that act locally or travel through circulation to modulate cellular responses at distant sites through paracrine signaling mechanisms, enabling complex cell-to-cell communication throughout the body. A human silhouette with various target organs and tissues arranged vertically alongside, including (from top to bottom): brain (neurological applications), heart (cardiovascular repair), lungs (respiratory conditions), liver (hepatic regeneration), kidneys (renal protection), knee joint (osteoarthritis and cartilage repair), skin (wound healing and dermatological conditions), and foot (diabetic ulcers). The comprehensive anatomical display effectively summarizes the multifaceted clinical utility of ADSC-Exos across different organ systems throughout the body.

Exosomes (~50–150 nm) differ from microvesicles in several key aspects. Their protein patterns typically diverge more from their parent cells than those of microvesicles^[19]. These vesicles express characteristic markers (e.g., CD9, CD63, CD81, Alix, TSG101) and are enriched in growth factors, cytokines, and microRNAs that influence processes such as angiogenesis, inflammation, and tissue remodeling^[4,20,21]. Exosomes are abundant in extracellular matrix components, heparin-binding proteins, receptors, immune response proteins, and adhesion proteins, whereas microvesicles are characterized by a higher concentration of endoplasmic reticulum, proteasome, and mitochondrial proteins. Their lipid profiles vary: exosomes possess a higher concentration of glycolipids and free fatty acids, while microvesicles are enriched with ceramides and sphingomyelins^[19].

Although exosomes are generally smaller than microvesicles, size alone cannot distinguish them due to overlapping ranges. Recent recommendations suggest the term “small EVs (sEVs)” for vesicles measuring 50–200 nm released by cells^[22]. Accurate classification of sEVs as “exosomes” requires confirming their endosomal origin, while producing pure exosomes necessitates protocols that remove non-endosomal vesicles – requirements that remain experimentally challenging and primarily of academic interest. Clinically, what matters most is that sEV preparations can be consistently manufactured and demonstrate therapeutic efficacy in robust models without significant side effects^[23]. For clarity, this review uses “exosomes” to describe these small vesicles harvested from stem cells.

Notably, ADSC-Exos recapitulate many beneficial effects of ADSC transplantation, including promoting tissue repair and reducing inflammation, but without containing viable cells, they have lower risks and potentially easier regulatory pathways. In the following sections, we review the current evidence for ADSC-Exo therapy across different organ systems and disease conditions (excluding cancer), highlighting the mechanisms of action and outcomes observed. The ADSC-derived exosomal cargos, targeted molecular pathways, therapeutic outcomes, and study models across various organ systems and inflammatory conditions are listed in Table 1. We then discuss challenges to clinical translation and future perspectives for integrating ADSC-Exos into clinical practice.

Table 1.

ADSC-derived exosomal cargos, targeted molecular pathways, therapeutic outcomes, and study models across various organ systems and inflammatory conditions

Organ	Exosomal Cargo	Affected pathways/mechanisms	Therapeutic outcomes
Brain	miR-126	miR-126 inhibits inflammatory signaling & apoptosis while stimulating angiogenesis. IGF-1 and BDNF support neurotrophic signaling and target apoptotic pathways, aiding neuron survival.	Improved neural tissue recovery after injury: smaller infarct volumes and better neurological function in stroke models. Enhanced neurogenesis, neuronal survival, and synaptic plasticity in injured brain regions Reduced neuroinflammation and glial scarring, promoting axonal regeneration in TBI/SCI mode
	IGF-1
	BDNF
	anti-apoptotic miRNAs
Heart	miR-205	miR-205 suppresses cardiomyocyte apoptotic pathways and promotes endothelial proliferation. miR-93-5p inhibits excessive autophagy and inflammatory signaling in the infarcted heart. circ-0008302 sponges miR-466i-5p, upregulating the antioxidant enzyme MsrA in cardiomyocytes.	Protects myocardium from ischemic injury: reduced cardiomyocyte death and fibrosis, smaller infarct size; increased capillary density in border zone; improved cardiac function after MI.
	miR-93-5p
	circ-0008302†
Lung	IL-10	Exosomal IL-10, PGE2, and IDO drive macrophages toward anti-inflammatory M2 phenotype miR-146a/miR-16-5p target TLR4/IRAK1/TRAF6 to inhibit NF-κB signaling. HGF and FGF2 promote alveolar repair/regrowth and enhance epithelial recovery miR-126 activates PI3K/Akt in endothelium to reduce vascular permeability with less edema circ-Fryl sponges miR-490-3p to upregulate SIRT3/AMPK as anti-apoptotic effector	Reduced lung inflammation and injury: lower levels of TNF-α, IL-6, IL-1β in injured lungs; decreased pulmonary edema and vascular leakage in acute lung injury; enhanced alveolar tissue regeneration and improved lung histology in ARDS models. In a pilot study of severe COVID-19 ARDS, ADSC-Exos improved oxygenation and reduced inflammatory markers, suggesting translation of these protective effects to humans.
	IL-1ra
	HGF
	VEGF
	FGF2
	Ang-1
	IDO
	COX-2
	miR-126
	miR-21
	miR-146a
	miR-16-5p
	circ-Fryl
	DLEU2
Liver	IL-10	Activates Nrf2/HO-1 pathway in macrophages, conferring antioxidant and anti-inflammatory effects. Inhibits TGF-β/Smad signaling in hepatic stellate cells, blocking their activation and reducing fibrosis. miR-148a induces M2 macrophage polarization via STAT3/KLF6 signaling, lowering inflammatory cytokines and fibrogenesis miR-20a-5p targets TGFBR2, downregulating p38 MAPK/NF-κB to further suppress inflammation and collagen deposition.	Attenuates liver injury and fibrosis: decreased collagen deposition and stellate cell activation in toxin-induced fibrosis models; reduced hepatic inflammation in sepsis Promotes liver regeneration: HGF in exosomes stimulates hepatocyte proliferation, while VEGF/FGF2/PDGF enhances angiogenesis for tissue repair. Net outcome is improved liver function and tissue recovery in chronic liver damage models.
	IL-1ra
	VEGF
	FGF2
	TGF-β1
	HGF
	GM-CSF
	miR-148a
	iR-20a-5p
Kidney	miR-486	miR-486 inhibits Smad1/mTOR signaling in podocytes, reducing apoptosis and proteinuria in diabetic nephropathy. miR-26a-5p targets TLR4, suppressing TLR4/NF-κB and excess VEGF-A, thereby attenuating inflammation and glomerular injury. miR-21-5p downregulates RUNX1 to protect against tubular cell apoptosis in AKI miR-146a/b inhibits IRAK1/TRAF6 in TLR pathways, curbing NF-κB–mediated inflammation. miR-342-5p inhibits TLR9, activating autophagy and reducing inflammatory injury in acute kidney injury. circ-0001295 preserves microvascular integrity and limits capillary leakage in septic AKI. CD73 generates anti-inflammatory adenosine, dampening inflammation and improving renal microcirculation.	In diabetic nephropathy, exosomes reduce proteinuria and podocyte loss; in acute kidney injury, they suppress inflammatory damage and enhance recovery. Enhanced autophagy and M2 macrophage polarization lead to reduced renal inflammation and fibrosis. In sepsis-induced AKI models, ADSC-Exos stabilized hemodynamics, reduced capillary leak, and improved survival.
	miR-26a-5p
	miR-21-5p
	miR-146a/b
	miR-342-5p
	circ-0001295
	CD73
Joint	miR-145	Upregulates chondrogenic transcription factors and extracellular matrix genes (e.g. SOX9, Collagen II, Aggrecan) in cartilage. Downregulates catabolic and inflammatory mediators in joints (e.g. matrix-degrading enzymes MMP-3, ADAMTS5) and suppresses inflammation that drives cartilage breakdown.	ADSC-Exos promote differentiation of progenitor cells into chondrocytes and enhance cartilage matrix formation. ADSC-Exos protect existing cartilage from degeneration by reducing breakdown enzymes, and actively aid in rebuilding cartilage tissue. In osteoarthritis models, ADSC-Exos lead to improved cartilage integrity and reduced progression of joint damage, ultimately preserving joint function.
	miR-221
Skin	VEGF	Exosomal VEGF and FGF2, along with miR-126/miR-130a, activate PI3K/Akt pro-angiogenic pathways to increase capillary formation in wounds. ADSC-Exos stimulate activation of dermal fibroblasts and keratinocytes, accelerating re-epithelialization and collagen synthesis. LncRNA MALAT1 in exosomes upregulates collagen production and downregulates MMPs, improving extracellular matrix remodeling. ADSC-Exos shift the wound environment from chronic inflammation to healing by promoting M2 macrophage polarization and reducing pro-inflammatory cytokines.	Accelerated closure of acute and chronic wounds: faster wound contraction and re-epithelialization observed with ADSC-Exo treatment. Enhanced granulation tissue and collagen deposition lead to stronger, better-quality healing. Chronic non-healing wounds are brought out of the inflammatory phase, allowing normal healing progression. ADSC-Exos have also improved outcomes in inflammatory skin diseases (e.g. atopic dermatitis, reducing Th2 cytokines) and even stimulated hair follicle growth in alopecia models (via miR-122-5p).
	FGF2
	MALAT1
	miR-126
	miR-130a
	HSP70
	HSP90
Diabetic ulcer	HSP90	HSP90 delivered by exosomes activates the LRP1/Akt pathway in diabetic skin cells, enhancing cell survival and stress resistance. circ-Snhg11 acts as a molecular sponge to promote M2 macrophage polarization in diabetic wounds, thereby reducing inflammation. Exosomal factors inhibit the Bax/caspase-3 apoptotic pathway in high-glucose conditions, preventing excessive cell death in wound tissues.	ADSC-Exos restore proliferation and collagen production function to fibroblasts in diabetic ulcers. Treated diabetic wounds show faster closure, with greater collagen deposition and re-epithelialization than untreated controls. Local oxidative stress and inflammation are reduced, creating a microenvironment conducive to healing rather than chronic inflammation.
	circRNA Snhg11
	Various anti-apoptotic and pro-angiogenic miRNAs
Inflammatory diseases (e.g. rheumatoid arthritis, etc.)	IL-1ra	IL-1ra blocks IL-1 signaling, dampening NF-κB–driven inflammation in tissues. TGF-β in exosomes promotes regulatory immune responses in Treg cells, helping resolve autoimmunity.- miR-146a in ADSC-Exos target IRAK1/TRAF6, suppressing TLR/IL-1 R pathways and reducing production of TNF-α, IL-6, etc. Skews macrophages toward an M2 anti-inflammatory phenotype in affected tissues (e.g. synovium in RA), thereby lowering pathogenic inflammation.	In collagen-induced rheumatoid arthritis model, ADSC-Exos reduce joint swelling, synovial inflammation, and bone erosion. Joint damage is ameliorated to a degree comparable to stem cell therapy, confirming exosomes carry the key immunosuppressive functions. In neuroinflammatory conditions like multiple sclerosis, exosomes crossing the blood-brain barrier mitigate microglial and T-cell activation. These immunomodulatory effects show promise in other autoimmune diseases (e.g. SLE), where early studies suggest restored immune homeostasis.
	TGF-β1
	miR-146a
	IDO

ADSC-Exos in clinical application

Therapeutic applications in cardiovascular disease

Ischemic heart disease and myocardial infarction (MI) result in irreversible loss of cardiomyocytes, which leads to heart failure. Adult cardiomyocytes have a low proliferative potential, making regenerating heart tissue extremely challenging. Cell therapy with stem cells has been investigated for cardiac repair, but issues like poor engraftment and arrhythmogenic risks persist. ADSC-Exos offer a cell-free therapeutic approach to post-MI cardiac repair that can harness the cardioprotective factors of stem cells without introducing living cells into the heart.

Recent studies have shown that ADSC-Exos can attenuate myocardial injury and improve cardiac function after MI. Wang et al injected ADSC-Exos into the border zone of infarcted mice hearts and noticed a significant improvement in left ventricular ejection fraction and scar reduction compared to controls^[24]. Histologically, hearts treated with exosomes demonstrated enhanced capillary density in the infarct region, signifying angiogenesis, and a reduction in cardiomyocyte death. Mechanistically, the beneficial effects were linked to specific microRNA cargo: ADSC-Exos are abundant in miR-205, which has been demonstrated to suppress apoptotic pathways and promote endothelial cell proliferation in the ischemic myocardium^[24]. In vitro, these exosomes facilitated the migration of human microvascular endothelial cells and the creation of tubular structures, thereby validating their pro-angiogenic potential^[24].

Another study demonstrated that exosomes engineered to carry miR-93-5p from ADSCs significantly improved cardiac outcomes in a rat MI model^[25]. The miR-93-rich exosomes suppressed excessive autophagy and inflammatory cytokine production in the injured heart, thereby protecting cardiomyocytes from cell death^[25]. Treated animals showed smaller infarct areas and better preserved cardiac function than untreated MI controls. These findings align with earlier work by Liu et al, who reported that exosomal miR-93-5p delivered to infarcted hearts reduced myocardial damage and fibrosis via downregulation of pro-apoptotic and pro-inflammatory signaling^[26]. Multiple exosomal miRNAs converge on TLR pathways; as an example beyond the kidney, miR-93-5p packaged in ADSC-Exos can simultaneously target Toll-like receptor 4 (TLR4) and autophagy gene Atg7, dampening inflammatory cytokine release and cell stress responses^[26].

In addition to promoting vessel formation and cell survival, ADSC-Exos may aid myocardial regeneration by activating resident cardiac progenitor cells. While true regeneration of myocardium is limited, exosome treatment has been observed to increase markers of cell proliferation in cardiac tissue post-MI, suggesting a possible stimulation of endogenous repair pathways^[27]. They also modulate the post-infarction immune response; for example, exosome therapy can reduce infiltration of inflammatory macrophages in the heart and promote a more reparative immune profile, which is conducive to healing^[27]. The net effect of these multi-pronged actions is an attenuation of adverse remodeling after MI. With ADSC-Exo therapy, the typical thinning and dilatation of the ventricular wall is less severe, and cardiac contractile function is better preserved^[24]. This holds great potential for treating MI patients, as improved healing of the infarct could translate to a lower incidence of heart failure.

While human trials specifically using ADSC-Exos for MI are still forthcoming, the strong preclinical evidence has spurred interest. Notably, extracellular vesicles from MSCs have already entered early clinical trials for other ischemic conditions (e.g., limb ischemia and stroke, as discussed below), and one phase I trial is evaluating an allogenic MSC-derived exosome product for preventing heart transplant rejection (indirectly exploring cardiac effects). Overall, ADSC-Exos show considerable promise in rejuvenating ischemic myocardium by promoting angiogenesis, inhibiting cell death, and modulating post-infarct remodeling. As such, leveraging ADSC-Exos for cardiac repair is a logical next step.

Therapeutic applications in neurologic disorders

The central nervous system has historically been considered immune-privileged and difficult to repair, but recent evidence suggests that stem cell-derived exosomes can cross the blood–brain barrier and influence neural tissue recovery^[4]. ADSC-Exos are under investigation for several neurological disorders, including stroke, spinal cord injury, and neurodegenerative diseases.

In ischemic stroke, where blood flow to the brain is interrupted leading to neuronal death, ADSC-Exos have demonstrated therapeutic benefit in preclinical studies. One pivotal study by Geng et al administered exosomes from miR-126–modified ADSCs to rats after middle cerebral artery occlusion (a stroke model). The treated rats showed significantly better neurological function recovery, smaller infarct volumes, and enhanced neurogenesis in the ischemic boundary zone compared to controls^[28]. The exosomes worked by shuttling miR-126 into recipient brain cells, which inhibited inflammatory signaling and cell apoptosis while stimulating new blood vessel growth in the brain^[28,29]. Importantly, the benefits were much greater with miR-126-enriched exosomes than with normal ADSC-Exos, highlighting how specific cargo molecules can amplify efficacy. Even without genetic modification, ADSC-Exos can aid stroke recovery through several mechanisms. They reduce neuroinflammation by tempering activated microglia (the brain’s resident immune cells) and astrocytes that contribute to secondary injury^[28,29]. They also promote angiogenesis in the ischemic brain, similar to their effect in peripheral wounds, which helps restore perfusion to endangered neurons^[28,29]. Additionally, exosome treatment has been associated with increased neuronal survival and synaptic plasticity in the peri-infarct area, likely due to exosome-carried growth factors like IGF-1 and BDNF, and delivery of miRNAs that target apoptotic pathways^[30,31].

Beyond stroke, ADSC-Exos have shown neuroprotective effects in models of spinal cord injury and traumatic brain injury, often by reducing inflammation and glial scar formation. They can promote axonal regeneration and remyelination in injured central nervous system tissue by supporting oligodendrocytes and Schwann cells (in the case of peripheral nerve or spinal roots)^[1]. While most neurological studies are in rodents, the positive findings have led to early clinical translation in at least one neurodegenerative condition: Alzheimer’s disease. In 2023, Xie et al published results from a phase I/II trial using allogenic ADSC-Exos in patients with mild to moderate Alzheimer’s disease^[32]. Patients received intravenous infusions of ADSC-Exos periodically and were monitored for safety and preliminary efficacy. The treatment was well tolerated with no serious adverse events. Moreover, patients demonstrated some improvements in cognitive function tests or stabilization of cognitive decline compared to expected worsening (although the trial was not powered for definitive efficacy conclusions)^[32]. This represents one of the first clinical applications of ADSC-Exos in chronic neurological diseases. The rationale is that exosomes may help reduce neuroinflammation in Alzheimer’s disease and possibly facilitate clearance of amyloid or tau pathology by modulating microglial activity. While very early, this trial provides proof-of-concept that ADSC-Exos can be delivered safely to human patients with brain disorders.

Other neurodegenerative diseases such as Parkinson’s disease^[33] and amyotrophic lateral sclerosis^[34–36] are also being explored in preclinical contexts with MSC-derived exosomes. The strong anti-inflammatory and neurotrophic effects of ADSC-Exos suggest they could protect neurons and support neural network recovery in these conditions as well. However, further studies are needed to understand optimal dosing, timing, and whether exosomes can meaningfully alter disease progression in chronic neurodegeneration.

Collectively, ADSC-Exos offer a multi-faceted therapeutic approach for neurological injuries: they reduce detrimental inflammation, provide growth support for neurons and glia, and enhance vascularization in injured neural tissue. These combined actions can translate to improved functional recovery, as evidenced in stroke models. With early-phase clinical trials like Alzheimer’s disease study underway, the central nervous system may soon become a target for exosome-based therapies. Continued research will clarify which neurological conditions are most amenable to exosome intervention and how to maximize exosome delivery to the brain.

Therapeutic applications for pulmonary injury

ADSC-Exos protect against pulmonary injuries through dual anti-inflammatory and regenerative mechanisms. Their immunomodulatory cargo includes IL-10, HGF, VEGF, FGF2, PGE₂, angiopoietin-1, and IDO^[37]. HGF enhances alveolar regeneration in emphysema models^[37], while FGF2 inhibits alveolar destruction^[38]. ADSC-Exos modulate lung macrophages by suppressing pro-inflammatory cytokine production and promoting anti-inflammatory M2 phenotypes^[39]. They inhibit IL-27 secretion, attenuating IL-6, TNF-α, and IL-1β elevation in septic lungs^[40], while paradoxically increasing local IL-6 to resolve acute lung injury through downstream anti-inflammatory signaling^[41].

The miRNA content contributes significantly to lung protection: miR-126 activates the PI3K/Akt pathway in pulmonary endothelial cells, reducing vascular permeability^[42], while miR-21 and miR-146a dampen NF-κB-mediated inflammation^[43,44]. Exosomal miR-16-5p drives M2 macrophage polarization by targeting TLR4 signaling^[39]. CircRNAs like circ-Fryl deliver anti-apoptotic signals by sponging miR-490-3p and upregulating SIRT3/AMPK signaling^[45]. LncRNA DLEU2 promotes M2 macrophage polarization via the miR-106a-5p/LXN axis, mitigating sepsis-induced lung injury^[46]. These combined mechanisms make ADSC-Exos promising for inflammatory pulmonary conditions^[47].

Therapeutic applications in hepatic disease

ADSC-Exos counteract liver injury and fibrosis by reprogramming the hepatic microenvironment. They ameliorate multi-organ inflammation in sepsis by activating the Nrf2/HO-1 pathway in macrophages^[40] and inactivate pro-fibrotic TGF-β/Smad signaling to inhibit hepatic stellate cell (HSC) activation^[48]. In toxin-induced fibrosis models, they correct glutamine metabolism abnormalities and reduce collagen deposition^[49]. The growth factor cargo (VEGF, FGF-2, TGF-β, HGF, GM-CSF) supports hepatic regeneration^[50]. HGF stimulates hepatocyte proliferation, while VEGF and PDGF promote angiogenesis to restore oxygenation^[50,51].

Anti-inflammatory cytokines (IL-10, IL-1ra) create a regenerative environment^[47]. Exosomal miR-148a promotes macrophage switching from M1 to M2 phenotypes via STAT3/KLF6 signaling, decreasing inflammatory cytokines and fibrosis^[48,52]. These mechanisms collectively reduce hepatic inflammation and enhance liver regeneration^[47]. In addition, ADSC-Exos attenuated liver fibrosis by suppressing the activation of the p38 MAPK/NF-κB pathway via the miR-20a-5p/TGFBR2 axis^[53] and inhibited abdominal aortic aneurysm by suppressing TXNIP-NLRP3 inflammasome via exosomal miR-17-5p^[54].

Therapeutic applications in renal injury

In kidney injury models, ADSC-Exos deliver renoprotective miRNAs. In diabetic nephropathy, miR-486 inhibits Smad1/mTOR signaling in podocytes, reducing apoptosis and proteinuria^[55]. Exosomal miR-26a-5p targets TLR4, suppressing the TLR4/NF-κB inflammatory cascade and downregulating excess VEGF-A to attenuate glomerular injury^[56]. ADSC-Exos activate pro-survival pathways in acute kidney injury (AKI) by upregulating SIRT1 signaling^[57] and enhancing autophagy in damaged podocytes^[55]. ADSC-Exo attenuated Type 2 diabetes mellitus-induced kidney injury and podocyte apoptosis and inflammation by releasing USP25^[58]. Hypoxia-pretreated ADSC-Exos inhibit sepsis-induced renal injury and improve outcomes in a mouse model of sepsis^[59]. Recent studies identified miR-342-5p as a critical exosomal miRNA that inhibits TLR9 expression, activating autophagy and attenuating inflammation in AKI models^[60]. Hypoxia-preconditioned ADSC-Exos enriched with circ_0001295 preserve renal microvasculature integrity, reducing capillary leakage in septic mice^[59]. Exosomal CD73 generates adenosine, dampening inflammation and improving microcirculation^[39].

While clinical studies for septic AKI are limited, a recent trial using ADSC infusions in septic patients showed improved survival and lower AKI incidence^[40], suggesting the exosome-mediated benefits could translate to human sepsis. These multifaceted mechanisms make ADSC-Exos promising for AKI, chronic nephropathy, and sepsis-associated kidney failure^[61].

Therapeutic applications in musculoskeletal and orthopedic repair

ADSC-Exos have also shown significant therapeutic potential in musculoskeletal systems, including muscle regeneration, tendon and cartilage repair, and bone healing. Skeletal muscle injuries and degenerative conditions can benefit from the regenerative signals delivered by ADSC-Exos. For example, Pu et al demonstrated that the secretome of ADSCs, especially the exosome fraction, reduced skin flap ischemia in mice after injury^[62]. The exosomes provided a rich mixture of microRNAs (such as miR-23a/b and members of the let-7 family) and growth factors that reduced fibrosis and promoted the formation of new muscle fibers^[1]. They also modulated macrophage activity in the injured muscle, curbing chronic inflammation and fostering a pro-regenerative environment^[1]. Treated animals showed increased muscle fiber diameter and reduced scar tissue, indicating more complete functional muscle recovery. In addition, ADSC-Exos promote tendon healing depending on the activation of the SMAD2/3 and SMAD1/5/9 pathways^[63].

In cartilage repair and osteoarthritis, ADSC-Exos can drive chondrogenesis and suppress inflammation in joint tissues^[64]. Zhao et al reported that human ADSC-Exos promoted the differentiation of progenitor cells into chondrocytes and simultaneously inhibited inflammatory pathways that contribute to cartilage breakdown^[65]. Specifically, exosomal microRNAs miR-145 and miR-221 were shown to be key effectors; they upregulated cartilage matrix genes (e.g., SOX9, collagen II, aggrecan) and downregulated catabolic enzymes (like MMP-3 and ADAMTS5) in osteoarthritic cartilage models^[66,67]. Another study found that pre-treating ADSCs with the small molecule kartogenin resulted in exosomes that even more potently induced chondrogenesis, suggesting that the exosome cargo (and therapeutic efficacy) can be enhanced by conditioning strategies^[68]. These findings highlight the ability of ADSC-Exos to not only protect existing cartilage from degeneration but also actively rebuild cartilage tissue – a promising strategy for osteoarthritis therapy.

For bone regeneration, ADSC-Exos help orchestrate angiogenesis and osteogenesis in bone defects and fractures^[69,70]. Several animal studies have shown improved bone healing with exosome treatment. Yang et al demonstrated that an exosomal microRNA (miR-130a-3p) from ADSCs targets the SIRT7 gene and activates Wnt/β-catenin signaling, thereby stimulating the osteogenic differentiation of ADSCs and enhancing bone formation^[71]. In a rat calvarial defect model, Meng et al found that exosomes from osteogenically induced ADSCs significantly increased new bone volume and mineral density compared to untreated controls^[72]. These exosomes carried osteogenic transcription factors and microRNAs that encouraged recipient stem cells to become osteoblasts. Combining exosomes with biomaterial scaffolds further amplifies bone repair – 3D-engineered scaffolds loaded with ADSC-Exos have yielded more robust bone regeneration in critical-size defects by providing a sustained release of osteogenic signals^[73,74]. Moreover, ADSC-Exos demonstrate protective effects in pathological bone loss conditions. Yao et al showed that administering ADSC-Exos mitigated osteoporosis-like bone loss induced by long-term glucocorticoid (dexamethasone) exposure^[75]. The exosomes activated the Nrf2/HO-1 antioxidant pathway in bone cells, reducing oxidative stress and apoptosis, which preserved bone density^[75]. This suggests a therapeutic role for exosomes in preventing or treating osteoporotic changes.

Beyond skeletal tissue, ADSC-Exos have aided peripheral nerve repair^[76,77]. Bucan et al used rat ADSC-Exos in a rat sciatic nerve crush injury model and found faster nerve regeneration and functional recovery^[78]. The exosomes enhanced Schwann cell proliferation and myelination, which facilitated axon regrowth across the injury gap^[78]. Treated nerves showed increased axonal count and diameter, as well as better electrophysiological conduction, compared to untreated injuries^[76–78]. These outcomes indicate that ADSC-Exos deliver neurotrophic factors and miRNAs that support the intrinsic repair mechanisms of peripheral nerves, making them a promising therapy for nerve injuries.

The common thread is that ADSC-Exos supply a potent combination of pro-regenerative signals. They reduce inflammation and fibrosis while boosting the growth and differentiation of local progenitor cells into functional tissue-specific cells (myocytes, chondrocytes, osteoblasts, Schwann cells). Consequently, structural and functional recovery is improved in these tissues. These findings lay the groundwork for translating exosome therapy into treatments for muscle trauma, osteoarthritis, difficult fractures, and nerve damage. Some early-stage clinical research is underway; for example, clinical trials are examining ADSC-derived products (including exosomes) for osteoarthritis and bone healing^[79]. Though human data are still limited in orthopedics, the robust preclinical evidence suggests ADSC-Exos could become a valuable tool in this arena.

Therapeutic applications in cutaneous and dermatologic conditions

One of the earliest and most active areas of ADSC-Exo research is in skin repair and wound healing^[80,81]. Chronic wounds, such as diabetic foot ulcers and burns, as well as other dermatological conditions have limited treatment options, and ADSC-Exos offer a novel regenerative approach. Multiple preclinical studies have shown that ADSC-Exos can significantly accelerate the closure of acute and chronic skin wounds^[82,83]. The exosomes promote key processes in wound healing, including:

• Angiogenesis: ADSC-Exos carry pro-angiogenic factors (e.g., VEGF, FGF) and microRNAs that stimulate new blood vessel formation. For instance, exosomes enriched with miR-126 or miR-130a enhance endothelial cell proliferation and migration, thus increasing capillary density in wound beds^[29,83]. Improved perfusion fosters granulation tissue formation and expedites healing.

• Fibroblast proliferation and migration: ADSC-Exos activate dermal fibroblasts and keratinocytes, promoting re-epithelialization and extracellular matrix production^[1,84]. They transfer long non-coding RNAs like MALAT1 and other RNAs that upregulate collagen synthesis and downregulate matrix-degrading enzymes, resulting in more robust wound closure^[84–87].

• Immunomodulation: Chronic wounds often stall in a pro-inflammatory state. ADSC-Exos can shift the wound microenvironment toward a healing phenotype by modulating immune cells. They promote macrophage polarization to an anti-inflammatory M2 phenotype and suppress excessive inflammation, which helps resolve the chronic inflammatory phase of wounds^[88,89].

In diabetic wounds, which heal poorly due to impaired angiogenesis and cell dysfunction, ADSC-Exos have demonstrated particularly notable benefits^[84,90]. In rodent models of diabetic ulcers, local or intravenous injection of ADSC-Exos resulted in faster wound closure, higher collagen deposition, and greater re-epithelialization than controls^[1,91]. The mechanism involves delivery of exosomal proteins and microRNAs that counteract diabetes-related impairments; for example, one study found ADSC-Exos reduced oxidative stress and apoptosis in high-glucose exposed skin cells by transferring heat shock protein 90 (HSP90) which activates pro-survival pathways^[82]. Another report showed ADSC-Exos restored the function of diabetic fibroblasts by inhibiting the Bax/caspase-3 apoptosis pathway, thereby promoting cell survival in the wound bed^[92].

Beyond wound healing, ADSC-Exos have shown promise in broader dermatological and cosmetic applications. Atopic dermatitis, a chronic inflammatory skin disease, was alleviated in mouse models by treatment with ADSC-Exos: inflammatory cytokines (IL-4, IL-13, IFN-γ, TNF-α) were reduced and skin barrier function improved^[1,93,94]. Hair regeneration is another area of interest – a 2021 study reported that ADSC-Exos promoted hair follicle development and increased hair growth in a murine model of alopecia^[95]. Research indicates that miR-122-5p, enriched in ADSC-Exos, promotes the proliferation and migration of dermal papilla cells. This miRNA targets specific signaling pathways, leading to increased hair follicle development and mitigating inhibitory effects on hair growth^[96].

In cosmetic dermatology, ADSC-Exos have been tested clinically. ADSC-Exos have also been used off-label to rejuvenate aging or photodamaged skin; their antioxidant and collagen-promoting effects can increase skin elasticity and reduce wrinkles. Notably, a split-face randomized trial in humans found that applying ADSC-Exos in combination with fractional carbon dioxide laser treatment led to improved healing of acne scars and better skin texture compared to laser treatment alone^[97]. Patients receiving exosome treatment showed enhanced collagen remodeling in the laser-treated areas, with no significant adverse effects. The side of the face treated with ADSC-Exos showed a 32.5% reduction in acne scar scores, while the control side exhibited a 19.9% reduction. Additionally, the ADSC-Exo-treated side experienced milder erythema and shorter post-treatment downtime^[97].

Furthermore, ADSC-Exos can improve outcomes in plastic surgery contexts such as fat grafting and flap survival. Autologous fat graft viability is often limited by poor vascularization; studies indicate that supplementing fat grafts with ADSC-Exos enhances graft retention by stimulating angiogenesis^[98–100]. In a rodent model, co-injection of ADSC-Exos with fat grafts increased new blood vessel formation and final graft volume compared to controls^[98–100]. Similarly, in reconstructive surgery, skin flaps are at risk of ischemia-reperfusion injury. Preclinical experiments have shown that preconditioning flaps with ADSC-Exos improves flap survival under ischemic conditions, partly by upregulating IL-6 and other angiogenic factors in the tissue^[101]. For instance, flaps treated with exosomes from H₂O₂-stimulated ADSCs had higher capillary density and tissue viability after reperfusion injury^[101].

Overall, the evidence substantially supports the use of ADSC-Exos to improve wound healing and treat skin problems. These exosomes consistently exhibit pro-angiogenic, pro-regenerative, and anti-inflammatory effects in skin, leading to faster and higher quality healing. Early clinical studies have begun to translate these findings, with encouraging safety and efficacy signals. Further trials in chronic wounds (e.g., diabetic ulcers) are ongoing^[1], indicating that ADSC-Exo-based skin therapies are moving closer to clinical reality.

Immunomodulatory applications and inflammatory diseases

Beyond organ-specific regeneration, ADSC-Exos have intrinsic immunomodulatory properties that make them attractive for treating inflammatory and autoimmune diseases. ADSCs are known to secrete factors that regulate immune cell activation – a feature that is largely preserved in their exosomes^[4]. Key immune-modulating molecules such as IL-1 receptor antagonist, transforming growth factor-beta (TGF-β), and various anti-inflammatory microRNAs have been identified in ADSC-Exo cargo^[4]. A notable application is in rheumatoid arthritis, an inflammatory joint disorder marked by persistent synovial inflammation. In collagen-induced rheumatoid arthritis (RA) mouse models, treatment with ADSC-Exos significantly attenuated joint swelling and tissue damage^[102,103]. Researchers found that systemically administered ADSC-Exos homed to the inflamed joints and induced a cascade of anti-inflammatory effects in the joints, and macrophages were skewed toward an M2 phenotype, resulting in less synovial inflammation^[102,103]. In one study, the therapeutic impact of exosomes was comparable to that of the parent ADSC cells in ameliorating arthritis, suggesting the exosomes are the principal conveyors of the cells’ immunosuppressive function^[4]. These findings are supported by Yan et al that ADSC-Exos loaded with icariin modulates macrophage polarization and alleviates rheumatoid arthritis^[104].

Advanced strategies are even engineering exosomes to enhance their targeting of immune cells. You et al created “metabolically engineered” ADSC-Exos designed to influence macrophage metabolism in RA^[105]. These exosomes, loaded with specific enzymes and signaling lipids, successfully reprogrammed macrophage subsets in arthritic joints, reducing the inflammatory M1 macrophages and increasing anti-inflammatory M2 macrophages^[105]. Treated animals showed not only decreased joint inflammation but also slower joint erosion, underscoring the potential of exosome-based immunotherapy in RA^[105].

ADSC-Exos have also been studied in other inflammatory conditions. For example, in inflammatory bowel disease models, MSC-derived exosomes have been reported to reduce colon inflammation and promote mucosal healing by delivering immunoregulatory microRNAs to intestinal macrophages and epithelial cells^[106]. These exosomes can repair the intestinal epithelial barrier, inhibit oxidative stress, and suppress colon fibrosis, contributing to the healing of the intestinal lining^[106]. In models of multiple sclerosis, ADSC-Exos have demonstrated the capacity to traverse the blood-brain barrier and mitigate neuroinflammation by influencing T cell and microglial activity^[107,108].

Another timely application is in hyperinflammatory states like severe COVID-19 and acute respiratory distress syndrome (ARDS). During the COVID-19 pandemic, clinicians explored MSC exosomes as a therapy to quell the unchecked inflammation in ARDS patients. A pilot clinical study in 2022 nebulized allogenic ADSC-Exos into the airways of patients with severe COVID-19 pneumonia^[109]. The treatment led to increased oxygenation and a drop in inflammatory markers in several patients, indicating that the exosomes helped control the excessive immune response in the lungs^[109]. While patient numbers were small, and it was not a controlled trial, the fact that no adverse safety signals emerged supports further investigation. Indeed, this application leverages the known anti-inflammatory and tissue-reparative effects of ADSC-Exos – by delivering them directly to injured lung tissue, they can potentially aid in reducing edema, promoting alveolar repair, and preventing fibrosis after ARDS.

Overall, the immunomodulatory capacity of ADSC-Exos broadens their utility beyond classical “regenerative” indications. They can function as biologic anti-inflammatory agents, restoring immune balance in diseases where inflammation or autoimmunity drives pathology. A salient advantage is that exosomes can exert these effects without globally suppressing immunity as drugs like corticosteroids do; instead, they tend to act by reprogramming immune cells to a homeostatic state. This precision could translate to fewer side effects. Ongoing and future trials in RA, systemic lupus erythematosus, and other immune-mediated diseases will shed light on the efficacy of ADSC-Exo therapy in these contexts. If successful, it may herald a new class of anti-inflammatory biologics derived from stem cell exosomes.

Barriers to clinical translation of ADSC-exosomes

Although ADSC-Exos hold promise as therapeutics, their clinical translation is hindered by numerous limitations. Biologically, their heterogeneity creates inconsistent potency and unpredictable biodistribution, risking off-target effects and immune clearance^[110]. Production challenges include scaling limitations with traditional isolation methods, batch variability, and difficulties achieving consistent purity and yield^[111]. Clinical application is complicated by the lack of standardized dosing protocols and efficient tissue-targeting strategies^[110]. The recommended amount of exosomes used for human application is mainly based on the body weight and size of the subjects; however, pharmacokinetic and pharmacodynamic data may vary differently in the translational medicine based on the animal study and require more evidence to validate. Additionally, regulatory pathways remain fragmented due to varying production methods and product definitions^[112]. Addressing these purification, manufacturing, and regulatory challenges is essential before EVs can realize their therapeutic potential.

Isolation and purification challenges

The exosome isolation techniques and the purity/consistency of ADSC-Exo preparations for clinical use is a big concern. Several challenges remain before ADSC-Exo therapies become mainstream. Standardization and manufacturing are critical issues. Ultracentrifugation (UC) is the conventional “gold standard” for EV isolation in research, pelleting vesicles at ~100 000 × g^[113]. However, UC has significant limitations: it is time-consuming, can cause vesicle aggregation, and often co-pellets protein contaminants, making it unsuitable for large-scale clinical production. The text now discusses newer methods like tangential flow filtration (TFF), which uses membrane filters in a crossflow system. TFF can achieve much higher yields than UC (on the order of 100-fold greater vesicle recovery in some studies) and improves removal of soluble impurities. Size-exclusion chromatography (SEC) is presented as another technique that can isolate exosomes with high purity by separating them from protein aggregates by size. Additionally, affinity-based methods (e.g., immunoaffinity or ligand capture) and polyethylene glycol (PEG)-based kits are briefly noted for completeness, though these may introduce other impurities. Figure 2 illustrates various kinds of isolation methods for exosomes.

Figure 2.

Comparison of various isolation methods for exosomes from biological samples. This comprehensive diagram illustrates eight distinct techniques currently employed for exosome isolation, each presented in a separate panel with its respective abbreviated name and visual representation of the procedural workflow. Tangential flow filtration (TFF) is depicted in the upper left, showing how exosomes are separated using a membrane filtration system where the sample flows tangentially across a semi-permeable membrane, allowing smaller particles and solutes to pass through while retaining exosomes for collection. Ultrafiltration (UF) appears in the upper right, illustrating a simpler filtration approach where samples are passed through membranes with specific molecular weight cut-offs to concentrate exosomes. Size exclusion chromatography (SEC) is shown in the middle-left panel, where samples pass through a column packed with porous beads that separate particles based on size differences, with exosomes eluting in specific fractions. Differential ultracentrifugation (dUC) is represented in the middle panel as a four-step process of increasingly higher-speed centrifugation (300 g, 2000 g, 10 000 g, and 100 000 g) that sequentially pellet cells, debris, larger vesicles, and finally exosomes. Polyethylene glycol precipitation (PEG) is illustrated in the middle right, demonstrating how this polymer causes exosomes to precipitate out of solution for subsequent collection. Affinity isolation (AI) appears in the lower left, showing how exosomes can be captured using specific antibodies or ligands that bind to exosomal surface markers, followed by elution of the purified vesicles. Microfluidic technology (MF) is depicted in the lower middle as a microchip-based separation system where exosomes flow through specially designed channels for isolation. Finally, density gradient centrifugation (DGC) is shown in the lower right in two variations (A and B), demonstrating how exosomes are separated based on their buoyant density in a pre-formed gradient medium. Each method offers distinct advantages in terms of purity, yield, processing time, and scalability, highlighting the technical challenges in standardizing exosome isolation for clinical applications. The diverse range of isolation techniques reflects the ongoing efforts to optimize exosome preparation protocols that maintain biological activity while achieving consistent purity and potency, which remains one of the fundamental difficulties for converting exosome-based treatments from bench to bedside in regenerative medicine.

Notably, minor variations in ADSC donor characteristics, culture conditions (e.g., normoxia vs hypoxia), or isolation methods can alter exosome content and therapeutic efficacy^[114]. Researchers are actively investigating optimal culture pre-conditioning (for example, growing ADSCs under hypoxia to enrich exosomes with pro-angiogenic factors) to maximize therapeutic cargo in the vesicles^[115]. We emphasize the importance of characterization following isolation – using nanoparticle tracking analysis for size distribution, protein markers (CD9, CD63, CD81) to confirm exosome identity, and purity metrics (minimal RNA/protein contamination) based on (Minimal Information for Studies of Extracellular Vesicles) MISEV 2023 guideline^[116]. While multiple isolation methods exist, no single technique is universally ideal^[113] and there is a need for standardized, scalable processes that ensure consistent purity and potency of the exosome product^[1,117].

Manufacturing scale-up challenges

Acquiring a clinical-grade amount of exosomes in sufficient quantities for clinical application is a big concern. Figure 3 reveals that a large amount of medium would be acquired to achieve the similar effect of ADSC-Exos found in the rodent animal model. As an illustrative example, treating a 20 g mouse with 100 µg of ADSC-Exos might correspond to requiring 300 mg (0.3 g) or more exosomal protein for an adult patient, approximately 3000-fold scale-up in production. This disparity underscores why manufacturing is a bottleneck.

Figure 3.

Scale-up challenges in translating ADSC-Exo therapies from preclinical models to human applications. This diagram illustrates the substantial scaling requirements for producing clinically relevant quantities of ADSC-Exos. The upper portion shows that treating a 20 g mouse with 100 μg of exosomes requires harvesting from 751 T-flasks (each with 25 mL culture medium). The lower portion demonstrates the 3000-fold scale-up necessary for human applications, where treating a 60 kg patient with 300 μg of exosomes would require production from approximately ten bathtubs of culture medium (each with 30 L). This visual comparison effectively highlights one of the major manufacturing challenges in clinical translation of ADSC-Exo therapies: the enormous volume of stem cell culture required to generate therapeutically effective quantities of exosomes. The figure underscores the need for more efficient isolation methods and standardized large-scale production protocols to make exosome-based treatments practically and economically viable for human applications.

Safety, biodistribution, and off-target risks

Preclinical and early clinical studies suggest that systemic ADSC-Exos have a favorable short-term safety profile, reporting good tolerability without significant toxicity or acute adverse events^[32]. However, theoretical risks include delayed immunogenicity, unintended immune modulation (e.g., excessive immune suppression or unintended pro-inflammatory responses), and tumor promotion, all of which require further validation^[118,119]. ADSC-Exos distribute primarily to the liver, lungs, spleen, and kidneys after systemic administration, raising concerns about potential off-target effects and interactions with normal cellular pathways^[120]. Furthermore, although incapable of directly inducing tumors, ADSC-Exos may facilitate tumor growth through pro-tumorigenic signals, affecting angiogenesis or immune responses, and could disrupt normal tissue signaling^[121,122].

Clinical translation and future perspectives

ADSC-Exos are steadily moving from bench to bedside. Several early-phase clinical trials have finished or are now underway to examine the safety and efficacy of ADSC-Exo-based treatments in humans (Table 2). As mentioned, trials in acne scar treatment, Alzheimer’s disease, and COVID-19 have reported encouraging results. Another notable trial is the EVENEW study (NCT04276941), which tested an exosome-based drug (EXOB-001) derived from MSCs, in preventing bronchopulmonary dysplasia in preterm infants^[123]. This Phase I/II trial, the inaugural of its kind sanctioned by the European Medicines Agency, principally evaluated safety and yielded significant insights into the dose and administration of exosome therapies in a clinical context^[123]. Although not focused on ADSC-Exos specifically, EVENEW demonstrates that regulatory bodies are open to testing exosome therapies in vulnerable patient populations, setting important precedents for ADSC-Exo trials in the future.

Table 2.

Summary of human studies using ADSC-Exos or closely related MSC exosome products in various clinical indications

Clinical indication	Study design and phase	Outcome/findings	References
Acne scarring (dermatology)	Randomized split-face trial (n = 20); topical ADSC-Exos + CO₂ laser vs laser alone	Exosome-treated side showed greater scar improvement and collagen remodeling; treatment well tolerated.	Kwon et al[84]
Facial skin aging.	A 12-week, prospective, randomized, split-face, comparative study (n = 28); ADSC-Exos with microneedling to treat facial aging skin	Improved cosmetic outcomes were observed, with histological analysis showing increased collagen and elastic fiber deposition compared to the control side.	Park et al[90]
Alzheimer’s disease (neurology)	Open-label Phase I/II (n = 15); IV allogenic ADSC-Exos biweekly for 12 weeks	Feasible and safe; no serious adverse events. Some patients showed cognitive stabilization or slight improvement on memory tests.	Xie et al[91]
Severe COVID-19 pneumonia (pulmonary)	Pilot cohort (n = 10); nebulized allogenic ADSC-Exos into lungs	No infusion reactions; improvements in oxygenation and reduction in inflammatory cytokines observed in majority of patients.	Zhu et al[75]
Bronchopulmonary dysplasia prevention (preterm infants)	Phase I/II (EVENEW study, 2020); intratracheal MSC-EVs (EXOB-001) in very low birth weight infants at risk of bronchopulmonary dysplasia	Primary outcome: safety confirmed (no severe adverse effects). Preliminary efficacy: trend toward reduced bronchopulmonary dysplasia incidence in treated group.	NCT04276941[76]

Clinical trial identifiers provided where applicable. Many trials are early stage; results should be interpreted with caution pending larger randomized studies.

A major advantage for clinical translation is the favorable safety profile observed so far. Exosomes are naturally occurring nanoparticles and are generally well tolerated; they lack the ability to self-replicate or form tumors and being derived from allogenic ADSCs they can be engineered to be hypoimmunogenic. None of the reported clinical studies on ADSC-Exos have noted significant adverse reactions attributable to the exosome product. This supports the notion that with proper isolation and purity controls, ADSC-Exos can be administered safely, even intravenously or via inhalation, in humans.

Dosing and delivery routes for exosomes are another area of ongoing study. It remains to be determined how frequent treatments need to be given and in what quantities for various conditions. Because exosomes are small, they may be cleared relatively quickly by the mononuclear phagocyte system if delivered intravenously. Strategies like incorporating exosomes into biomaterial scaffolds or hydrogels at the target site are being explored to provide sustained release and retention^[124,125]. For instance, in wound healing, loading ADSC-Exos into a collagen scaffold or fibrin gel has been shown to prolong their local activity and significantly improve outcomes compared to free exosome injection^[126]. Similar approaches are considered for cardiac patches in MI or injectable hydrogels for cartilage repair.

From a regulatory standpoint, exosome therapies currently navigate a pathway analogous to other biologics. In the United States, the FDA has not yet issued specific guidance on exosomes, but products are evaluated under existing frameworks for biologics and cell-based therapies, meaning rigorous preclinical safety, potency, and purity data are required. In Europe, the European Medicines Agency has begun drafting guidelines that acknowledge exosomes explicitly, emphasizing characterization and Good Manufacturing Practice (GMP) production requirements. As more clinical trial data emerge, regulators will refine these guidelines. An important regulatory consideration is the potential for exosome cargo to carry nucleic acids (like miRNAs or mRNAs) that could have off-target effects. Thus, thorough molecular profiling and perhaps engineering exosomes to remove unwanted cargo will be part of future development.

Looking ahead, future perspectives for ADSC-Exos in medicine are bright. They could be used as standalone therapies or as adjuncts to existing treatments. For example, combining exosome therapy with surgical intervention (as seen in fat grafting or flap surgeries) could enhance surgical outcomes. Exosomes might also synergize with pharmacological treatments – for instance, pairing them with growth factors or chemotherapy (in non-cancer contexts) to improve tissue resilience. Furthermore, the ability to bioengineer exosomes opens doors to tailor-made therapeutics: scientists can load specific drugs or genes into ADSC-Exos, turning them into targeted delivery vehicles. Since exosomes naturally home to sites of injury or inflammation (likely via surface adhesion molecules and chemokine receptors), engineered exosomes could selectively deliver their payload to diseased tissue, minimizing systemic exposure.

The proposed near-term and long-term strategies may maximize therapeutic impact from bench research to bedside (Fig. 4). Near-term ADSC-Exo advancements focus on (1) direct drug cargo loading or preconditioning cultures to enrich therapeutic cargo; (2) GMP-compliant multilayer flasks and small bioreactor scaling; (3) Targeting method to leverage exosome home to injury sites by local administration; and (4) employing biomaterial scaffolds such as hydrogel for sustained released via local injection. Long-term strategies involve (1) genetically modified ADSCs to produce tailored exosomes; (2) large-scale bioreactors or cell-free exosome mimetics for scalable production; (3) surface modifications with peptides or antibodies for tissue-specific targeting; and (4) innovative delivery systems or routes (implantable depots, responsive nanoparticles, medical device integration) to significantly enhance clinical applicability.

Figure 4.

Diagram demonstrates both near-term and long-term strategies across four domains – engineering the exosomes, scaling production, targeting, and delivery methods – to maximize therapeutic impact.

Conclusion

ADSC-Exos represent a cutting-edge biomedical innovation straddling the fields of cell therapy and nanomedicine. Extensive preclinical evidence across various organ systems demonstrates their capacity to enhance healing, modulate inflammation, and improve functional outcomes. Early clinical studies are validating these findings in humans, setting the stage for larger trials. While challenges in production and regulation need to be addressed, ongoing research and technological advances are rapidly paving the way. It is conceivable that in the next decade, off-the-shelf exosome therapeutics could become available for conditions ranging from chronic wounds and osteoarthritis to heart failure and neurodegenerative diseases. The therapeutic application of ADSC-Exos thus holds significant promise for transforming the clinical approach to tissue repair and immune modulation. Unlike prior reviews that focused on single organs or small-scale isolation techniques, this review offers truly cross-disciplinary synthesis of preclinical efficacy, emerging clinical trials, isolation technologies, and regulatory pathways in one place, mapping how ADSC-Exos promote angiogenesis, immunomodulation, and antifibrotic repair across skin, heart, brain, and musculoskeletal tissues. The article adds new insight by benchmarking the isolation methods, translating rodent-to-human dose calculations, and proposing phased roadmaps for near- and long-term product development.

Ethical approval

Not applicable.

Consent

Not applicable.

Sources of funding

This research was funded by the Chang Gung Memorial Hospital (grant number CMRPG8P0301).

Author contributions

C.S.R.: writing – original draft; P.J.K.: writing – review & editing, funding acquisition; C.H.H.: conceptualization, supervision.

Conflicts of interest disclosures

The authors declare no conflicts of interest.

Guarantor

Ching-Hua Hsieh.

Research registration unique identifying number (UIN)

Not applicable.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

Data sharing not applicable – no new data generated.

Announcement of AI assistance

The use of AI aid in manuscript drafting is consistent with the TITAN 2025 criteria^[127], which provide complete transparency of AI engagement. OpenAI GPT-4o was used for reference search with the inputs restricted to publicly available literature metadata among PubMed, Scopus, and Medline. No statistical analysis or image generation was performed. No plug-ins or local deployments were used. OpenAI GPT-4o was also used to check spelling, grammar, syntax, and correction of references. The full prompt transcripts for ChatGPT were: determine whether there is an abbreviation without a full name before it, or whether the full name is used again in the text despite the fact that an abbreviation has already been provided. Then, as a reviewer, look for flaws in the linked reference and its textual description. Check the consistency of in-text citations and metadata (e.g., author, title, journal), as well as whether research descriptions correspond to the cited articles. Report any minor formatting, grammatical, syntax or citation problems. All AI-generated text was fact-checked, reviewed, or edited, by the senior author; non-verifiable outputs were discarded. The authors declare no financial ties to AI vendors and follow ICMJE and WMA ethics frameworks.

Acknowledgement

We thank the support from Core Laboratory for Animal Phenomics & Diagnostic and Genomics and Proteomics Core Laboratory form Kaohsiung Chang Gung Memorial Hospital.