Использование естественных экзоцитозных везикул для борьбы с возрастными заболеваниями: от возрастных драйверов до терапевтических возможностей.

Introduction

The global aging population is bringing about a series of age-related health challenges. 1 Aging is a complex biological process that predisposes individuals to various chronic diseases such as neoplasms, cardiovascular diseases, neurodegenerative disorders, and bone diseases. 2–5 These diseases are referred to as age-related diseases (ARD), specifically defined as chronic noncommunicable diseases that increase in prevalence with advancing age among the adult population. 6

At the cellular level, one of the core manifestations of aging is the progressive accumulation of senescent cells. 7 , 8 Cellular senescence is a stress-induced, largely irreversible state of cell cycle arrest. It is marked not only by growth arrest, resistance to apoptosis, and altered gene expression, but also by the upregulation of a series of aging-associated biomarkers. 7 , 8 Substances secreted by senescent cells constitute the senescence-associated secretory phenotype (SASP). The SASP primarily consists of various pro-inflammatory factors, chemokines, growth factors, and matrix metalloproteinases, which readily induce localized or systemic chronic low-grade inflammation. This process accelerates tissue dysfunction and organ decline, ultimately promoting the onset and progression of multiple ARDs. 9 , 10 Given this role, controlling cellular senescence has emerged as a promising strategy to slow down aging and prevent ARD.

In recent years, Natural extracellular vesicles (NEVs) have garnered increasing attention in the field of aging and related disease. NEVs are nanoscale vesicles secreted by nearly all cell types, ranging from 30 to 2000 nm in diameter. 11 As key carriers of intercellular communication, NEVs participate in regulating processes such as inflammatory responses, immune responses, and tissue regeneration by transporting various bioactive components including proteins and miRNAs. 12 Extensive studies indicate that NEVs from various sources can either accelerate the aging process or exert anti-aging effects. For example, NEVs derived from senescent endothelial cells, senescent macrophages, and senescent plasma can transmit senescence phenotypes via miRNA transmission. 13–15 Conversely, NEVs from primary cells isolated from young donors, low-passage stem cells, and some plants or bacteria can improve senescent cell metabolism and restore cellular function. 16–18 Therefore, NEVs are promising both as biomarkers to evaluate aging and disease progression, and as potential therapeutic carriers or direct therapeutics. Although there have been reports of NEVs being used in clinical settings, the clinical translation of their therapeutic potential still faces challenges such as delivery difficulties, suboptimal efficacy, and high costs. 19–21

Based on the above, this review systematically summarizes the dual roles of NEVs in regulating cellular aging processes. It highlights the potential applications of NEVs in treating ARD, existing challenges, and future research directions. The aim is to provide a theoretical foundation and research insights for developing NEV-based anti-aging strategies, thereby advancing their clinical translation.

NEVs

EVs can be divided into NEVs and engineered EVs. Increasing evidence indicates that NEVs not only promote disease progression but also have broad potential in indicating physiological status, diagnosing diseases, treating illnesses, and predicting prognosis. 21–24 This review focuses on NEVs to clarify their clinical application potential and provide theoretical foundations for EV engineering.

Definition of NEVs

NEVs are membrane-bound vesicles that cells naturally produce and release into their surroundings. This release occurs through normal cellular processes, without artificial interventions such as genetic modification, drug stimulation, or the physical loading of foreign substances. 25–27 They represent the primary carriers for information transfer and material exchange during normal physiological states or when cells adapt to environmental changes. 25 , 26 The function of NEVs highly depends on their cellular/tissue origin and the context. 27 , 28 In general, NEVs have diverse origins, including animal cells and body fluids, plant cells, and bacteria. 18 , 29 , 30 Figure 1 illustrates the diversity of NEV sources relevant to ARD research. We have selected representative sources from each category based on their research prominence and therapeutic potential: animal cells and body fluids (including MSCs, endothelial cells, immune cells, plasma, and urine) represent the most extensively studied sources; plant-derived NEVs (from fruits and vegetables) are included due to their advantages in scalable, low-cost production and their emerging role in cross-kingdom regulation; bacteria-derived NEVs are highlighted for their unique ability to modulate host immunity and the gut–organ axis, which is increasingly recognized in aging research.

Biogenesis of NEVs from Different Sources

For the same source, vesicles of different sizes arise through distinct mechanisms. Moreover, due to differences in cellular structure, the biogenesis of NEVs also varies across different sources. The following primarily introduces NEVs derived from animal, plant, and bacterial sources ( Figure 2 ).

Animal-Derived NEVs

Based on their mode of biogenesis, NEVs can be classified into exosomes and ectosomes. Exosomes originate from the endosomal membrane. 31 During their formation, transport molecules help bind specific cargo to the membrane of early endosomes. The endosomal membrane then invaginates inward, creating a bud inside the endosomal lumen. This bud pinches off to form a small internal vesicle called an intraluminal vesicle (ILV). Over time, these ILVs accumulate within larger structures known as multivesicular bodies (MVBs). MVBs can follow one of two paths: they may fuse with lysosomes and be degraded, or they can merge with the cell’s plasma membrane to release their ILVs into the extracellular space as exosomes. 31 This entire process is regulated by a group of proteins known as the endosomal sorting complexes required for transport (ESCRT). 32

Unlike exosomes, ectosomes originate from the outer bud of the cell membrane and are released through fission. 33 This release is driven by reorganization of the cell’s internal skeleton and changes in membrane shape. Proteins such as CD9, CD63, CD81, and integrins are involved in this process. 32

Plant-Derived NEVs

There are two primary biogenesis pathways: one is similar to the exosome pathway in animal cells, the MVB pathway involving the ESCRT complex. 34 The other is unique to plant cells and is called the EXPO pathway. EXPO is a specialized organelle representing an unconventional protein secretion pathway, serving as a unique structure enabling vesicles to traverse plant cell walls. Specifically, EXPO fuses with the cell membrane and releases individual vesicles into the cell wall. 35 , 36 Marker proteins such as Exo70H1 and Exo70B2 have been identified as essential components of EXPO-mediated vesicle transport. 37 In addition, some studies suggest that plant cells may also have a vacuolar pathway and an autophagic pathway, but both lack sufficient evidence. 38 , 39

Bacteria-Derived NEVs

Gram-negative bacteria produce NEVs mainly through two pathways: outer membrane blebbing and explosive cell lysis. Blebbing from the outer membrane forms outer membrane vesicles (OMVs). This process is often caused by disruptions in peptidoglycan biosynthesis or the insertion of hydrophobic molecules into the outer membrane, which destabilizes its structure. 29 Explosive cell lysis, on the other hand, is typically initiated by phage-derived endolysins that break down the bacterial cell wall. After peptidoglycan degradation, the cell shrinks and ruptures. The resulting membrane fragments then aggregate and self-assemble into two types of vesicles: outer-inner membrane vesicles (OIMVs) and explosive outer membrane vesicles (EOMVs). 40 In Gram-positive bacteria, a process called “bubbling cell death” is the primary route for vesicle formation. This process is mainly driven by enzymes acting on the bacterial inner membrane and generates cytoplasmic membrane vesicles (CMVs). CMVs may carry both membrane-associated and cytoplasmic components. 40

Secretion and Uptake of NEVs

Following the formation of late MVB, it fuses with the cell membrane to release NEVs. The components regulating NEV secretion are RAB proteins such as RAB27A, RAB27B, RAB11, RAB35, and RAB7, whose functions depend on the contextual environment. 41 For example, RAB22A gene expression increases under hypoxic conditions within tumors, leading to enhanced vesicle secretion and promoting tumor metastasis. 42 In contrast to exosome release, ectosomes are generated by direct outward budding and fission of the plasma membrane. 33 This process is driven by reorganization of the actin cytoskeleton and local changes in membrane curvature, and involves proteins such as ARF6, RHO family GTPases, and the ESCRT-I component TSG101. 32 Unlike the delayed release of exosomes following MVB trafficking, ectosome shedding occurs rapidly in response to cellular stimulation, including calcium influx, shear stress, and receptor activation. 33

The uptake of NEVs by recipient cells involves both non-endocytic and endocytic mechanisms. Non-endocytic pathways include two major types. One is direct receptor-mediated signaling, where proteins on the outer leaflet of NEV lipid bilayers interact directly with surface receptors on target cells to trigger downstream signaling cascades without internalization. 43 The other is membrane fusion, where NEVs fuse directly with the plasma membrane, allowing cargo to be released directly into the cytoplasm, thereby bypassing endosomal sorting and lysosomal degradation. 43

However, some NEVs exert their biological effects after being internalized by target cells. Endocytic uptake mechanisms encompass clathrin-dependent endocytosis, caveolin-dependent endocytosis, lipid raft-dependent endocytosis, phagocytosis, and macropinocytosis. 44–48 Phagocytosis is primarily mediated by professional phagocytes such as macrophages and dendritic cells, which recognize NEVs through opsonins or scavenger receptors. 46 Macropinocytosis, on the other hand, involves actin-driven membrane ruffling that engulfs NEVs in large, non-selective fluid-filled vacuoles, and is particularly important for the uptake of larger vesicles. 46

Cellular Senescence

Classification and Characteristics of Cellular Senescence

Cell senescence is a complex, multifaceted biological process representing a cellular fate. It is characterized by permanent arrest of the cell cycle along with phenotypic alterations. 49 , 50 Cell senescence is categorized into two types: replicative senescence, which occurs due to the gradual shortening of telomeres during cell proliferation; 51 and premature senescence, 52 encompassing stress-induced premature senescence (SIPS) and developmental programmed senescence (DPS). The former occurs under sub-cytotoxic stress conditions, 53 , 54 while the latter occurs during early embryonic development. 55

Senescent cells exhibit distinct characteristics. In terms of morphology, the cell nucleus becomes enlarged with folded nuclear membranes and altered chromatin structure; the cell body size decreases, accompanied by an increased number of lysosomes and pigment accumulation. 54 , 56 , 57 In terms of metabolism, NAD⁺ concentrations decrease; glutamine metabolism is reduced. 58 Other relatively typical features include DNA damage, accumulation of dysfunctional mitochondria and oxidative damage, SASP, SA-β-galactosidase (SA-β-gal) accumulation, and senescence-associated heterochromatin foci (SAHF). 59 , 60 These typical characteristics serve as biomarkers for identifying senescent cells ( Figure 3A ).

General Molecular Mechanisms of Cellular Senescence

The stimuli that induce cellular senescence are diverse, and most of these stimuli have similar molecular mechanisms. The DNA damage response (DDR) is a critical initiator of cell cycle arrest. 61 , 62 Based on whether the stimulus triggers DDR, the mechanisms leading to senescence can be grouped into two main categories. The first category includes stimuli that cause DNA damage and activate DDR. Examples are mitochondrial dysfunction, telomere shortening, and certain oncogenic signals. These ultimately lead to the accumulation of the cell cycle inhibitor p21. 63–67 The second category includes stimuli that do not directly cause DNA damage, such as oxidative stress and certain oncogenic signals like RAS activation. These mainly result in the accumulation of another cell cycle inhibitor, p16. 68 , 69 Both p21 and p16 work by binding to specific cyclin-dependent kinases (CDKs). This prevents the formation of CDK-cyclin complexes, which are needed for cell cycle progression. 66 , 70 , 71 As a result, the retinoblastoma (RB) protein remains in a hypophosphorylated state. This leads to permanent cell cycle arrest in the G1 phase. 66 , 70 , 71

The activation of DDR depends on its response to DNA damage. Telomere shortening, ROS accumulation, and oncogenes all lead to DNA double-strand breaks (DSBs), thereby activating the DDR. 64 , 65 , 67 Once activated, DDR involves key DNA damage kinases such as CHK2, CHK1, ATR, and ATM. 49 , 72 These kinases phosphorylate and stabilize p53, a transcription factor that enhances the expression of p21. 70 , 71 DDR also promotes the degradation of MDM2, a protein that normally inhibits p53. 73 In aged tissues, the CDKN2A gene can undergo alternative splicing to produce both p16 and ARF. 74 p16 inhibits CDK4 and CDK6 to block cell cycle progression, 75 while ARF promotes p53 stability by degrading MDM2. 76 The mTOR signaling pathway also influences senescence. Through the ATM/Akt/mTORC1 cascade, it can promote mitochondrial ROS production, which in turn activates DDR and sustains the SASP. 77 ROS can also activate the p38 MAPK pathway, which enhances p53 activity and strengthens the p21-mediated arrest. 78

Compared to the above molecular mechanisms, the ERK-p38 MAPK pathway induces cell cycle arrest without relying on DDR activation, often under oxidative stress or RAS activation. 68 , 69 Here, RAS triggers MEK/ERK signaling, leading to p38 MAPK activation. This reduces repression of the p16 gene and increases its expression. 68 , 69 Additionally, mTORC1 and mTORC2 can stabilize p53 and promote p21-related senescence via PI3K/AKT signaling and MDM2 inhibition, independent of DDR. 79

In summary, cellular senescence can be induced by various stimuli, and the primary key factors involved are p53, p21, p16, and RB. Overexpression of any one of these proteins can lead to cell cycle arrest ( Figure 4 ).

It should be noted that beyond the general molecular mechanisms of cellular senescence, many other regulatory factors influence its progression through different targeting mechanisms. Specific studies on aging regulatory factors in recent years are listed in Table 1 .

The Effects of Cellular Senescence

As shown above, one of the key characteristics of senescent cells is the secretion of the SASP. The SASP has complex effects, exerting both beneficial and harmful influences on the tissue environment.

Regarding beneficial effects, first, a transient aging phenomenon occurs during embryonic morphogenesis. Senescent cells in the developing placenta secrete matrix metalloproteinases such as MMP2 and MMP9, thereby promoting tissue remodeling and normal placental development. 97 Second, senescent cells contribute to wound healing through the secretion of PDGF-AA. 98 Finally, senescent cells suppress excessive cell proliferation by inhibiting the cell cycle and secreting pro-inflammatory factors, thereby inhibiting tumorigenesis. 99

Despite these benefits, substantial evidence links cellular senescence to the onset and progression of ARD. 100–102 Three primary mechanisms explain how senescent cells may contribute to diseases. First, with age, the aging microenvironment becomes increasingly unstable, and when exposed to stressors or disease, this can lead to metabolic dysfunction and further tissue imbalance. Second, SASP primarily contains several potent inflammatory factors that continuously influence the senescent microenvironment, creating a chronic inflammatory environment. Third, senescent cells can spread the senescence signal to nearby healthy cells, for example by releasing NEVs carrying SASP components. 103–105 Under the influence of the above factors, the aging microenvironment readily transforms into a pathological microenvironment, thereby promoting the development of ARD ( Figure 3B ).

Regulating Cellular Senescence via NEVs

The typical characteristics of cellular senescence include cell cycle arrest, mitochondrial dysfunction, oxidative stress, DNA damage, telomere shortening, secretion of the SASP, and upregulation of senescence-associated markers. These are also the factors and mechanisms that influence cellular senescence. Below, we specifically discuss how cellular senescence is promoted or suppressed from different perspectives ( Table 2 ).

Regulation of the Cell Cycle

NEVs released from senescent cells or non-senescent cells (such as tumor cells or immune cells) can trigger cell cycle arrest, either by directly affecting cyclin expression or by activating signaling pathways that lead to cyclin overexpression. It was reported that in renal transplant rejection, plasma-NEVs induce senescence in renal tubular epithelial cells. This effect is mediated by the upregulation of p21 and p16 through specific miRNAs. 15 Liu et al found that in the tumor microenvironment, myeloid-derived suppressor cells (MDSCs) transfer the GPR84 protein to CD8+ T cells via exosomes. This process activates the p53 pathway and leads to T cell senescence. 113 Furthermore, studies have also expanded our understanding of the “bystander effect” associated with NEVs. They demonstrated that genomic instability causes senescent cells to secrete NEVs carrying fragmented small DNA. These vesicles deliver signals that induce cell cycle arrest in neighboring recipient cells. 106 , 107 Despite these findings, in vivo validation remains limited. Most current evidence is derived from co-culture systems or knockout models. There is a lack of direct tracking of NEV dynamic distribution and targeting within living organisms.

In NEVs derived from MSC, mechanisms targeting the cell cycle are similarly present, primarily through downregulating p53 expression. Peng et al revealed that sEVs from MSCs deliver miR-3594-5p to downregulate p53 and its downstream aging-related proteins p21 and p16, significantly alleviating stress-induced aging in nucleus pulposus stem cells. 130

Targeting Mitochondrial Balance

For senescent cells, disrupting mitochondrial function by increasing ROS levels and inhibiting mitochondrial autophagy is the primary pathway for propagating the senescence phenotype. Eswaran et al first reported that the tumor suppressor protein DOC2B can be delivered to recipient cells via NEVs, leading to increased ROS levels and lipid peroxidation, thereby inhibiting the progression of cervical cancer. 125 Building on this work, Lee et al expanded the understanding of the underlying mechanism to the nucleic acid level. They demonstrated that NEVs secreted by senescent fibroblasts are enriched with miR-10a, miR-30c , and miR-451a . These microRNAs promote ROS production and suppress mitophagy by targeting genes such as EPHA4 and RUNX2. 121 Subsequently, some studies extended the application of this mechanism from the local tumor microenvironment to systemic metabolic diseases. It was shown that NEVs derived from adipocytes in obese individuals carry NOX4 and can induce oxidative DNA damage in placental tissues across different tissues. 123 Importantly, they validated this causal relationship in animal models. 123

MSC-NEVs can slow cellular senescence by reducing oxidative stress and improving mitochondrial function. It was found that NEVs derived from adipose-derived stem cells (ADSCs) can reduce oxidative stress levels in bone marrow mesenchymal stem cells (BMSCs) from diabetic patients by enhancing the expression of protective antioxidant enzymes. 131 Additionally, NEVs from young or preconditioned stem cells can delay aging by enhancing mitochondrial quality. For example, NEVs from hypoxia-treated MSCs contain high levels of BNIP3 protein. 132 Through the BNIP3–ANXA2–TFEB pathway, these NEVs promote the removal of damaged mitochondria via autophagy, restoring mitochondrial balance. 132

Genomic Instability and Repair

DDR is a key mechanism that initiates cellular senescence. One of the main ways DDR is activated is through genomic instability, which includes DNA damage, telomere shortening, and epigenetic changes. For instance, senescent endothelial cells release large quantities of sEVs rich in miR-21 and miR-217 , leading to localized DNA hypomethylation in neighboring cells. 13 This indicates that aging signals transmitted by NEVs can directly disrupt genomic epigenetic stability, thereby consolidating and spreading the aging program. More directly, Yin et al found that macrophage-derived exosomes deliver miR-155 to renal tubular cells, directly targeting and inhibiting the telomere-protective protein TRF. This resulted in severe telomere dysfunction. 128 This process clearly delineates an NEV-driven, telomere-dependent aging pathway from inflammatory cells to parenchymal cells.

Genomes can be damaged, but they can also be repaired. It was discovered that apoptotic cell-derived vesicles (apoVs) are rich in DNA repair enzymes and can be transferred to damaged cells to promote the repair of double-strand breaks in DNA. 133 Additionally, it was demonstrated that when gastric cancer-derived NEVs are taken up by normal cells, they significantly upregulate the expression of the telomerase catalytic subunit hTERT and telomerase activity, thereby promoting telomere maintenance. 134

Balancing Inflammatory Signaling

A key feature of SASP is the massive release of inflammatory cytokines, which spread the senescence phenotype to induce a systemic, low-grade chronic inflammatory state. 135 A study on the liver found that miR-30b-5p exhibits elevated expression levels in senescent liver cells and their derived NEVs. 115 This miRNA promotes and sustains a chronic inflammatory state by targeting and inhibiting SIRT1, thereby activating the NF-κB signaling pathway and enhancing the expression of pro-inflammatory cytokines in macrophages. 115 A similar mechanism has also been observed in small airway epithelial cells of chronic obstructive pulmonary disease (COPD) patients. 120 This is termed “inflammatory aging”, a state closely associated with the maintenance of the SASP. 135

On the contrary, some NEVs from MSCs can reduce SASP expression. For example, Sun et al found that sEVs from urine-derived stem cells (USC‑sEVs) increase Sirt1 levels in aged human skin fibroblasts. 136 This reversed signs of aging and lowered the release of SASP. 136 Additionally, when exosomes from human USC‑EVs were injected into mice, levels of inflammatory cytokines like IL‑1α, IL‑1β, IL‑6, and TNF‑α decreased in the blood, indicating a comparable anti‑inflammatory effect. 137

Metabolic Reprogramming

When cellular metabolism becomes dysregulated, the resulting byproducts and signals can promote aging. For example, during ovarian cancer peritoneal metastasis, tumor-derived vesicles interact with macrophages via specific membrane proteins (such as CD36 involved in lipid transport), enhancing the macrophages’ ability to absorb lipids from the surrounding environment, ultimately driving them toward a senescent state. 23 Also, Hou et al observed that aged bone marrow macrophages undergo significant metabolic reprogramming. 129 They transmit this altered metabolic signal to distant metabolic organs, including the liver, fat, and muscle, via NEVs containing miR-378a . This process disrupts the body’s metabolic balance and contributes to systemic aging. 129

Conversely, it was demonstrated that intravenous administration of sEVs from young mouse plasma to aged mice reduced the accumulation of ROS, advanced glycation end products (AGEs), and lipofuscin deposition in senescent cells. 138 Mechanistically, young sEVs upregulate PGC-1α expression through specific miRNAs they carry (eg, miR-144-3p, miR-149-5p , and miR-455-3p ), thereby improving mitochondrial energy metabolism and enhancing ATP synthesis. 138

In summary, the preceding sections demonstrate that NEVs serve as bidirectional regulators of cellular senescence. NEVs from senescent cells propagate senescence signals through various mechanisms, including the delivery of pro-senescent miRNAs, chromatin fragments, and inflammatory mediators that induce cell cycle arrest, mitochondrial dysfunction, and genomic instability in recipient cells. Conversely, NEVs derived from mesenchymal stem cells, young organisms, or preconditioned cells exhibit anti-aging effects by transferring protective miRNAs, antioxidant enzymes, and mitochondrial quality regulators that restore cellular homeostasis and suppress the SASP. This dual functionality establishes NEVs as sophisticated modulators of senescence rather than mere passive carriers of aging signals.

To fully appreciate the significance of NEVs, however, it is necessary to consider them in the context of the broader SASP. The SASP comprises both soluble factors and extracellular vesicles. 139 While soluble cytokines, chemokines, growth factors, and proteases have been extensively studied as paracrine effectors of senescence, emerging evidence indicates that EVs constitute functionally important and biologically distinct components of the SASP. 139

Several lines of evidence support the distinct role of NEVs. Proteomic characterization has revealed that senescent NEVs exhibit a molecular signature enriched for extracellular components and processes related to wound healing and hemostasis, distinguishing them from the soluble SASP fraction. 140 Functionally, pharmacological inhibition of NEV biogenesis using GW4869 or genetic downregulation of the NEV secretion mediator RAB27A markedly attenuates paracrine senescence without affecting soluble SASP factor secretion. 140 Importantly, purified senescent NEVs, devoid of soluble SASP factors, can fully recapitulate paracrine senescence induction in recipient cells. 140 These findings identify senescent NEVs as key autonomous SASP effectors that possess functional capabilities not shared by soluble factors alone. In addition, compared to soluble factors, NEVs offer several unique functional advantages. First, their lipid bilayer-encapsulated structure protects unstable nucleic acid cargo from degradation, thereby enabling stable long-distance delivery. 141 Second, they can simultaneously carry multiple synergistic cargoes, enabling complex signal transduction that cannot be mimicked by a single cytokine. 141 Third, their cell-type-specific surface markers allow for the identification of the tissue of origin, making them superior liquid biopsy biomarkers for monitoring the aging of specific organs. 141 In terms of therapy, their inherent biocompatibility and ease of engineering make them more versatile drug delivery platforms than recombinant proteins or synthetic nanoparticles. 142

Methodologically, distinguishing between these two components requires rigorous approaches. Soluble SASP factors can co-isolate with NEVs following differential ultracentrifugation, a common isolation method. 139 Size-exclusion chromatography has been proposed as a more reliable method for separating the soluble and vesicular components of the senescent secretome. 139 This methodological consideration is critical because it affects the interpretation of functional studies and the assignment of observed effects to either NEVs or soluble factors.

Despite these advances, several important questions remain. The relative contribution of NEVs versus soluble factors to specific senescence-associated pathologies has not been systematically quantified across different cell types and senescence inducers. The SASP is a heterogeneous phenotype that varies in composition between cell types and senescence triggers, and it remains unclear whether this heterogeneity applies equally to the vesicular and soluble components. Furthermore, most functional studies have been conducted in vitro, and the in vivo relevance of NEV-mediated paracrine senescence, particularly in the context of complex tissue microenvironments and organismal aging, requires further investigation. The interplay between these two modes of intercellular communication is complex and warrants continued exploration. Nonetheless, the evidence clearly positions NEVs as essential and functionally distinct mediators of senescence that complement and extend the actions of the soluble SASP.

NEVs and ARD

It is demonstrated that aging is a primary risk factor for most chronic noncommunicable diseases. As people grow older, the incidence of most ARD becomes more prevalent, including tumors, atherosclerosis, osteoporosis (OP), Alzheimer’s disease (AD), and others. 135 , 143–145 This type of disease is referred to as ARD. The burden of ARD is substantial and multifaceted. Neoplasms, including lung, colorectal, and breast cancers, exhibit a sharp increase in incidence after age 50, driven by accumulated genetic mutations and immune surveillance decline. 146 Cardiovascular diseases (CVDs), such as atherosclerosis and heart failure, remain the leading cause of death globally, with aging-associated vascular stiffening, endothelial dysfunction, and chronic inflammation as core drivers. 147 Neurodegenerative disorders (NDs), particularly Alzheimer’s disease and Parkinson’s disease (PD), affect millions of elderly individuals, leading to progressive cognitive and motor decline, and their prevalence doubles every five years after age 65. 148 Bone diseases like osteoporosis and osteoarthritis (OA) compromise mobility and quality of life, resulting from an imbalance between bone resorption and formation, as well as chondrocyte senescence and cartilage degradation. 149 Beyond these, T2DM and age-related macular degeneration (AMD) further illustrate the systemic nature of aging, where metabolic dysregulation and tissue-specific degeneration converge to create a multisystem disease burden. 150 , 151

Aging-derived NEVs serve as key mediators of cellular senescence phenotypes, participating in aging and pathological processes by secreting diverse cargo 152 ( Figure 5 ). Furthermore, it is worth considering whether NEVs from other sources, such as MSCs, play a positive role in ARD therapy ( Figure 6 ). The following sections will delve into the mechanisms of NEVs in ARD and their significance as biomarkers ( Table 3 ).

Neoplasms

Recent studies have shown that under prolonged stress and hypoxic conditions in the tumor microenvironment, senescent tumor cells and stromal cells significantly increase their release of NEVs. 242 These NEVs differ from those released by proliferating cells in several ways. They tend to be larger in size, carry more protein cargo, and contain specific ligands or functional molecules. As a result, they play complex regulatory roles in tumor progression. 242 Treatment-induced senescent tumor cells can promote malignant progression through NEVs. For example, senescent cells in colorectal cancer secrete NEVs rich in SERPINE1, activating the NF-κB pathway to enhance tumor cell proliferation and metastasis. 243 Senescent stromal cells can also upregulate the expression of drug resistance-associated proteins (such as ABCB4) in cancer cells via NEVs, 244 or remodel the microenvironment through pro-inflammatory miRNAs (such as miR-21a and miR-155 ), 245 thereby promoting tumor survival and growth.

NEVs have also shown significant value in integrated tumor diagnosis and treatment. Traditional diagnostic approaches primarily focus on analyzing differences in NEV contents to distinguish cancer types. 246 However, recently, it was revealed that chemotherapy-induced senescence in tumor cells can dynamically alter the glycosylation patterns of NEVs. These changes are closely associated with drug resistance and disease progression, indicating a conceptual shift from static “content-based differences” to a dynamic “phenotypic evolution” perspective. By tracking changes in NEV characteristics throughout treatment, it is possible to enhance early diagnosis, monitor therapeutic response, and improve prognosis evaluation. 247 Currently, NEVs are used as clinical biomarkers in multiple areas, including cancer staging detection, 248 cancer risk factor assessment, 249 metastasis risk evaluation, 248 , 249 and prognosis determination. 250 , 251

Some NEVs released by cells show therapeutic potential due to their inherent ability to fight cancer. Notably, NEVs derived from different immune cell types possess intrinsic antitumor activity, providing new approaches for cancer immunotherapy. For example, NEVs from M1 macrophages exert multiple antitumor effects. They deliver miRNAs such as miR-150 161 and miR-181a-5p , 162 or carry immune-activating molecules like TNF-α and IL-12. 162 , 252 Through these mechanisms, they help inhibit metastasis, 161 , 253 induce tumor cell apoptosis, 162 , 163 and activate T cell responses. 164 Dendritic cell-derived NEVs present antigens and activate both T cells and NK cells via surface molecules, thereby enhancing immune-mediated tumor killing. 165 , 254–256 In addition, NEVs derived from MSCs have shown anticancer effects under certain conditions. For instance, miR-145 carried by human amniotic MSC-derived NEVs can induce apoptosis in prostate cancer cells. 160 Likewise, bone marrow MSC-derived NEVs containing let-7i suppress lung cancer cell proliferation by modulating downstream signaling pathways. 153 By combining the natural anti-tumor properties of NEVs from different cell types with bioengineering or chemical modifications, researchers aim to develop improved cancer vaccines or targeted delivery systems. 257 Such strategies could reshape the tumor immune environment, strengthen immune responses, and ultimately enhance the effectiveness of cancer therapies 257 ( Figure 7 ).

Cardiovascular Diseases

Aging is a major driver of CVDs. 3 It was shown that senescent endothelial cells and vascular smooth muscle cells significantly increase the secretion of NEVs, which promote the progression of cardiovascular diseases through various mechanisms. 260–263 For instance, they enhance vascular calcification via calbindin, promote amyloid fiber formation through Medin protein, and increase matrix stiffness by secreting LH3. 260–263 These findings help explain why aging blood vessels are more likely to become calcified. They also suggest that NEVs and their contents could serve as new biomarkers for assessing cardiovascular risk and as potential targets for future treatments.

Additionally, some NEVs have been found to possess significant potential for treating CVDs. Currently, MSC-NEVs derived from different tissues have been shown to promote the restoration of cardiovascular homeostasis through multiple mechanisms, including anti-inflammatory, anti-fibrotic, anti-apoptotic, pro-angiogenic, and pro-proliferative effects. 264–268 Through these multifaceted mechanisms, MSC-NEVs significantly enhance myocardial repair and restore cardiovascular function, positioning them as promising candidates for regenerative therapies in CVDs. In recent years, NEVs derived from M2 macrophages have been extensively studied for their anti-inflammatory and reparative properties. First, M2-NEVs can suppress inflammation and promote tissue repair by polarizing macrophages toward a reparative phenotype via miR-21-5p, miR-148a , and miR-221-3p . 175 , 176 , 269 Second, M2-NEVs can transfer miR-132-3p to endothelial cells, downregulate thrombospondin-1 mRNA expression, significantly promote angiogenesis, and improve cardiac function. 177 Third, M2-NEVs significantly reduce pyroptosis in cardiomyocytes by suppressing oxidative stress and the NLRP3 pathway. 176 , 178 Furthermore, substantial evidence indicates that NEVs secreted by cardiovascular cells or surrounding tissues, including vascular endothelial cells, 184 , 270–272 cardiomyocytes, 179 , 273 fibroblasts, 180 , 181 adipocytes, 182 , 183 , 274 and platelets, 275–277 also play a crucial role in mediating cardiovascular repair.

In terms of exogenous sources, plant-derived NEVs show the following effects: carrot-derived NEVs suppress ROS production; blueberry-derived NEVs protect blood vessels by regulating TNF-α expression; bitter melon-derived NEVs promote cardiomyocyte proliferation; and rice-derived NEVs inhibit LDL expression. 187 , 188 , 278 , 279 Currently, certain plant-derived NEVs have entered clinical trials for application in mammalian organisms. 280–282 With regard to bacterial sources, NEVs derived from probiotics containing microbial bile salt hydrolases, E.coli, Lactobacillus muciniferus, Lactobacillus plantarum , and F.prausnitzii were also found to exhibit a similar mechanism 189 , 283–285 ( Figure 8 ).

Neurological Disorders

It has found that neurons in patients with NDs secrete excessive amounts of NEVs, which play a significant role in the pathological process. 287 , 288 AD and Parkinson’s disease (PD) are the two most common and extensively studied types of age-related neurodegenerative disorders. In AD, NEVs derived from microglia transmit β-amyloid and tau proteins, with β-amyloid also inducing neuronal toxicity. 289–291 In addition, NEVs derived from astrocytes can promote neuroinflammation and neurodegeneration by transmitting ceramides. 292 In PD, NEVs secreted by neurons cause synaptic dysfunction both through direct delivery of α-synuclein 292 , 293 and by promoting α-synuclein accumulation and neurodegeneration via the miR-4443 they carry. 294 The above studies reveal a key role in which senescent cells promote the progression of neurodegenerative diseases through NEVs.

Recent studies have focused on the therapeutic role of NEVs derived from stem cells in neurodegenerative diseases, including BMSCs, urine-derived mesenchymal stem cells (USCs), dental pulp-derived mesenchymal stem cells (DPSCs), adipose-derived mesenchymal stem cells (ADSCs), and neural stem cells (NSCs). 295–298 For AD, NEVs derived from healthy stem cells can reduce β-amyloid levels, decrease neuroinflammation and oxidative stress, mitigate neuronal apoptosis, suppress astrocyte activation, and repair neurons. 190 , 191 , 193 , 195 , 299 For PD, NEVs derived from healthy stem cells can reduce α-synuclein levels, decrease neuroinflammation and oxidative stress, mitigate dopaminergic neuron loss, enhance nigrostriatal system function, reduce microglial activation, and promote neurovascular regeneration. 201–203 , 300 In addition, astrocytes release NEVs that are rich in beneficial proteins such as synaptophysin and glutamate transporters. These molecules participate in neuroprotection, neurite outgrowth, synapse formation, synaptic plasticity, regulation of neurotransmitter release, and glutamate reuptake. 196 , 197 From exogenous sources, NEVs derived from Lactobacillus plantarum, Bifidobacterium , and Akkermansia mucosae have also been found to employ similar mechanisms to improve AD and PD. 189 , 200 , 301–305

It has shown that neuron-derived NEVs can be found in human plasma, and they contain measurable levels of α-synuclein. 306 This confirms that NEVs are able to cross the blood-brain barrier (BBB). It offers opportunities for early diagnosis. By analyzing NEVs and their contents in blood or other accessible body fluids, it may be possible to detect neurodegenerative conditions before symptoms appear. Current studies focus on identifying neuron-derived NEVs in cerebrospinal fluid, blood, saliva, and urine. 295 AD biomarkers include Aβ (1–42), total tau, miR-212, miR-132 , and miR-23a-3p . 307–312 PD-associated biomarkers include α-synuclein, miR-19b-3p , and lncRNA-POU3F3 . 313–316 Measuring these NEVs and their cargo provides a dynamic and non-invasive way to monitor the health of the cells they come from ( Figure 9 ).

Bone Diseases

Bone health depends on a balance between bone formation and resorption, which is regulated by BMSCs and their differentiated descendants, osteoblasts and osteoclasts. 320 It is indicated that NEVs derived from different senescent cells or tissues influence the osteogenic differentiation of BMSCs. These include miR-183-5p and miR-31a-5p in NEVs from senescent BMSCs; 321 , 322 miR-483-5p in NEVs from aged bone matrix; 323 significantly reduced myosin-1 in NEVs from aged osteocytes; 324 and downregulated integrin signaling pathway-related proteins in aged serum NEVs. 325 Together, these changes tend to suppress osteoblast differentiation while encouraging BMSCs to become fat cells, leading to increased fat accumulation in bone marrow. Meanwhile, after being taken up by osteoclasts, miR-31a-5p in aged BMSC-NEVs can promote osteoclast differentiation and bone resorption activity by targeting the RhoA pathway. 322 OA is another typical age-related bone disease characterized by chondrocyte death, loss of cartilage matrix, and inflammation. 326 It was found that connexin 43 (Cx43) in NEVs derived from senescent chondrocytes can induce chondrocyte dedifferentiation and extracellular matrix degradation. 112 , 327 , 328 Another cargo, miR-449a-5p , can inhibit autophagy, increase mitochondrial ROS production, promote NLRP3 inflammasome activation, and enhance the secretion of mature IL-1β. 112 , 327 , 328

The primary therapeutic strategy for OP involves promoting osteoblast differentiation and proliferation while inhibiting osteoclast differentiation and proliferation. NEVs derived from BMSCs, adipose-derived stem cells (ASCs), umbilical cord stem cells (UC-SCs), USCs, and dDPSCs have all been found to promote osteoblast differentiation and inhibit osteoclast differentiation through distinct mechanisms. 329–331 These NEVs released by the tissue cells primarily target BMSCs, followed by osteoblasts and osteoclasts. 330 , 332 Similarly, NEVs derived from stem cells are a preferred therapeutic approach for OA. These include NEVs from BMSCs, ADSCs, endometrial mesenchymal stem cells (eMSCs), and UC-MSCs promote chondrocyte proliferation, inhibit chondrocyte degeneration and apoptosis, and suppress inflammatory cytokine secretion. 216 , 217 , 219 , 220 , 333 The primary target cells are chondrocytes. Additionally, NEVs derived from M2 macrophages exhibit potent anti-inflammatory potential in OA. 221 NEVs derived from chondrocytes, neutrophils, tendon cells, synovial fluid, and platelet-rich plasma also exhibit similar mechanisms 221–224 , 334 ( Figure 10 ).

T2dm

Aging and T2DM are causally interrelated. Growing evidence indicates that NEVs derived from different senescent cell sources play a crucial role in inducing IR. For instance, NEVs from senescent adipocytes and macrophages in adipose tissue suppress IR in myocytes via miR-27a by inhibiting downstream PPARγ. 336 , 337 Senescent BMSC-EVs target SIRT1 via miR-29b-3p to mediate IR in adipocytes, myocytes, and hepatocytes. 338

In therapeutic applications, MSC-NEVs show significant promise. They primarily work by improving IR through enhanced glucose and lipid metabolism, promoting cellular autophagy, and reducing inflammation. 219 , 227–230 , 339 , 340 Besides this, NEVs from other sources can also be effective. In vivo, NEVs derived from adipose tissue can actively regulate fatty acid metabolism and gluconeogenesis. 231 , 341 NEVs derived from skeletal muscle cells can restore the function of glucose transporter type. 232 , 342 Endothelial progenitor cells and β-cell-derived NEVs can induce pancreatic vasculogenesis to promote β-cell survival. 233 , 234 In vitro, exosome-like nanovesicles derived from citrus peel significantly improve T2DM-induced hepatic IR by modulating gut microbiota, enhancing bile acid metabolism, and regulating key genes involved in lipid metabolism. 236 NEVs derived from mung bean sprouts improve T2DM by promoting glucose uptake and glycogen synthesis while alleviating oxidative stress. 235

It is worth noting that the diminished capacity to maintain glucose homeostasis during aging leads to widespread glucotoxicity. 343 This stress may drive cellular senescence in various cell types, such as renal cells, thereby contributing to the development of diabetic kidney disease (DKD). 343 All of the above treatment measures for T2DM can also be applied to the treatment of DKD. Besides, MSC-NEVs can inhibit podocyte apoptosis, promote angiogenesis, and suppress mesangial cell collagen synthesis, representing therapeutic mechanisms for DKD. 344–346

In terms of diagnosis, β-cells have emerged as the primary cells for diagnosing diabetes, with miR-15a, miR-375-3p , and lncRNA-p3134 secreted in their NEVs demonstrating diagnostic potential. 345 , 347 , 348 Furthermore, AEBP1 in plasma-derived NEVs has recently been identified as a novel biomarker for distinguishing patients with DKD, T2DM, and healthy individuals 349 ( Figure 11 ).

Age-Related Macular Degeneration

AMD is a progressive retinal disease closely associated with dysfunction of the retinal pigment epithelium (RPE). 351–353 In this process, NEVs play a crucial role. Under age-related stress, such as oxidative damage, RPE cells release NEVs that contribute to AMD pathology in several ways. These vesicles can carry damaged mitochondrial DNA and complement proteins, which activate microglia and inflammasomes, worsening local inflammation. 354–356 Additionally, NEVs may transfer molecules like histone deacetylase 6, disrupting the blood-retinal barrier, promoting epithelial-mesenchymal transition (EMT), and encouraging subretinal fibrosis. 357–359

Conversely, NEVs from certain sources show potential for treating AMD. Several studies have confirmed that MSC-NEVs exert neuroprotective effects in AMD models, with mechanisms involving the delivery of key molecules such as miR-21 . 238–240 Embryonic stem cell-derived NEVs can delay retinal degeneration by upregulating transcription factors such as Oct4. 241 In a pigmentary retinopathy model, MSC-NEVs mediate anti-inflammatory responses via the miR-146a -Nr4a3 axis, offering novel therapeutic insights for AMD-like degenerative diseases. 237

For diagnosis, exosomes offer a promising non-invasive approach because they carry disease-specific biomarkers. It is shown that the protein content of exosomes in the aqueous humor of AMD patients is significantly altered, which could serve as a diagnostic indicator. 360 Circulating microRNAs also show distinct patterns in AMD: for instance, exosomes from patient serum contain higher levels of miR-486-5p and miR-626 , and lower levels of miR-885-5p , compared to healthy individuals. 361 Moreover, oxidative stress induces changes in the phosphoprotein profile of exosomes released by retinal cells, further supporting their value in reflecting cellular metabolism and stress responses. 362 These findings collectively establish the dual application prospects of NEVs in the precision diagnosis and treatment of AMD ( Figure 12 ).

Future Perspectives and Challenges

Recent research on NEVs in the biomarker field has moved from single-molecule detection to multi-omics integrated diagnostics. Zhang et al combined plasma NEV proteomic and lipidomic analyses to identify EV protein features that can distinguish prodromal Parkinson’s disease from multiple system atrophy. Their machine learning model achieved stable classification across different age groups. 363 In the field of aging assessment, a study systematically analyzed plasma EV miRNA profiles from a healthy aging cohort. It found that elderly individuals showed NEV immune phenotype changes consistent with immunosenescence. NEV miRNA and particle counts were significantly correlated with biological aging indicators such as GDF-15, visceral fat, and muscle mass. 364 NEV Alu RNA was also found to increase with age and was associated with neuronal damage. 365 These findings suggest that NEV multi-omics features may serve as effective tools for evaluating biological age and functional decline. In the field of drug delivery, engineering strategies for NEVs have achieved breakthroughs. One study loaded dasatinib and quercetin into NEVs and displayed avidin on the surface as a modular platform. This platform used biotinylated anti-VCAM1 to achieve senescent cell targeting and biotinylated phosphatidylserine to promote clearance of senescent cells. 366 This marks a transition of NEVs from simple delivery functions to combined functions of targeted clearance and clearance enhancement. Another important study demonstrated that NEVs can serve as natural delivery vehicles for functional telomerase. In aged mice, they restored endogenous telomerase activity and reduced multi-tissue aging. 367 These studies point to future directions for NEV engineering, but bottlenecks in drug loading efficiency, targeting accuracy, and large-scale production remain to be solved. 21 In addition, some NEVs can be used as direct therapeutic agents. The mechanisms of action of NEVs from multiple novel cell sources have been clarified in detail. Choi et al elucidated the complete signaling pathway through which embryonic stem cell-derived NEVs exert anti-aging effects. Fibronectin on the NEV surface binds to cell integrins, activates FAK and AKT, then inhibits GSK3β and stabilizes Nrf2, preventing fibroblasts and astrocytes from entering a senescent state. 368 In addition, iPSC-derived sEVs were found to deliver RNA-binding proteins to suppress the upregulation of CISH in senescent NK cells, activate p-STAT3, and reverse the immunosenescence phenotype in aged mice. 369 Plant-derived NEVs have attracted attention due to their sustainability and cost advantages. 18 Bacterial-derived NEVs show application potential because of their stable membrane structures and encapsulation capabilities. 29 These findings together indicate that the therapeutic mechanisms of NEVs are shifting from the simple logic of supplementing missing molecules to a deeper paradigm of reprogramming signaling networks in senescent cells. Understanding the functional spectrum of NEVs from different sources and their optimal application scenarios in specific aging contexts will be an important topic for future research.

In terms of clinical translation, NEV therapies have begun to enter early clinical validation stages. The 2025 Annual Meeting of the International Society for Cell and Gene Therapy clearly stated that MSC-NEV therapies are ready to move from the laboratory to the clinic, but this goal can only be achieved through coordinated progress in science, regulation, and strategy. 370 A 2025 study for the first time demonstrated in middle-aged rhesus monkey models that after biweekly infusions of young donor cell-derived NEVs for one and a half years, the treatment group showed better working memory and healthier brain connectivity. 371 This provided direct evidence for the neuroprotective effects of NEVs in primates. In the field of osteoarthritis, intra-articular injection of hUC-MSC-derived exosomes did not cause adverse effects. Clinical scores and MRI examinations both showed a certain degree of efficacy. 372 However, we still need to remain cautious about these advances. Although the results from the rhesus monkey model are evolutionarily closer to humans, the sample size was limited, and long-term safety and optimal dosing regimens have not been determined. The number of clinical trials is increasing, but most are in early stages and lack validation from large-scale randomized controlled studies. A deeper issue is that most clinical trials use NEVs as black-box preparations, without a clear understanding of their active components and mechanisms of action. 370 This “test first, use later” strategy may be acceptable for safety verification, but it is not conducive to dose optimization and efficacy prediction. Clinical translation research needs to establish mechanism-based potency evaluation systems alongside ongoing trials, rather than relying solely on empirical dose exploration.

NEV research also faces several common challenges. NEV heterogeneity is seriously underestimated. Conventional bulk analysis averages NEV populations of different sizes, different cellular origins, and different cargo compositions. This may obscure key functional subpopulations. 370 The development of single-vesicle analysis technologies will be key to overcoming this bottleneck. Active components are difficult to pinpoint precisely. The therapeutic effects of NEVs often come from the synergistic actions of multiple cargo molecules, which makes it difficult to establish potency assays based on single markers. 372 Production standardization issues constrain the advancement of clinical applications. The heterogeneity among batches of NEVs and the limitations of current isolation technologies make it extremely difficult to establish a pharmaceutical-grade quality control system. 21 In addition, no drug regulatory agency has yet issued specific technical evaluation guidelines for NEV-based drugs, which further increases the uncertainty of clinical translation. 372

Different disease areas also face their own specific translational barriers. In neurological diseases, although MSC-NEVs have a natural ability to cross the blood-brain barrier, their delivery efficiency and precision are still far from meeting therapeutic needs. 373 A Phase I clinical trial for early Alzheimer’s disease (the RESTORE trial, NV-101) specifically used intracisternal injection to bypass the blood-brain barrier, which itself indicates the limitations of systemic administration. 374 The lack of standardized large-scale production and long-term safety data are the main bottlenecks limiting the advancement of NEV therapies for neurological diseases. 373 The challenges in oncology are particularly complex. Tumor-derived NEVs can induce drug resistance in chemotherapy-sensitive cells by transferring miRNAs and efflux transporters. HNSCC-derived NEVs carry miR-21, miR-214 , and others that can promote angiogenesis, apoptosis escape, and immunosuppression. 375 NEV-mediated epithelial-mesenchymal transition, immunosuppression, and extracellular matrix remodeling further exacerbate tumor heterogeneity, making treatment responses more difficult. 375 These findings mean that NEVs in tumors are a double-edged sword. They can serve as therapeutic targets but also as vehicles for spreading drug resistance. Targeting efficiency, in vivo stability, and clinical scalability are core issues that need to be urgently addressed for NEV-based anti-tumor therapies. Osteoarthritis treatment is limited by the avascular nature of articular cartilage. Drugs face rapid joint clearance and poor cartilage uptake. 376 Researchers are attempting to construct cartilage-targeting exosomes by reversing the surface charge of NEVs to achieve sustained delivery of IL-1 receptor antagonists, 376 but this is still in early exploration. In addition, endogenous NEVs released from osteoarthritic cells actually exacerbate disease progression, 376 suggesting that therapeutic NEVs must overcome interference from harmful endogenous NEVs. NEV research in diabetic kidney disease faces severe standardization issues. Although preclinical evidence supports that NEVs can serve as early biomarkers and mechanistic drivers of DKD, there is a lack of unified standards in isolation, characterization, dosing, and endpoint measures. This makes it difficult to compare and translate findings across studies. 377 High glucose conditions themselves can induce disordered NEV cargo loading, 377 meaning that autologous NEVs from diabetic patients may already be functionally impaired, further increasing the complexity of therapeutic strategy design.

NEV heterogeneity, while providing diagnostic value, also hinders clinical translation. 370 Future breakthroughs will depend on advances in single-particle resolution analysis platforms to identify key active biomolecules that determine the mechanisms of action of different NEV subtypes. 370 The safety of NEVs from cross-species sources also requires systematic evaluation. The functional and metabolic stability of plant miRNAs in mammalian cells remains controversial. 18 The risks of endotoxin contamination and excessive immune activation from bacterial-derived NEVs cannot be ignored. 29 NEV research is currently at a critical stage of transitioning from phenomenological description to mechanistic understanding and engineering applications. Future efforts need to advance synergistically in single-vesicle analysis technologies, causal validation experimental designs, humanized model systems, and disease-specific delivery strategies.

Conclusion

This review innovatively proposes the concept of NEVs, focusing on the dual mechanisms by which NEVs derived from animals, plants, and bacteria regulate cellular senescence and their potential applications in ARD therapy. Despite the promising prospects, the successful translation of NEVs into clinical treatments still faces many challenges. In the future, combining bioengineering, nanotechnology, systems biology, and multi-omics analysis for in-depth research and rational engineering of NEVs is expected to overcome the existing bottlenecks. Ultimately, NEV-based intervention strategies are anticipated to be developed into a class of precise, efficient, and safe innovative therapies, providing powerful new tools for achieving healthy aging and treating ARDs.

Funding Statement

This work was supported by grants from the National Natural Science Foundation of China to Zhengjun Shang (No. 82273306), Xin Huang (No. 82401121), Zhengguo Cao (No. 82571093, No. 82370967) and Jirong Xie (No. 82501166), the Fundamental Research Funds for the Central Universities to Zhengguo Cao (2042025kf0006), the National Key Research and Development Program of China to Zhengguo Cao (No. 2023YFC2506300), Research Project of School and Hospital of Stomatology Wuhan University to Zhengguo Cao (ZW202402), Hubei Provincial Natural Science Foundation of China to Xin Huang (2024AFB024).

Data Sharing Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Author Contributions

First authors: Shijie Lv, Jirong Xie, Xin Huang. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

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Associated Data

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.