Exosomes in oncofertility: emerging roles in chemotherapy-induced reproductive damage and fertility preservation.

Introduction

Advances in cancer therapy have markedly improved survival among patients of reproductive age, bringing long-term quality of life – and fertility preservation – into sharper clinical focus. Oncofertility has emerged as an interdisciplinary field at the interface of oncology and reproductive medicine, aiming to prevent or mitigate treatment-related reproductive damage ( La Rosa et al. 2020 ). Despite therapeutic success, chemotherapy remains a major cause of gonadal injury, frequently resulting in reduced ovarian reserve, impaired spermatogenesis, and permanent infertility in cancer survivors.

Several fertility-preserving strategies are currently available, including gonadotropin-releasing hormone agonists, cryopreservation of oocytes or embryos, and ovarian tissue cryopreservation ( Zaami et al. 2022 ). While these approaches have expanded reproductive options, they are not universally effective and are often limited by invasiveness, time constraints, patient age, or the urgency of cancer treatment. Consequently, there is a clear need for alternative, less invasive strategies that can protect reproductive function without delaying oncologic care.

In this context, exosomes have gained increasing attention as biologically active mediators with relevance to reproductive health. Exosomes are nanosized extracellular vesicles (30–150 nm) of endosomal origin that facilitate intercellular communication through the transfer of proteins, lipids, and regulatory RNAs ( Lee et al. 2024 ). They participate in a wide range of physiological and pathological processes, including immune regulation, cancer progression, and reproductive biology ( Saadeldin et al. 2025 ) ( Fig. 1 ). Importantly, chemotherapy can alter exosomal cargo, enabling the dissemination of stress signals that may exacerbate gonadal damage beyond direct cellular toxicity.

At the same time, exosomes derived from regenerative sources – such as mesenchymal stem cells (MSCs) and induced pluripotent stem cells – have shown promising protective and reparative effects in experimental models. These vesicles can reduce apoptosis, modulate inflammation, promote angiogenesis, and support germ cell survival, suggesting a potential role in preserving or restoring reproductive function. Together, these findings position exosomes as having a dual role in oncofertility: contributors to chemotherapy-induced reproductive injury and emerging tools for fertility protection ( Ludwig & Giebel 2012 ; Qamar et al. 2021 ).

In this review, we synthesize current knowledge on chemotherapy-induced gonadotoxicity in both females and males, explore the mechanistic and regenerative roles of exosomes in reproductive damage and repair, and discuss the key challenges and future directions for translating exosome-based approaches into oncofertility practice.

Chemotherapy-induced reproductive damage

Cancer is one of the most pressing global public health challenges, with a rising incidence among younger populations ( Siegel et al. 2019 ). For example, between 2001 and 2010, childhood cancers were reported at 140 cases per million individuals under 14 years ( Steliarova-Foucher et al. 2017 ). Advances in screening and treatment have markedly improved survival, with an ∼20% increase over the past three decades ( Xiao et al. 2017 ).

However, the expanding population of survivors faces long-term adverse effects of chemotherapy, including neurocognitive impairment, cardiotoxicity, secondary malignancies, and notably, gonadotoxicity, which threatens fertility, endocrine function, and quality of life ( Silva et al. 2018 ). Chemotherapy-induced reproductive toxicity arises through mechanisms such as DNA damage, oxidative stress, germ cell apoptosis, and disruption of the gonadal microenvironment. In females, this manifests as loss of the ovarian reserve and premature ovarian insufficiency, whereas in males it leads to impaired spermatogenesis, poor sperm quality, or azoospermia.

The extent of gonadotoxicity varies by drug class, cumulative dose, treatment duration, and age at exposure, with alkylating agents recognized as the most damaging. Common regimens include single agents, such as cyclophosphamide, doxorubicin, paclitaxel, and cisplatin, or combinations, such as MOPP and ABVD for Hodgkin’s lymphoma and CHOP for non-Hodgkin’s lymphoma ( Hao et al. 2019 ). While effective in cancer control, these regimens inevitably compromise reproductive health, underscoring the need for fertility-preserving interventions.

Having outlined the general mechanisms and regimens, the following section examines the drug-specific gonadotoxic profiles, highlighting how individual agents exert distinct reproductive effects based on their molecular targets.

Impact of chemotherapeutic agents on female fertility

Doxorubicin, an anthracycline antibiotic derived from Streptomyces peucetius and marketed as Adriamycin or Rubex, is a widely used chemotherapeutic for leukemia, breast, lung, stomach, and ovarian cancers ( Spears et al. 2019 ). Its anti-tumor activity stems from DNA intercalation, topoisomerase II inhibition, and disruption of mitochondrial electron transport, leading to free radical generation and oxidative stress ( Bhardwaj et al. 2020 ). However, doxorubicin is profoundly ovotoxic, causing amenorrhea, premature ovarian failure (POF), and infertility in female cancer survivors ( Molina et al. 2005 ). Animal studies demonstrate dose-dependent reductions in ovarian and uterine weight, follicular atresia, peri-ovarian edema, and impaired ovulation, largely linked to oxidative stress ( Nishi et al. 2018 ). Histology reveals stromal and vascular damage, cortical fibrosis, and uterine abnormalities ( Bhardwaj et al. 2023 ). Doxorubicin also disrupts estrous cycles, lowers estrogen levels, and impairs mammary gland development ( Nishi et al. 2018 ). Mechanistically, it crosses the blood–follicle barrier, accumulates in granulosa cells and oocytes, and induces mitochondrial dysfunction, DNA double-strand breaks, ER stress, and Ca 2+ overload, activating caspase-3, caspase-12, and cytochrome c-mediated apoptosis ( Aziz et al. 2019 ). Moreover, doxorubicin alters steroidogenesis by dysregulating FOXO3/AKT signaling, modifying miRNA expression (e.g. miR-132-3p), and downregulating key enzymes such as P450scc and aromatase, reducing progesterone and estrogen synthesis ( Wang et al. 2019 b , Al-Kawlani et al. 2020 ). Deficiency of MDR1, normally expressed in ovarian and uterine tissue, further exacerbates its toxicity ( Duan et al. 2012 ). Collectively, these findings establish doxorubicin as a major contributor to female reproductive failure through oxidative stress, DNA damage, ER stress, apoptosis, and steroidogenic disruption.

Cyclophosphamide, an alkylating agent used for lymphomas, breast cancer, and autoimmune disorders, was the first drug linked to amenorrhea and ovarian failure ( Li et al. 2019 c ). As a prodrug, it is metabolized by hepatic cytochrome P-450 into phosphoramide mustard (PM) and acrolein – potent ovotoxins. PM intercalates into DNA, causing crosslinks and extensive ovarian damage, while both PM and chloroethylaziridine accelerate primordial and primary follicle loss ( Ponticelli et al. 2018 ). Animal and clinical studies show reduced ovarian/uterine weight, granulosa cell arrest, and nearly tenfold increased risk of ovarian insufficiency. Histology reveals stromal edema, vascular injury, fibrosis, and follicular atresia ( Ganesan & Keating 2015 , Abdel-Aziz et al. 2020 ). Mechanisms include oxidative stress, DNA double-strand breaks, apoptosis, and inflammatory cytokines (TNF-α, IL-1, and IL-6), with caspase-3 activation and altered antioxidant enzymes (SOD, GSH, and HO-1) promoting apoptosis. Endocrine disruption – reduced estradiol, progesterone, FSHR, and PCNA – further impairs folliculogenesis and embryo development ( Delkhosh et al. 2019 , Bhardwaj et al. 2023 ). Thus, cyclophosphamide induces severe gonadotoxicity via DNA crosslinking, oxidative/inflammatory stress, and hormonal imbalance, culminating in POF and infertility.

Cisplatin, a platinum-based chemotherapeutic approved in 1978, is widely used for ovarian, breast, lung, bladder, and testicular cancers ( Bhardwaj et al. 2023 ). Its cytotoxicity arises from DNA crosslinking at guanine/adenine residues, blocking replication, impairing repair, and inducing apoptosis. Despite its efficacy, cisplatin causes severe female reproductive toxicity, including embryonic lethality, blastocyst defects, teratogenicity, and growth retardation ( Hassan et al. 2019 ). Mechanistically, cisplatin promotes granulosa cell apoptosis, depletes primordial follicles, and leads to follicular degeneration, vascular congestion, and oocyte loss ( Kulhan et al. 2019 ). It also drives oxidative stress – reducing superoxide dismutase and glutathione while elevating lipid peroxidation and reactive oxygen species (ROS) ( Bhardwaj et al. 2023 ). Endocrine disruption occurs via PTEN/Akt/FOXO3a signaling, accelerating premature follicle activation and reducing AMH and inhibin levels. In parallel, apoptotic pathways involving p53, ATM, and MAPK signaling activate TAp63α in oocytes, upregulating PUMA and NOXA and triggering follicular apoptosis ( Jang et al. 2017 , Bhagat et al. 2021 ). Together, these findings confirm cisplatin-induced infertility results from a combination of oxidative stress, endocrine disruption, and apoptosis, ultimately causing irreversible ovarian reserve loss.

Paclitaxel, a natural chemotherapeutic from Taxus brevifolia , is widely used for breast, ovarian, lung, and germ cell tumors ( Ettinger et al. 2019 ). Unlike alkylating or platinum agents, it stabilizes microtubules and prevents depolymerization, blocking cell division but rendering granulosa cells highly vulnerable ( Zhang et al. 2017 ). Paclitaxel reduces primordial follicle counts, induces atresia, and causes ovarian failure ( Kim et al. 2019 ). It suppresses GDF9 and BMP15 transcription, disrupts granulosa cells, and triggers lipid accumulation and mitochondrial injury. Antral follicles and MII oocytes are especially sensitive, showing meiotic arrest, spindle abnormalities, and chromosomal misalignment, leading to reduced fertilization and pregnancy rates ( Ma et al. 2020 ). At the molecular level, paclitaxel inhibits CDK1 and cyclin A, causing G2/M arrest, and promotes apoptosis via Bcl-2 and XIAP downregulation alongside pro-apoptotic gene activation. It also elevates PARP cleavage and DNA damage markers, further impairing oocyte quality et al. , 2019). Endocrine effects include reduced estrogen with relatively stable progesterone levels ( Palomino et al. 2024 ). Overall, paclitaxel impairs female fertility by stabilizing microtubules, inducing follicular loss, triggering apoptosis, and disrupting hormonal balance.

Impact of chemotherapeutic agents on male fertility

Although much of the clinical literature emphasizes female reproductive damage, males are also significantly affected by chemotherapy-induced gonadotoxicity. Male fertility experiences two main chemotherapy side effects which result in oligospermia and azoospermia leading to possible long-term or short-term infertility. The two alkylating agents, cyclophosphamide (CP) and busulfan (BF), serve as primary treatments for pediatric cancer patients who have multiple myeloma and sarcomas, chronic myeloid leukemia, and lymphomas. Male cancer survivors who become infertile experience psychological damage that affects their self-esteem and emotional health, their relationships, social position, financial security, and life quality ( Liakath Ali et al. 2023 ).

The causes of male infertility associated with cancer treatment can be broadly categorized into four groups: i) testicular dysfunction, where the testes fail to produce adequate sperm; ii) obstruction or structural abnormalities of the seminal tract; iii) sexual dysfunction, including erectile dysfunction and ejaculatory disorders ( Yumura et al. 2018 ); and iv) hypogonadism, resulting from reduced gonadotropin secretion and impaired spermatogenesis, which may arise after cranial radiation therapy, central nervous system tumors, or surgical interventions, such as partial or total orchiectomy ( Elenkov & Giwercman 2022 ). Moreover, hypogonadism can also be triggered by pituitary inflammation caused by immune checkpoint inhibitors, such as nivolumab ( Özdemir 2021 , Yumura et al. 2023 ).

Testicular dysfunction remains one of the most critical long-term complications of chemotherapy and radiotherapy in young male cancer survivors. Schrader et al. (2001) reported that 15–30% of survivors lose fertility potential, with many showing abnormal semen parameters. For example, oligozoospermia has been observed in 28% of testicular cancer, 25% of Hodgkin’s disease, 57% of leukemia, and 33% of gastrointestinal cancer patients ( Chung et al. 2004 ). Among those undergoing sperm banking, about 50% have sperm counts ≤10 million ( Williams et al. 2009 ), while 5–11% present with azoospermia ( Johnson et al. 2013 ). Poor nutrition, endocrine abnormalities, and elevated cytokine levels may further exacerbate sperm decline, and these conditions often persist even after treatment ( Dohle 2010 , Yumura et al. 2023 ).

Studies indicate that chemotherapeutic agents such as cyclophosphamide, cisplatin, and doxorubicin can induce apoptosis in spermatogonial stem cells (SSCs) by causing DNA damage ( Smart et al. 2018 ). In particular, drugs such as cyclophosphamide, cisplatin, etoposide, and vincristine predominantly activate programmed cell death in spermatogonia and primary spermatocytes ( Park et al. 2022 ). Doxorubicin, however, may also elicit testicular injury through alternative mechanisms, including necrosis or autophagy ( Allen et al. 2018 , Ghafouri-Fard et al. 2021 ). While Sertoli cells can be directly affected, their dysfunction often arises secondarily due to germ cell loss. Beyond direct cytotoxicity, chemotherapy also provokes cellular stress within the testes, leading to impaired testicular function and activation of apoptotic signaling cascades. These effects are further amplified by enhanced pro-inflammatory cytokine release, nuclear translocation of NF-κB, and suppression of the antioxidant regulator Nrf2, ultimately promoting oxidative stress and gonadal damage ( Ghafouri-Fard et al. 2021 , Taher et al. 2025 ).

Surgical interventions can also impair fertility: prostatectomy or cystectomy may cause aspermia, retroperitoneal lymph node dissection can lead to anejaculation, radical prostatectomy often results in erectile dysfunction, and bilateral orchiectomy causes irreversible azoospermia ( Huang & Berg 2021 ). Oxidative stress is another contributor, with reactive oxygen species detected in semen of 42% of chemotherapy-treated patients, persisting long after therapy ( Takeshima et al. 2019 , Yumura et al. 2023 ).

Large-scale studies confirm the elevated risk: in a cohort of 1,622 survivors, infertility prevalence was 46% compared with 17.5% in siblings (RR = 2.34) ( Wasilewski-Masker et al. 2014 ), aligning with the general infertility rate of ∼15% in developed countries ( Sharlip et al. 2002 , Yumura et al. 2023 ). Notably, infertility in survivors was largely linked to gonadotoxic therapies rather than baseline causes, with additional risks from genital or spinal surgeries ( Wasilewski-Masker et al. 2014 ). Chemotherapy exposure in both childhood and adulthood has been associated with semen deterioration, increased sperm DNA fragmentation, and reduced birth rates ( Delessard et al. 2020 ). While cancer treatment rightly prioritizes survival, these findings underscore the need to anticipate and mitigate infertility risks in male patients.

Spermatogenesis in seminiferous tubules depends on Sertoli cell support and the blood–testis barrier, but many drugs – especially alkylating agents, such as ethyl methanesulfonate, and tyrosine kinase inhibitors, such as imatinib – can cross and damage germ cells ( Chang et al. 2021 ). Differentiating spermatogonia are highly sensitive, while late-stage germ cells are more resistant ( Trottmann et al. 2007 , Yumura et al. 2023 ). Sperm counts can drop to 1/10–1/100 of normal within 1–2 months of therapy, with azoospermia appearing in ∼12 weeks depending on drug and dose ( Meistrich 2013 , Yumura et al. 2023 ). Recovery is regimen-dependent: mild treatments may normalize counts in ∼12 weeks, but alkylating agents often cause lasting or irreversible damage ( Meistrich 2013 , Mulder et al. 2021 ). Cumulative dose strongly predicts toxicity – CED ≥ 4,000 mg/m 2 links to azoospermia; ifosfamide > 42 g/m 2 and cisplatin >400 mg/m 2 are also highly gonadotoxic ( Green et al. 2014 ). Targeted therapies may impair fertility too, since sperm rely on tyrosine kinases for meiosis and capacitation, though data remain limited ( Wyns et al. 2021 ).

While the mechanisms and clinical outcomes of chemotherapy-induced reproductive toxicity are well documented, mounting evidence suggests that these effects extend beyond direct cellular injury. Extracellular vesicles, especially exosomes, have emerged as key mediators that amplify gonadotoxic signals. By transferring proteins, lipids, and regulatory RNAs between cells, exosomes act as intercellular messengers that shape the onset, progression, and persistence of chemotherapy-induced damage. This underscores the need to explore in depth the role of exosomes in mediating chemotherapy-induced reproductive toxicity.

Role of exosomes in chemotherapy-induced reproductive toxicity

Origin and biogenesis of exosomes

Exosomes were first described in the early 1980s in reticulocyte culture media and are now recognized as nanoscale vesicles present in nearly all body fluids. According to MISEV 2023, small extracellular vesicles (sEVs) include exosomes (<200 nm), derived from the endosomal system, and ectosomes, which bud directly from the plasma membrane and often overlap in size ( Taher et al. 2025 ).

Exosome formation begins with endosomal trafficking, where inward budding of early endosomes generates intraluminal vesicles (ILVs) that accumulate within multivesicular bodies (MVBs). These MVBs fuse with either lysosomes for degradation or the plasma membrane to release ILVs as exosomes ( Gurung et al. 2021 ). Their biogenesis is largely governed by the endosomal sorting complex required for transport (ESCRT), comprising ESCRT-0 to ESCRT-III, together with accessory proteins such as VPS4, TSG101, and ALIX ( Gurung et al. 2021 ). ESCRT-0 captures ubiquitinated cargos, ESCRT-I/II induce membrane deformation, and ESCRT-III with VPS4 mediates scission. ALIX and TSG101 also contribute to selective cargo loading by interacting with syndecans ( Hessvik & Llorente 2018 , Yue et al. 2020 ).

Alongside this canonical pathway, ESCRT-independent mechanisms have been identified. Lipid-driven processes involving sphingomyelinase-derived ceramides promote membrane curvature and budding ( Skryabin et al. 2020 ), while tetraspanins such as CD63 and CD81 cluster receptors and signaling proteins in microdomains, guiding their incorporation into exosomes ( Mohammadi et al. 2024 ). These dual pathways highlight the versatility of exosome biogenesis, with the balance between ESCRT-dependent and lipid/tetraspanin-driven processes varying by cell type and physiological context ( Mohammadi et al. 2024 ).

Unlike exosomes, ectosomes form by direct budding from the plasma membrane, involving lipid-anchored proteins (e.g., myristoylation/palmitoylation), cargo clustering, and ESCRT-I recruitment ( Lim et al. 2021 ). Key regulators include small GTPases such as Arf6 (vesicular trafficking) and Rho family proteins (RhoA, Rac1, and Cdc42) that remodel cortical actin ( Meldolesi 2018 ). Final scission requires Ca 2+ -dependent lipid rearrangements (via flippases) and ESCRT-III activity ( Yu et al. 2024 ).

Molecular cargo of exosomes

sEVs carry a molecular profile reflecting their parent cells, including proteins, lipids, and nucleic acids ( Rahimian et al. 2024 ). Databases such as EVpedia, Vesiclepedia, and ExoCarta catalog their contents.

Lipid content

sEV membranes are enriched in sphingomyelin, gangliosides, phosphatidylserine, and ceramide but show reduced phosphatidylcholine and diacylglycerol. These features, along with cholesterol enrichment, confer greater rigidity and stability compared to the cell membrane ( Chen & Yu 2022 ). Exosomes are enriched in tetraspanins and ICAM-1, while ectosomes carry a wider array of proteins, including glycoproteins and metalloproteinases ( Taher et al. 2025 ).

Protein content

sEV proteins reflect their biogenesis, often including ESCRT components, tetraspanins, and transmembrane signaling molecules. Proteins from the nucleus, Golgi, and ER are generally absent ( Abels & Breakefield 2016 ).

Nucleic acid content

sEVs transport diverse RNAs, including mRNA, miRNA, lncRNA, tRNA, circRNA, and snRNA, as well as double-stranded DNA ( Chen et al. 2021 b ). These molecules regulate gene expression and are promising biomarkers ( Taher et al. 2025 ).

Their distinct size, cargo, and biogenesis differentiate them from microvesicles and apoptotic bodies ( Aheget et al. 2021 ). Morphologically, they appear cup-shaped under preparation but spherical in TEM ( Yellon & Davidson 2014 ). Their density ranges from 1.13 g/mL (B-cell exosomes) to 1.19 g/mL (epithelial-cell exosomes) ( Zakharova et al. 2007 ).

Exosomes are nanosized vesicles that mediate the transfer of molecular cargos – such as proteins, lipids, and nucleic acids – from donor cells to recipient cells, thereby serving as a central mechanism of intercellular communication ( Hannafon & Ding 2013 , Shirani et al. 2025 ). A wide variety of cells, including dendritic cells, macrophages, cancer cells, and MSCs, exploit this pathway to regulate both local and systemic signaling. Once secreted, exosomes profoundly influence cellular functions, as their cargos can induce new biological responses in recipient cells, thereby modulating key mechanisms in both health and disease ( Gurung et al. 2021 ).

Following release into the extracellular matrix (ECM), exosomes reach target cells via multiple routes, including autocrine, juxtacrine, paracrine, or endocrine signaling ( Hao et al. 2022 ). Uptake mechanisms depend on the recipient cell type and typically occur through two major modes. In the first, exosomes bind directly to surface receptors (e.g., glycans, lectins, integrins, and adhesion molecules), thereby activating downstream signaling pathways without internalization. In the second, internalization occurs through various forms of endocytosis, including clathrin-dependent or clathrin-independent endocytosis, phagocytosis, and macropinocytosis. Once internalized, exosomes may be degraded in lysosomes, recycled back to the plasma membrane, or release their cargos into the cytoplasm, thereby influencing recipient cell function ( Gurung et al. 2021 , Shirani et al. 2025 ).

Exosome isolation and characterization

The isolation of exosomes is a critical step for obtaining pure and concentrated vesicles for research ( Ayala-Mar et al. 2019 ). Several techniques are commonly employed. Differential ultracentrifugation remains the gold standard, separating vesicles by size and density ( Huang et al. 2022 ). Ultrafiltration, using molecular weight cutoff membranes, offers faster processing of large volumes ( Diaz et al. 2018 , Abady et al. 2023 ). Size exclusion chromatography separates exosomes through porous beads, while immunocapture methods use antibodies against exosomal markers, providing high specificity but limited by antibody availability ( Logozzi et al. 2020 , Abady et al. 2025 ). More recently, microfluidic platforms have emerged, allowing size- and marker-based isolation with rapid processing and integration into downstream analyses ( Kumar et al. 2023 ). No single method ensures complete purity; thus, combining methods or using commercial kits often improves results ( Ayala-Mar et al. 2019 , Mohammadi et al. 2024 ).

To assess purity and efficiency, density gradient centrifugation is widely used to separate exosome subpopulations ( Willms et al. 2016 ). Exosomal markers such as tetraspanins (CD9, CD63, and CD81) help confirm identity and purity ( Schorey et al. 2015 ). Molecular profiling of RNA and miRNAs provides additional insights, distinguishing healthy from diseased states ( Mohammadi et al. 2024 ). Morphology and protein cargo can be validated using TEM and Western blotting ( Jiao et al. 2019 ). Lipid profiling, including cholesterol and sphingolipids, further contributes to quality assessment ( Yasuda et al. 2022 ).

Exosomes in infertility pathogenesis and diagnosis

Exosomes are present in nearly all biological fluids, and their contents can be analyzed through liquid biopsies ( Jahanbani et al. 2023 b ). Their molecular cargo – including miRNAs, proteins, and lipids – serves as a unique ‘fingerprint’ of the donor cell, reflecting both its cellular origin and physiological state ( Yu et al. 2021 ). Because of these features, exosomes are increasingly recognized as non-invasive diagnostic and prognostic biomarkers ( Yu et al. 2022 ). They hold great promise for the detection of diseases affecting the reproductive system, liver, cardiovascular system, and various cancers ( Pillay et al. 2017 ).

Exosomes are increasingly recognized as central regulators in female reproductive disorders through their ability to transfer RNAs, proteins, and other cargos that alter cell behavior ( Fig. 2 ). In reproductive medicine, exosomes have demonstrated diagnostic potential for conditions such as polycystic ovary syndrome (PCOS), POF, endometriosis, intrauterine adhesion (IUA), Asherman’s syndrome, and preeclampsia ( Vickram et al. 2021 , Yu et al. 2022 ). For example, exosomal RNA sequencing from human follicular fluid (HFF) has shown potential as a molecular biomarker for PCOS ( Hu et al. 2020 ). Similarly, a serum exosome profiling study revealed 54 miRNAs with significant differences between PCOS patients and controls, introducing hsa-miR-1299, hsa-miR-6818-5p, hsa-miR-192-5p, and hsa-miR-145-5p as potential biomarkers ( Zhang et al. 2021 b ).

In PCOS, which affects 6–8% of women ( Esfandyari 2020 ), exosomal miRNAs such as miR-25-3p and miR-143-3p are upregulated while others such as miR-10a-5p are downregulated, thereby reshaping metabolic pathways ( Hu et al. 2020 ). Likewise, serum exosomal miR-146a-5p and miR-126-3p influence MAPK and circadian signaling ( Jiang et al. 2021 ), whereas adipose exosomal miR-323-3p protects granulosa cells by targeting PDCD4 ( Zhao et al. 2019 ). Notably, circRNAs such as hsa-circ-0006877 and proteins such as S100-A9 further implicate exosomes in inflammation and insulin resistance ( Tehrani et al. 2021 ).

Moving to POF, which occurs in 1% of women between 30 and 39 years ( Zhang 2020 ), MSC-derived exosomes demonstrate restorative potential. For example, bone marrow MSC exosomal miR-144-5p regulates PTEN ( Sun et al. 2019 ), hAEC-derived miR-1246 activates PI3K/AKT ( Zhang et al. 2019 b ), and amniotic fluid stem cell (AFSC)-derived exosomes transfer miR-10a and miR-146a to inhibit apoptosis. Placental MSC exosomes also enhance antioxidant defenses such as catalase and PRDX1, offering further protection ( Seok et al. 2020 ).

Importantly, recent mechanistic studies have identified AFSC-derived extracellular vesicles enriched in miR-21 as potent mediators of ovarian regeneration in chemotherapy-induced POF models. These EVs restored follicular counts, normalized serum anti-Müllerian hormone (AMH) levels, and improved fertility outcomes, primarily through suppression of the PTEN/caspase-3 apoptotic pathway. Notably, selective loading of AFSC-EVs with miR-21 mimics reproduced the regenerative effects, whereas inhibition of miR-21 abrogated ovarian recovery, underscoring the functional relevance of exosomal miRNA cargo in mediating therapeutic efficacy ( Thabet et al. 2020 ).

Beyond therapy, exosomes also hold promise in POF diagnosis. Reduced levels of Yy2 mRNA in peripheral blood-derived exosomes have been reported in POF patients, with expression levels correlating with disease severity and hormonal status ( Liu et al. 2021 ). In IUA, miR-326 has emerged as both a prognostic biomarker and a therapeutic target, as its downregulation correlates with enhanced fibrosis, while its overexpression suppresses the TGF-β1/Smad3 signaling pathway ( Javadi et al. 2022 ). Although no specific exosome biomarker has yet been confirmed for IUA, miR-326 remains a promising candidate.

Exosomes also show potential in endometriosis research, a condition lacking reliable diagnostic biomarkers. Investigations into miRNA signatures have been promising, with studies identifying five unique miRNAs in endometriotic epithelial cells, absent in healthy tissues ( Shomali et al. 2020 ). This supports exosome analysis as a tool for understanding endometriosis pathophysiology and improving diagnosis.

In Asherman’s syndrome, MSC-derived exosomes reduce fibrosis and stimulate angiogenesis by modulating MMP-2/9, VEGFR1, and CD31 while suppressing TIMP-2, suggesting a novel therapeutic approach ( Saribas et al. 2020 ). In endometriosis, affecting 6–10% of reproductive-aged women, exosomal lncRNAs (aHIF and CHL1-AS1) and miRNAs (miR-22-3p and miR-214-3p) regulate angiogenesis and fibrosis ( Zhang et al. 2021 a ), while proteins such as CD47 and PRDX1 show diagnostic potential ( Nazri et al. 2020 ). Macrophage- and stromal-derived exosomes further promote immune evasion and lesion progression ( Zhang et al. 2021 a ). In endometrial cancer, tumor and stromal exosomes transfer oncogenic cargos: CAF exosomes suppress miR-148b/miR-320a, activating DNMT1 and VEGFA ( Zhang et al. 2020 a ), plasma exosomal LGALS3BP stimulates PI3K/AKT/VEGFA signaling ( Song et al. 2021 ), and hypoxic exosomes enriched in miR-21 polarize macrophages ( Xiao et al. 2020 ). Urinary exosomal miR-200c-3p and circ_0109046 are promising non-invasive biomarkers ( Shi et al. 2020 ).

In cervical cancer, HPV-driven exosomes carry survivin ( Honegger et al. 2015 ) and miRNAs (miR-21, miR-146a, and miR-221) that regulate EMT, angiogenesis, and metastasis. lncRNAs such as HOTAIR and MALAT1 ( Guo et al. 2020 ) and proteins linked to Hedgehog and RAS signaling ( Bhat et al. 2018 ) enhance drug resistance and progression. In ovarian cancer, the deadliest gynecological malignancy, exosomes are enriched in CD9, CD63, HSPs, EpCAM, and CA-125 ( Wyciszkiewicz et al. 2019 ). They drive angiogenesis, metastasis, and platinum resistance via annexin A3 ( Yin et al. 2012 ). Exosomal miRNAs (miR-21, miR-200, and miR-221) regulate invasion, drug resistance, and angiogenesis, with several (e.g., miR-200f and miR-21) being tested as liquid biopsy markers ( Yoshida et al. 2020 ).

In preeclampsia, responsible for 10–15% of fetal deaths, placental exosomes are elevated ( Salomon & Rice 2017 ). They carry altered syncytin proteins ( Pillay et al. 2016 ), pro-coagulant tissue factors ( Gardiner et al. 2011 ), and dysregulated miRNAs (↓miR-23a-3p, ↓miR-144-3p, ↑let-7a-5p, and ↑miR-221-3p) that impair angiogenesis and trophoblast invasion ( Truong et al. 2017 ). Conversely, MSC-derived exosomes enriched in VEGF or miR-18b promote vascular repair ( Esfandyari et al. 2021 ). Placental trophoblast-derived exosomes containing disease-specific miRNAs (hsa-miR-525-5p, hsa-miR-526b-5p, and hsa-miR-1269b) are being explored as early biomarkers ( Truong et al. 2017 , Jahanbani et al. 2023 b ).

The diagnosis of male infertility-related disorders has shown encouraging preliminary outcomes through exosome research. Several studies highlight that exosome-associated proteins, particularly annexin II, play a critical role in male fertility and may serve as promising biomarkers for male infertility disorders ( Kowalczyk et al. 2022 ). Early evidence from Diamandis et al. (1999) demonstrated that levels of prostaglandin D2 synthase (PTGDS), an enzyme-coding gene product, declined progressively from healthy individuals to azoospermic patients, reaching almost undetectable levels in vasectomized men ( Diamandis et al. 1999 ). Follow-up studies further confirmed the diagnostic potential of PTGDS, showing that its expression was significantly reduced in obstructive azoospermia (OA) patients compared to those with non-obstructive azoospermia (NOA) ( Heshmat et al. 2008 ) ( Fig. 2 ).

Overall, research investigating the role of exosomes in the pathophysiology of reproductive system disorders is advancing rapidly and has yielded valuable insights. However, despite these promising findings, the clinical application of exosomes as FDA-approved biomarkers remains unrealized, emphasizing the need for further validation through large-scale and standardized studies ( Jahanbani et al. 2023 a ).

Sex-dependent reproductive effects of chemotherapy-associated exosomes

Exosomes are abundant in circulating body fluids and reflect the molecular state of their cells of origin, carrying diverse cargos such as proteins, RNAs, and DNA ( Feng et al. 2019 ). Beyond their established role as cancer biomarkers, exosomes are now recognized as key mediators of intercellular communication, influencing immune regulation, cellular survival, and tissue homeostasis ( Alharbi et al. 2021 ). In the context of chemotherapy, circulating exosomes have emerged as important contributors to systemic, sex-specific reproductive outcomes by transmitting bioactive signals that affect gonadal function and fertility-related processes.

Experimental evidence indicates that exosomes derived from human umbilical cord MSCs (h-UCMSC-Exo) can protect testicular tissue from chemotherapy-associated injury. Using in vitro Sertoli cell models and prepubertal mouse models exposed to cyclophosphamide and busulfan, h-UCMSC-Exo preserved the SSC niche, reduced cellular damage, and improved fertility outcomes. Repeated exosome administration was associated with enhanced testosterone production and higher fertility success rates, highlighting a potential fertility-preserving strategy for prepubertal boys undergoing chemotherapy ( Liakath Ali et al. 2023 ). Given the sex-dependent nature of reproductive vulnerability and recovery, Table 1 summarizes the major exosome-mediated effects of chemotherapy on female and male reproductive systems.

Female reproductive system

In females, chemotherapy-associated exosomes have been extensively studied in reproductive system cancers, where they also provide insight into systemic reproductive effects relevant to oncofertility. Exosomal proteins and non-coding RNAs participate in immune modulation, cellular survival, and tissue remodeling within the ovarian and uterine microenvironments.

Proteomic profiling of exosomes from female reproductive cancers has identified cargos linked to angiogenesis, immune regulation, and cellular stress responses, processes that are closely related to ovarian and endometrial function. Similarly, exosomal miRNAs regulate signaling pathways involved in cell survival, inflammation, and vascular remodeling, thereby shaping tissue responses following chemotherapy exposure ( He et al. 2019 b ). Beyond miRNAs, exosomal lncRNAs and circRNAs contribute to transcriptional and epigenetic regulation, influencing apoptosis, DNA repair, and immune responses, all of which are critical determinants of reproductive tissue resilience after systemic therapy ( Alharbi et al. 2021 ).

Importantly, immune-modulatory exosomes derived from tumor and stromal cells influence macrophage polarization, T-cell activity, and cytokine secretion in ovarian and uterine tissues. These immune effects may indirectly affect follicular survival, endometrial receptivity, and long-term reproductive outcomes following chemotherapy ( Masoumi-Dehghi et al. 2020 ). Collectively, these findings suggest that chemotherapy-associated exosomes contribute to female reproductive vulnerability or recovery through coordinated effects on immune balance, cellular stress responses, and tissue remodeling.

Male reproductive system

In males, semen represents a unique source of reproductive exosomes, with a substantial proportion originating from the prostate and accessory glands ( Roberts et al. 2011 , Barceló et al. 2019 ). Seminal exosomes carry proteins and regulatory RNAs that influence spermatogenesis, sperm maturation, and immune regulation within the male reproductive tract.

Chemotherapy-associated alterations in exosomal cargo have been linked to changes in germ cell survival, endocrine signaling, and testicular immune homeostasis. Exosomal miRNAs regulate apoptosis, proliferation, and oxidative stress responses in spermatogenic and somatic testicular cells, processes that are central to fertility preservation following gonadotoxic treatments ( Mashouri et al. 2019 ). In addition, exosome-mediated communication between Sertoli and Leydig cells influences testosterone synthesis and testicular recovery after systemic chemotherapy exposure ( Liang et al. 2021 ).

Prostate-derived exosomes (prostasomes) further illustrate how circulating and seminal exosomes reflect systemic treatment effects while directly modulating male reproductive function. Although extensively studied in prostate cancer, their ability to regulate immune evasion, lipid metabolism, and cellular stress responses also has implications for reproductive health in cancer survivors ( Ronquist & Nilsson 2004 , Barceló et al. 2019 ).

Exosomes in regenerative and therapeutic strategies in oncofertility

Exosomes are increasingly recognized as active mediators of tissue repair and functional recovery, making them attractive tools for fertility preservation and restoration. As naturally occurring nanovesicles secreted by many cell types, exosomes deliver proteins, lipids, and regulatory RNAs that can promote cell survival, modulate inflammation, enhance angiogenesis, and support tissue remodeling ( Kalluri & LeBleu 2020 ). Compared with stem cell transplantation, exosome-based therapy offers a cell-free and more controllable approach with reduced concerns related to immune rejection and uncontrolled cell behavior ( Haider & Aramini 2020 , Haider & Aramini 2020 , Kalluri & LeBleu 2020 ). In reproductive medicine, exosomes derived from reproductive tissues (e.g. endometrium, follicular cells, embryos, oviduct, and seminal plasma) contribute to physiological communication ( Sun et al. 2019 ); however, for therapeutic applications, MSC-derived exosomes (from bone marrow, adipose tissue, umbilical cord, placenta, and amniotic sources) are most widely investigated because they are accessible and show strong regenerative activity ( Fig. 3 ) ( Chen & Yu 2022 ) ( Table 2 ).

Exosomes in female fertility preservation

A growing body of evidence now supports the use of stem cell-derived exosomes as effective tools for preserving female fertility and promoting reproductive recovery. Importantly, these nanoscale vesicles act as cell-free mediators capable of restoring ovarian and uterine function and improving fertility-related outcomes ( Chiu et al. 2018 ). In preclinical models relevant to fertility preservation, MSC-derived exosomes (MSC-Exos) have consistently been shown to enhance follicle survival and support endocrine recovery by improving granulosa cell viability and limiting apoptosis ( Borghese et al. 2020 ). Consequently, these protective effects are often accompanied by restoration of ovarian reserve markers and improved follicular architecture, reinforcing the concept that exosomes function as regenerative signals within the ovary ( Fig. 4 ).

In addition to direct cellular protection, angiogenesis plays a pivotal role in successful ovarian recovery, and exosomes have been repeatedly linked to vascular support. For instance, adipose-derived MSC exosomes improve endothelial cell function and stimulate angiogenic signaling, thereby helping to reestablish the microvascular environment required for folliculogenesis and corpus luteum formation ( Casagrande et al. 2019 ). At the same time, exosome-mediated anti-inflammatory activity further contributes to ovarian preservation. By suppressing NF-κB activation and reducing pro-inflammatory cytokine expression, exosomes create a more permissive ovarian milieu that supports follicle maintenance and growth ( Chu et al. 2019 ).

Beyond ovarian protection, therapeutic exosomes have also demonstrated promising regenerative effects within the uterus. In models of thin endometrium, umbilical cord MSC-derived exosomes improved endometrial epithelial cell viability while attenuating inflammatory signaling ( Liang et al. 2021 ). Similarly, in Asherman’s syndrome, adipose-derived MSC exosomes promoted tissue remodeling, enhanced angiogenesis, and facilitated regeneration of a more functional endometrial structure ( Gharibeh et al. 2022 ). Taken together, these findings highlight a coordinated role for MSC-derived exosomes in supporting both ovarian and endometrial recovery through integrated effects on cell survival, vascularization, and inflammatory balance.

Finally, pharmacological strategies aimed at fertility preservation are continuing to expand. Tamoxifen has been reported to exert ovarian protective effects in gonadotoxic settings ( Nynca et al. 2023 ). Notably, transcriptomic analyses suggest that lncRNA-mediated regulation contributes to these protective mechanisms in tumor-bearing models ( Oktay et al. 2003 , Swigonska et al. 2024 ). Within the context of oncofertility, these observations provide a strong rationale for further investigating exosome-associated non-coding RNAs as therapeutic mediators or biomarkers of female fertility preservation following cancer treatment.

Exosomes in male fertility preservation

In male oncofertility, therapeutic strategies increasingly focus on restoring spermatogenesis, protecting germ cells, and re-establishing endocrine function. Alongside established fertility preservation approaches – such as sperm cryopreservation and testicular tissue cryopreservation ( Goossens et al. 2020 ) – exosome-based therapy is emerging as a promising cell-free modality with the potential to support testicular repair and functional recovery ( Vickram et al. 2021 ).

In particular, MSC-derived exosomes have demonstrated notable regenerative effects in preclinical models. These vesicles promote germ cell survival and enhance spermatogenic activity by activating pro-survival and stress-response signaling pathways. For example, bone marrow MSC-derived exosomes protected spermatogonia and supported recovery of spermatogenesis in gonadotoxic injury models ( Guo et al. 2021 ). Moreover, related studies indicate that MSC-derived exosomes can facilitate hormonal recovery and improve overall testicular function, including restoration of testosterone production in chemotherapy-associated hypogonadism models ( Liang et al. 2023 ).

Beyond stem cell sources, testicular cell-derived exosomes provide an additional and physiologically relevant therapeutic avenue ( Gao et al. 2023 ). Sertoli cell-derived exosomes carry microRNAs that regulate apoptosis, proliferation, and differentiation of SSCs, underscoring their role as endogenous regulators of spermatogenic recovery ( Wang et al. 2023 ). A2t the same time, exosome-mediated communication between Sertoli and Leydig cells contributes to the regulation of steroidogenesis and maintenance of testicular homeostasis, thereby supporting recovery of endocrine function ( Ma et al. 2021 ).

In addition, alternative regenerative exosome sources are being actively explored. Amniotic fluid-derived exosomes have been shown to improve spermatogenesis indices and sperm parameters in azoospermia models, suggesting that they may represent an accessible and effective cell-free option for future translational applications ( Mobarak et al. 2021 ). Taken together, these findings position exosomes as promising therapeutic candidates for male fertility preservation, with mechanistic relevance to germ cell support, intercellular communication within the testis, and recovery of endocrine function following gonadotoxic cancer therapies.

Exosomes as delivery platforms and nanotherapeutics in oncofertility

Beyond their regenerative roles, exosomes are increasingly recognized as versatile delivery platforms that may support fertility-sparing cancer therapies in oncofertility settings ( Fig. 5 ). Owing to their nanoscale size, intrinsic stability, low immunogenicity, and ability to cross biological barriers, exosomes provide a natural nanocarrier system capable of improving therapeutic precision while potentially limiting off-target toxicity to reproductive tissues ( Chen et al. 2021 a ). Nevertheless, challenges such as rapid systemic clearance and limited tissue targeting remain barriers to clinical translation. To address these limitations, bioengineering strategies have been developed, including internal cargo loading with drugs, nucleic acids, or gene-editing tools, as well as surface modification to enhance tissue-specific delivery ( Patil et al. 2020 , Jahanbani et al. 2023 a ).

In gynecological cancers, exosome-based nanotherapeutic approaches have demonstrated promising anticancer efficacy with improved targeting profiles. In ovarian cancer, exosomes loaded with miR-199a-3p suppressed C-met signaling, resulting in reduced tumor cell proliferation and aggressiveness ( Yumura et al. 2018 ). More advanced strategies include tumor-derived exosomes engineered to deliver CRISPR/Cas9 plasmids, which enabled efficient silencing of PARP-1 and induction of apoptosis in ovarian cancer cells ( Kim et al. 2019 ). In endometrial cancer, cancer-associated fibroblast-derived exosomes carrying miR-320a inhibited tumor growth by downregulating HIF-1α and VEGFA expression, further highlighting the versatility of exosome-mediated delivery systems ( Zhang et al. 2020 ).

Additional studies underscore the adaptability of exosome-based nanoplatforms for drug and nucleic acid delivery. Exosome membrane-coated nanoparticles improved siRNA stability and enhanced in vivo tumor suppression ( Zhao et al. 2020 ), while aspirin-loaded exosomes increased drug solubility and cytotoxic efficacy ( Tran et al. 2019 ). In cervical cancer models, MSC-derived exosomes delivering inhibitory oligonucleotides targeting miR-142-3p and miR-150 significantly reduced tumor progression ( Naseri et al. 2018 ). Moreover, milk-derived exosomes transporting anthocyanidins or curcumin demonstrated superior antiproliferative and anti-inflammatory effects compared with free compounds in ovarian and cervical cancer models ( Aqil et al. 2017 , Bai et al. 2020 ).

Furthermore, preclinical studies demonstrate that exosome-based and synthetic nanocarrier systems can efficiently deliver small interfering RNAs (siRNAs) and other nucleic acid cargos to tumor cells, achieving robust gene silencing while limiting off-target exposure ( Jangde et al. 2025 ). In prostate cancer (PC) models, lipid nanoparticles, polymeric carriers, metallic nanoparticles, and exosome-mimetic vesicles have been shown to enhance siRNA stability, intracellular uptake, and tumor selectivity ( Saeinasab et al. 2024 ).

Targeted delivery of oncogene-directed siRNAs (e.g., EGFR, AR, and SNHG15) using ligand-functionalized nanocarriers – such as PSMA-, folate-, or EpCAM-targeted systems – resulted in marked tumor growth inhibition, apoptosis induction, and suppression of metastatic potential in vitro and in xenograft models ( Heris et al. 2023 , Saeinasab et al. 2024 ). Importantly, by improving delivery precision, these approaches may reduce dependence on aggressive chemoradiotherapy, thereby indirectly preserving spermatogenesis and endocrine balance ( Jangde et al. 2025 ).

From a reproductive safety perspective, preclinical evidence also highlights potential risks. Nanocarriers may accumulate in non-tumor tissues, including testes, depending on size, surface charge, and biodegradability ( Jangde et al. 2025 ). Although siRNA sequence specificity limits unintended gene silencing, experimental models indicate that poorly optimized nanocarriers can impair spermatogenesis, alter testicular architecture, and disrupt hormonal signaling ( Shafi et al. 2013 ). These findings emphasize the need for fertility-aware nanocarrier design and biodistribution profiling.

Recent preclinical work has expanded the scope of exosome-based fertility preservation by exploring cell -free, primed sEVs as nanotherapeutics for premature ovarian insufficiency (POI) ( Seegobin et al. 2025 ). In a cyclophosphamide-induced granulosa cell (GC) injury model, primed avian MSC-derived sEVs (primed AMSC-sEVs) demonstrated superior physicochemical stability and bioactivity compared with naïve sEVs, exhibiting smaller and more uniform particle size, higher vesicle concentration, and increased negative zeta potential – features associated with enhanced cellular uptake and therapeutic performance ( Shieh et al. 2025 ). Functionally, primed sEVs restored GC proliferation, suppressed apoptosis, and rescued steroidogenic capacity, reversing chemotherapy-induced reductions in AMH, FSHR, LHCGR, estradiol, and progesterone. These effects were accompanied by downregulation of pro-apoptotic markers (cleaved caspase-3, BAX, and PARP) and upregulation of BCL-2. Mechanistically, next-generation sequencing revealed enrichment of fertility- and survival-associated miRNAs, including miR-21, miR-22, miR-23b, miR-145, and miR-199a, implicating coordinated post-transcriptional regulation of apoptosis and steroidogenesis. Although confined to in vitro human granulosa cell models, this study provides compelling proof-of-concept evidence that engineered or primed sEVs can enhance the regenerative efficacy of exosome-based nanotherapies, supporting their future translation for fertility preservation and early ovarian insufficiency management ( Shieh et al. 2025 ).

Beyond direct drug delivery, engineered exosomes also offer opportunities for immunomodulation and biodistribution control. For example, exosomes have been engineered to modulate immune responses, redirecting effector cell activity and opening new avenues for cancer immunotherapy ( Cheng et al. 2018 ). In parallel, modulation of nanoparticle biodistribution using peripheral blood-derived exosomes has been shown to reduce hepatic accumulation and enhance therapeutic efficiency of plant-derived nanovectors ( Wang et al. 2018 ).

On the other hand, tumor-derived exosomes actively shape anti-tumor immunity by transferring immunosuppressive cargos, including immune checkpoint molecules, cytokines, and regulatory RNAs, thereby modulating T-cell activation and antigen presentation ( Caserta et al. 2024 ). Notably, exosomal PD-L1 has been shown to suppress cytotoxic T-cell responses and contribute to resistance against immune checkpoint inhibitors, positioning exosomes as both biomarkers and functional mediators of immunotherapy response ( Silva et al. 2019 ). Conversely, immune cell-derived and engineered exosomes are being explored as novel immunotherapeutic platforms capable of delivering tumor antigens, immune-stimulatory RNAs, or drugs to enhance anti-tumor immunity with reduced systemic toxicity ( Huang et al. 2023 ).

Preclinical studies have also highlighted the regenerative potential of umbilical cord-derived MSC exosomes (UC-MSC-Exos) as a cell-free alternative for treating intrauterine adhesions (IUAs) ( Xin et al. 2022 ). In a rat model of endometrial injury, UC-MSC-Exos incorporated into a collagen scaffold (CS/Exos) significantly enhanced endometrial regeneration, promoted collagen remodeling, restored estrogen receptor-α and progesterone receptor expression, and ultimately recovered fertility ( Xin et al. 2020 ). Mechanistically, CS/Exos therapy exerted strong immunomodulatory effects, driving CD163 + M2 macrophage polarization, suppressing local inflammation, and enhancing anti-inflammatory signaling both in vivo and in vitro . RNA-sequencing analyses identified exosome-enriched miRNAs as key mediators of macrophage reprogramming and tissue repair. Although limited to animal models, this work provides compelling proof-of-concept that combining exosomes with biomaterial scaffolds can overcome poor retention and delivery efficiency, supporting their future translation as regenerative therapies. Although this study was not conducted in an oncological setting, the regenerative mechanisms identified are highly relevant to fertility preservation and may inform future oncofertility interventions aimed at restoring uterine function after cancer treatment ( Xin et al. 2020 ).

In ovarian cancer models, tumor-derived exosomes promote immune suppression by enhancing regulatory T-cell (Treg) activity and inhibiting cytotoxic immune responses through immunosuppressive factors such as TGF-β1 and interleukin-10 (IL-10) ( Gong et al. 2023 ). Exosomes isolated from ovarian cancer ascites have been shown to induce apoptosis of peripheral blood lymphocytes and dendritic cells (DCs), further impairing anti-tumor immune surveillance ( Inagaki et al. 2016 , Nakamura et al. 2019 ). At the same time, ovarian cancer-derived exosomes carry tumor-associated antigens, including EpCAM and CD44, supporting their potential use as immunogenic platforms for targeted immunotherapy ( Grasso et al. 2015 ). Experimental studies also highlight the complexity of exosome-mediated immune regulation. While dendritic cell-derived exosomes can stimulate T-cell activation, tumor-derived exosomes expressing Fas ligand (FasL), TRAIL, or galectin-9 can induce apoptosis of CD8 + T cells and suppress T-cell receptor signaling pathways, thereby promoting immune tolerance ( Klibi et al. 2009 ).

Within the context of oncofertility, these delivery-based strategies are particularly relevant, as targeted exosome-mediated therapies may achieve effective tumor control while reducing systemic exposure and preserving reproductive potential. When integrated with regenerative approaches, exosome-based nanotherapeutics represent a complementary strategy aimed at balancing cancer treatment efficacy with long-term fertility preservation in reproductive-age patients.

Translational and clinical perspectives of exosomes in reproductive disorders

Building on the strong body of preclinical evidence, recent years have witnessed the first steps toward clinical translation of exosome-based regenerative strategies in reproductive medicine. While most data supporting the protective and reparative effects of stem cell-derived exosomes originate from animal models and in vitro studies, these findings have laid the groundwork for early-phase human investigations. Accordingly, a limited but growing number of registered clinical trials have now begun to evaluate the safety, feasibility, and preliminary efficacy of exosome-based interventions in patients with reproductive dysfunction. In addition, while clinical translation of exosome-based therapies has begun to emerge in female reproductive disorders corresponding clinical studies in male infertility remain scarce. This disparity highlights a clear translational gap and underscores the need for well-designed clinical trials to evaluate the safety, efficacy, and long-term outcomes of exosome-based therapies in male oncofertility. These studies represent critical milestones in bridging experimental discoveries with real-world clinical applications in oncofertility and fertility preservation ( Park et al. 2024 ).

A registered human clinical study ( ClinicalTrials.gov Identifier: NCT06841328 ) is currently investigating the safety and feasibility of intra-gonadal administration of adipose-derived stem cells (ADSCs) or stem cell-derived exosomes in patients with gonadal failure, including POF, ovarian insufficiency, hypogonadism, and testicular dysfunction. This open-label, single-arm pilot study enrolls both male and female participants who have shown inadequate responses to conventional treatments such as hormone replacement therapy or assisted reproductive technologies. The intervention involves direct intraovarian or intratesticular injection, with longitudinal follow-up at 3, 6, 9, and 12 months to assess hormonal recovery (e.g. estradiol, testosterone, follicle stimulating hormone (FSH), and AMH), structural gonadal changes, reproductive function, and treatment-related adverse events.

Beyond gonadal regeneration, clinical translation of exosome-based therapies has also expanded toward uterine and endometrial repair, addressing another major cause of infertility in cancer survivors and women with refractory reproductive disorders. In contrast to intra-gonadal approaches, recent clinical efforts have focused on the regenerative capacity of stem cell-derived exosomes within the endometrium, particularly in cases of thin endometrium and severe intrauterine adhesions. In this context, a registered prospective clinical study ( ClinicalTrials.gov ID: NCT06896747 ) is currently evaluating the safety and efficacy of umbilical cord-derived MSC exosomes for the treatment of thin endometrium secondary to severe intrauterine adhesions. This non-randomized, parallel-controlled trial compares mechanically engineered exosomes with conventional exosomes and platelet-rich plasma (PRP), a widely used regenerative intervention in reproductive medicine. Participants receive a single hysteroscopically guided subendometrial injection during the proliferative phase of the menstrual cycle. The primary endpoint is improvement in endometrial thickness, while secondary outcomes include implantation rate, clinical pregnancy rate, live birth rate, miscarriage rate, and safety assessments. Importantly, this study introduces mechanically engineered exosomes, produced through biophysical modulation during stem cell culture, with the aim of enhancing regenerative potency compared to conventional exosomes.

Moreover, Reza et al. (2016) demonstrated that conditioned medium derived from human adipose mesenchymal stem cells (hAMSCs) suppressed ovarian cancer (OC) cell growth by inducing cell cycle arrest and mitochondria-mediated apoptosis. Notably, exosomes isolated from hAMSC-conditioned medium enhanced these effects through upregulation of pro-apoptotic markers, including BAX, CASP9, and CASP3, and downregulation of the anti-apoptotic protein BCL2. Exosomal miRNAs were identified as key mediators of these anticancer effects ( Reza et al. 2016 ).

In parallel, Li et al. reported that exosomes isolated from malignant ascites of OC patients carried tumor-associated antigens capable of being presented by dendritic cells derived from unrelated cord blood, leading to tumor-specific cytotoxic immune responses. This finding supports the use of exosome-based immunotherapeutic strategies in OC ( Li et al. 2008 a ). Furthermore, Bretz et al. showed that ascites-derived exosomes activated Toll-like receptor-dependent pathways in mononuclear precursor cells, triggering broader immune activation. These observations underscore the role of exosomes in shaping tumor immunity.

Investigation has explored the regenerative potential of autologous platelet-derived exosomes for ovarian rejuvenation in women with diminished ovarian reserve. The Exosomas 2024-1 trial ( ClinicalTrials.gov ID: NCT06773572 ) represents one of the first randomized, double-blind clinical studies directly comparing exosome-based ovarian therapy with platelet-derived growth factors and placebo. This prospective pilot study enrolled 30 women aged 38–46 years with established diminished ovarian reserve who declined oocyte donation. Participants were randomized into three treatment arms receiving intraovarian injections of i) autologous platelet-derived exosomes, ii) activated platelet growth factors (PRP), or iii) physiological saline as control. Treatments were administered monthly over four consecutive menstrual cycles during the early follicular phase. The rationale for this intervention was grounded in age-related ovarian stromal fibrosis, mitochondrial dysfunction, oxidative stress, and depletion of key regenerative signals, including reduced expression of exosomal markers (CD63 and CD81) and regulatory microRNAs (miR-21, miR-125, miR-132, and miR-199). Autologous exosomes were isolated from platelet-rich plasma using standardized protocols, yielding highly concentrated vesicle preparations (approximately 5–6 trillion exosomes/mL) for targeted ovarian delivery.

Clinical outcomes were evaluated through hormonal profiling (FSH, estradiol, and AMH) and antral follicle count, measured before treatment initiation and after the final intervention. By directly comparing exosomes with PRP and placebo, this study provides early clinical evidence suggesting that cell-free exosome therapy may exert superior regenerative effects on ovarian function relative to conventional platelet-based approaches.

Translation of exosome-based immunotherapy into the clinic has been most advanced in the context of dendritic cell-derived exosomes (Dexs). Following the seminal discovery by Raposo et al. (1996) that exosomes participate in antigen presentation and acquired immunity, Dexs were developed as cell-free cancer vaccines capable of delivering tumor antigens and major histocompatibility complex (MHC) molecules to elicit antigen-specific T-cell responses ( Gong et al. 2023 ). Importantly, phase I clinical trials have confirmed the feasibility and safety of Dex-based vaccines, demonstrating that exosome-based immunotherapies can be administered to patients without significant toxicity while inducing measurable immune activation ( Jaiswal & Sedger 2019 , Saumell-Esnaola et al. 2022 ). These trials represent a pivotal milestone that enabled the transition of exosome research from experimental immunology to clinical oncology.

In ovarian cancer, translational studies further support immunotherapeutic relevance, as higher intratumoral T-cell infiltration correlates with improved survival outcomes ( Yang et al. 2020 b ). Building on these observations, combination strategies integrating exosome-based antigen delivery with immune adjuvants, such as Toll-like receptor-3 (TLR3) agonists, have been proposed to overcome tumor-induced immune tolerance and potentially prolong progression-free survival in patients with high-grade ovarian cancer ( Adams et al. 2005 ).

Collectively, these studies demonstrate that exosomes derived from MSCs or tumor-associated fluids can modulate apoptosis, antigen presentation, and immune signaling in ovarian cancer. Within the context of oncofertility, such approaches are particularly relevant, as exosome-based therapies may enable effective tumor control while reducing systemic toxicity and preserving reproductive potential. Accordingly, exosomes represent promising tools for integrating cancer treatment with fertility preservation strategies in female reproductive system malignancies ( Table 3 ).

Biological limits of regeneration in the reproductive system

Despite the rapid expansion of regenerative research in oncofertility, it is essential to clearly distinguish between functional recovery and true biological regeneration within the reproductive system. Unlike highly regenerative tissues such as skin or liver, reproductive organs operate under strict biological constraints that fundamentally limit their capacity for de novo germ cell formation ( Mäkelä & Hobbs 2019 , Martin et al. 2019 ).

In the female reproductive system, the idea of new oocyte formation in adult ovaries remains highly controversial. The prevailing consensus supports the concept that the ovarian reserve is finite and established early in life, with follicle depletion occurring progressively thereafter ( Martin et al. 2019 ). To date, no definitive experimental or clinical evidence has demonstrated sustained de novo oogenesis in adult mammals, including humans ( Saitou 2009 ). As a result, interventions described as ‘regenerative’ in ovarian biology typically reflect preservation of existing follicles, enhancement of follicular survival, or restoration of stromal and endocrine support, rather than true germ cell neogenesis ( Brinster & Zimmermann 1994 , De Rooij 2017 , Lord & Oatley 2017 ).

A similar distinction applies to the male reproductive system. While adult testes retain SSCs that support continuous spermatogenesis, recovery after gonadotoxic injury primarily depends on the survival, activation, and niche support of these pre-existing cells ( Mäkelä & Hobbs 2019 , Kalluri & LeBleu 2020 ). Importantly, this process represents functional restoration rather than the generation of entirely new germ cell lineages ( Mäkelä & Hobbs 2019 ).

Within these biological boundaries, exosomes have emerged as potent regulators of cell survival, angiogenesis, immune modulation, and microenvironmental repair. Extensive preclinical evidence shows that exosome-based interventions can improve ovarian and testicular function by reducing apoptosis, limiting oxidative stress, enhancing vascularization, and stabilizing germ cell niches ( Yang et al. 2020 a , Chen & Wang 2022 , Liu et al. 2023 , Izadpanah et al. 2024 ). However, despite these benefits, no study to date has conclusively shown that exosomes induce true germ cell neogenesis in either female or male reproductive organs.

Notably, the majority of evidence supporting exosome-mediated fertility restoration arises from animal models, where outcomes are commonly assessed through improved hormone levels, follicle counts, spermatogenic indices, or reproductive performance ( Turner et al. 2021 , Rives et al. 2022 , Dimik et al. 2023 ). While encouraging, these endpoints reflect functional recovery rather than structural regeneration. In humans, clinical evidence remains limited, and there is no proof that exosome-based therapies can generate new oocytes or germ cells ( Jahanbani et al. 2023 b , Ghasroldasht et al. 2025 ).

Taken together, exosomes represent promising tools for fertility preservation and tissue repair, but their regenerative capacity must be interpreted within the inherent biological limits of the reproductive system. Recognizing this distinction is critical for precise terminology, realistic clinical expectations, and responsible translation of preclinical findings into oncofertility practice ( Sehring et al. 2021 , Wyns et al. 2021 ).

Challenges and future directions

Despite the remarkable progress in understanding the diagnostic and therapeutic potential of exosomes, particularly exosomal lncRNAs, significant challenges still limit their clinical application. Issues related to isolation, characterization, and standardization remain unresolved, while biological questions about selective cargo loading, donor–recipient specificity, and exosome heterogeneity continue to complicate their use. Addressing these obstacles is essential for advancing exosome-based strategies from experimental models to effective clinical tools in oncology and reproductive medicine.

Therapeutic application faces its own barriers. While exosomes are being engineered as drug delivery systems, limitations include efficient drug loading, optimizing producer–target cell pairing, and ensuring ligand–receptor specificity for targeted uptake. Rapid clearance by macrophages and their short half-life in vivo ( Parada et al. 2021 ) further reduce efficacy. To counter this, bioengineering approaches, such as combining exosomes with biomaterials, are being explored to improve retention and controlled release at target sites ( Chen et al. 2022 , Jahanbani et al. 2022 ).

Recent studies have highlighted the promise of exosome–biomaterial hybrids. For example, UC-MSC-derived exosomes combined with collagen scaffolds enhanced endometrial repair in rats, not only improving ERα and PR expression but also significantly increasing pregnancy rates ( Xin et al. 2020 ). Similarly, PEG hydrogel systems carrying AMSC-derived exosomes provided antibacterial protection and long-term release for endometrial regeneration and fertility restoration ( Lin et al. 2021 ).

Exosomal lncRNAs have drawn considerable interest as potential diagnostic and prognostic biomarkers, owing to their secretion by nearly all cell types and detectability in body fluids. However, their clinical translation remains hampered by technical and biological challenges ( Hosseini et al. 2022 ).

Isolation and purification remain among the greatest hurdles. Ultracentrifugation yields high-purity vesicles but is time-consuming, costly, and requires specialized equipment, while other methods often result in contamination from lipoproteins or ribonucleoprotein complexes, complicating downstream analysis – especially when RNA yields are low ( Hosseini et al. 2022 ). Likewise, RNA extraction methods are highly variable; Eldh et al. (2012) demonstrated that yield, purity, and size distribution differ markedly across protocols, emphasizing the need to match methods to research goals ( Tellez-Gabriel & Heymann 2019 ).

Characterization and quantification pose additional limitations. Distinguishing tumor-derived exosomes from those secreted by normal cells remains difficult, particularly in plasma samples where platelet-derived RNAs dominate. The available detection platforms – including flow cytometry, ELISA, and nanoparticle tracking analysis – offer valuable insights but are hindered by high costs, contamination risks, and inconsistent reproducibility ( Makler & Asghar 2020 ). For lncRNA profiling, RT-qPCR is widely used due to affordability and practicality, while NGS and microarrays provide comprehensive data but remain resource-intensive. Digital PCR (dPCR) is emerging as a more sensitive option, but requires further validation ( Wu et al. 2020 ).

Biological questions also remain unresolved. Why certain lncRNAs are selectively packaged into exosomes, how donor–recipient specificity is maintained, and the degree to which exosomes alter the activity of their own cargo are still poorly understood ( Yuan & Huang 2021 ). Contradictory findings further complicate interpretation – for instance, Yang et al. (2019) reported that HOTAIR upregulation enhanced exosome release in hepatocellular carcinoma, while other studies observed the opposite effect ( Li et al. 2021 ). Moreover, tumors secrete heterogeneous populations of exosomes, each potentially carrying distinct molecular signatures. Systematically classifying these subtypes – akin to the classification of blood cells – could enhance their precision as biomarkers and therapeutic agents ( Karamian et al. 2021 ).

Finally, the field is witnessing a transition from discovery to translation. Early research focused heavily on plasma and serum exosome profiling for biomarker discovery. Today, attention is shifting toward clinical validation, with studies evaluating efficacy, safety, treatment combinations, and measurable outcomes ( Mohan et al. 2026 ). This evolution underscores the shift from foundational research toward applied clinical applications in oncology and reproductive medicine.

Conclusion

In conclusion, chemotherapy effectively treats cancer but often causes long-term harm to reproductive function in both women and men. These effects represent a major quality-of-life issue for cancer survivors. Exosomes have emerged as important players in this process, reflecting cellular damage while also offering new opportunities for diagnosis and therapy. Their ability to carry biologically active molecules makes them valuable biomarkers of reproductive toxicity and promising tools for fertility protection and restoration. Although technical and biological challenges still limit their clinical use, continued research, improved standardization, and careful clinical evaluation may enable exosomes to bridge cancer treatment and reproductive health. Ultimately, they hold the potential to support cancer survival while preserving reproductive capacity.

Declaration of interest

The authors have no relevant financial or non-financial interests to disclose.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Author contribution

MMA and IMS conceived the study. MMA, BA, KA, AA, and IMS prepared the original draft of the manuscript. MMA, BA, KA, AA, and IMS reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

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