Emerging roles of exosomes in diagnosis, prognosis, and therapeutic potential in ovarian cancer: a comprehensive review

Ovarian cancer remains a significant global health challenge with high mortality rates due to late detection and chemoresistance [1]. Despite advancements in treatment approaches, the prevalence of this disease continues to rise, indicating a need for the accurate identification of early diagnostic markers and novel targeted therapeutic strategies [2]. Although chemotherapy is the cornerstone of treatment, drug resistance creates a significant challenge, leading to recurrence and poor prognosis of the disease [3]. This need has resulted in recent studies being focused on the potential role of exosomes as predictive biomarkers and therapeutic targets in cancer [4, 5]. Exosomes are secreted by various cell types, including cancer cells. They play a crucial role in intercellular communication, facilitating tumor progression, metastasis, and drug resistance [6]. Exosomes are small extracellular vesicles (30–150 nm in diameter) formed when multivesicular bodies fuse with the plasma membrane and release their intraluminal vesicles into the extracellular space. This biogenesis process, regulated by the endosomal sorting complex required for transport machinery and other molecular mechanisms, results in vesicles containing specific carogo that reflects their cell of origin. The unique molecular composition of exosomes, specifically proteins, lipids, and nucleic acids, reflects the physiological state of the parent cells, rendering them attractive candidates for diagnostic, prognostic biomarkers, and therapeutic applications for cancers [7].

Exosomes associated with ovarian cancer have been implicated in several key processes contributing to chemoresistance, including drug efflux, modulation of apoptotic pathways, and the establishment of a tumor-supportive microenvironment [8, 9]. Furthermore, exosomes derived from chemoresistant ovarian cancer cells exhibited distinct molecular signatures, potentially serving as predictive markers for treatment response and disease progression [10]. Notably, exosomes have been shown to have the potential to be therapeutic delivery vehicles, capable of encapsulating and delivering therapeutic agents, such as small molecule drugs, nucleic acids, and proteins, to target cancer cells [11, 12].

This comprehensive review aims to summarize and discuss the role of exosomes as predictive markers and potential therapeutic targets for chemoresistance in ovarian cancer. Findings from the present study would contribute valuable information to the ongoing efforts to improve patient outcomes and advance the management of ovarian cancer.

All publications from 4 October 2005 to 30 June 2024 were collected from MEDLINE (via PubMed). The search terms were “ovarian cancer,” “extracellular vesicles or exosome,” and “cisplatin or carboplatin or docetaxel or paclitaxel or doxorubicin resistance”. The search criteria were original research articles published in English. Forty-four articles were found to be relevant (comprising 43 in vitro studies, 24 in vivo studies, and 18 clinical studies) and were included in this comprehensive review.

Data from clinical studies that investigated the alterations in the profiles of exosomal protein and gene expression in samples of chemosensitive and chemoresistant ovarian cancer patient are shown in Table 1. In chemosensitive ovarian cancer tissues, increased expression of the following proteins and genes was observed: UCA1, circ_C20orf11, circ_PIP5K1A, miR-21-5p, miR-1246, DNMT1, CLPTM1L, GATA3, circ_0025033, and PANDAR, when compared to non-cancerous ovarian tissue [13,14,15,16,17,18,19,20,21,22]. The expression of UCA1, circ_C20orf11, circ_PIP5K1A, and miR-21-5p was also significantly higher in chemoresistant patients than in chemosensitive patients [17, 19, 21, 22]. Additionally, miR-6836 and circ_0007841 were upregulated in chemoresistant ovarian cancer cases in comparison to chemosensitive cases, however there was no comparison to normal ovaries [23, 24].

Conversely, the expression of miR-18a-5p and Cdr1as was decreased in chemosensitive ovarian cancer compared to non-cancerous ovaries, and this decrease was more pronounced in chemoresistant ovarian cancer [25, 26]. Previous studies have shown a decrease in the expression of miR-181c in chemosensitive ovarian cancer tissues when compared to non-cancerous [27]. Furthermore, a decrease in the expression of Bifidobacterium longum was observed in chemoresistant ovarian cancer when compared to chemosensitive ovarian cancer tissues [28].

The prognosis and survival of ovarian cancer patients have been shown to be closely associated with the levels of expression of proteins and genes, including Circ_C20orf11, PANDAR, miR-1246, CLPTM1L, GATA3, miR-6836, miR-18a-5p, circFoxp1, and Annexin A3 [14, 16, 18, 20, 21, 24, 25, 29, 30]. Elevated expression of Circ_C20orf11, PANDAR, miR-1246, GATA3, miR-6836, and circFoxp1 has been identified as a significant indicator of poor overall survival in ovarian cancer patients [14, 16, 24, 29]. Similarly, high levels of Annexin A3 have shown a correlation with a markedly decreased disease-free time [30]. CLPTM1L overexpression has been linked to both poor overall survival and unfavorable progression-free survival outcomes [18]. In contrast, low expression of miR-18a-5p has been found to be indicative of reduced survival compared to high miR-18a-5p expression in ovarian cancer patients [25]. These data suggest that several proteins and genes have the potential to serve as biomarkers for predicting chemosensitivity in ovarian cancer patients. It is important to note that the expression of these proteins and genes is obtained from cancer tissue, which requires invasive procedures. Therefore, the detection of proteins or genes in the serum that are involved in chemosensitivity could provide a more feasible approach for developing predictive biomarkers.

In serum samples, circFoxp1 and annexin A3 levels were increased in chemosensitive ovarian cancer when compared to healthy controls and were further elevated in chemoresistant patients [29, 30] Serum miR-6836 levels were increased only in chemosensitive patients, while miR-18a-5p levels were decreased when compared to healthy controls [24, 25]. Serum UCA1 and circ_C20orf11 levels were higher in chemoresistant ovarian cancer than in those with chemosensitive cancer, whereas a reduction in serum. Cdr1as levels was observed in cases of chemoresistant when compared to chemosensitive ovarian cancer [17, 21, 26]. There are no reports on the levels of serum UCA1, circ_C20orf11, and Cdr1as in healthy controls [17, 21, 26]. While these findings are promising, several technical and biological challenges must be acknowledged in the clinical application of exosomal biomarkers. Current exosome isolation techniques face limitations including low extraction rates, variable purity, and high processing costs, which could impact the feasibility of large-scale clinical implementation. Additionally, the heterogeneous nature of exosomes in body fluids presents a unique challenge, as variations in exosome numbers and content could potentially lead to false results in tumor diagnosis. However, recent technological advances offer potential solutions to these challenges. The development of microfluidic-based isolation techniques has shown promise in improving extraction efficiency and purity while reducing costs. Furthermore, the combination of multiple exosomal markers, rather than relying on single markers, could enhance diagnostic accuracy and overcome the heterogeneity issue.

Therefore, while changes in these exosomal markers correlate with other types of cancer, such as breast cancer and lung cancer [31,32,33], their clinical utility could be optimized through a comprehensive diagnostic approach. We propose that the analysis of serum exosomal biomarkers when combined with traditional clinical examinations and emerging isolation technologies, could provide a powerful tool for non-invasive monitoring of chemotherapy response in ovarian cancer patients. Future studies focusing on standardization of isolation methods and validation of multi-marker panels will be crucial in translating these findings into clinical practice.

Various epithelial ovarian cancer cell lines have been used to test whether chemosensitivity influences changes in the expression of exosomal proteins and genes. The expressions of UCA1, circFoxp1, circ_C20orf11, circ-PIP5K1A, CLPTM1L, circ_0025033, and circ_0007841 were increased in chemosensitive ovarian cancer cells when compared to normal ovarian cells [15, 17,18,19, 21, 29]. Their expression levels were further elevated in chemoresistant cells [15, 17,18,19, 21, 29]. Conversely, miR-1246 expression increased in chemosensitive cells, but not in chemoresistant cells, when compared to normal ovarian cells [16]. DNMT1 and GATA3 were also upregulated in chemosensitive cells; however, their expression levels were not compared between chemosensitive and resistant cells in these studies [13, 14]. The expression of PANDAR, pGSN, miR-21, miR-433, miR-548aq-3p, hsa-miR-675-3p, EpCAM-specific EVs, miR-21-5p, miR-21-3p, and miR-891-5p was increased in chemoresistant ovarian cancer cells in comparison to chemosensitive cells, but findings were not compared to the proteins in normal ovarian cells [8, 20, 22, 34,35,36,37,38,39].

On the other hand, Cdr1as and miR-181c showed a decreased level of expression in chemosensitive ovarian cancer cells, with an even greater decrease in Cdr1as expression in chemoresistant cells [26, 27]. These findings indicate distinct exosomal protein and gene expression profiles in association with chemosensitivity in ovarian cancer cells, which could serve as potential biomarkers and therapeutic targets for further investigation. Data from in vitro studies that investigated the alterations in exosomal protein and gene expression profiles in chemosensitive and chemoresistant cell lines are shown in Table 2.

Several studies reported that exosomal proteins and genes are involved in the chemotherapeutic sensitivity of ovarian cancer [40, 41]. Gene modification by miRNA transfection, or the addition of exosomes/extracellular vesicle (EVs), has been used to confirm the roles of the exosomes in the level of aggressiveness of ovarian cancer [8, 42]. Exosomal miRNAs also played a significant role in modulating chemosensitivity and cell behavior in ovarian cancer [43, 44]. The transfection of miR-21 decreased apoptosis in chemosensitive ovarian cancer cells [8]. The transfection of miR-429 increased the IC50 of cisplatin at 24 h, while its knockdown decreased the level of IC50, suggesting a role of miR-429 in chemoresistance [45]. The addition of miR-18a-5p derived from human mesenchymal stem cell EVs (hMSC-EVs) decreased cell viability and number in chemosensitive ovarian cancer cells, while its knockdown had the opposite effect [25]. In chemoresistant ovarian cancer cells, miR-18a-5p also decreased colony formation, whereas its knockdown increased colony formation [25]. Addition of exosomes derived from fetal bovine serum treated with cisplatin or exosomes derived from A2780cis cells increased the invasiveness of chemosensitive ovarian cancer cells [46, 47]. Similarly, small EVs derived from ovarian cancer spheroids treated with cisplatin for 24 h enhanced cell migration in chemosensitive ovarian cancer cells [48]. Intriguingly, these findings reveal a complex interplay between exosomal content and chemoresistancedevelopment. The paradoxical effects of different miRNAs suggest the existence of multiple, potentially competing pathways in chemoresistance regulation. Most notably, while miR-21 and miR-429 promote chemoresistance, miR-18a-5p demonstrates tumor-suppressive properties, highlighting the context-dependent nature of miRNA function. The diversity in miRNA effects presents both a challenge and an opportunity for therapeutic development. Although it complicates the development of simple therapeutic approaches, it simultaneously offers multiple potential intervention points for personalized treatment strategies [8, 25, 45].

Conversely, the addition of EVs containing Bifidobacterium longum (B. longum-EVs) at 10 μg/ml decreased cell viability, proliferation, migration, and invasion, as well as increasing apoptosis in chemosensitive ovarian cancer cells [28]. Furthermore, incubation with exosomes derived from cord blood-expanded natural killer cells (eNK-Exo) at 10–100 μg/ml for 24 h decreased the rate of cell survival and the EdU/DAPI ratio in chemosensitive ovarian cancer cells, with a more pronounced effect in chemoresistant ovarian cancer cells, with no effect on non-cancerous cells [49]. The differential effects of various exosome sources represent a particularly promising avenue for therapeutic development. The selective toxicity of eNK-Exo towards cancer cells while sparing normal cells suggests a potential breakthrough in addressing one of chemotherapy’s greatest challenges. Moreover, the discovery that B. longum-EVs can reduce cancer cell aggressiveness opens an entirely new therapeutic frontier, potentially linking the microbiome to cancer treatment through exosomal mechanisms. This finding could revolutionize our approach to combination therapy, suggesting that probiotic interventions might enhance conventional chemotherapy through exosome-mediated effects.

These observations collectively point to three critical insights: First, the source of exosomes appears to be as important as their content in determining their effects on cancer cells. Second, the dual nature of exosomes—both as potential therapeutic agents and as mediators of chemoresistance—suggests they might serve as “double agents” in cancer treatment, requiring careful therapeutic targeting. Third, the selective effect of certain exosomes on cancer cells versus normal cells indicates the possibility of developing highly targeted therapies with minimal side effects.

Therefore, these exosomes, including exosomes derived from fetal bovine serum treated with cisplatin, exosomes derived from A2780cis cells, small EVs derived from ovarian cancer spheroids treated with cisplatin for 24 h, exosomes derived from cord blood-expanded natural killer cells, and exosomes containing miR21, miR-429, miR-18a-5p, and Bifidobacterium longum might be novel therapeutic targets for reducing the aggressiveness of ovarian cancer. A summary of data regarding the effects of exosomal proteins or genes in ovarian cancer cells is shown in Supplementary Table 1.

The modulation of exosomal proteins and genes was tested in mice with xenografts. In chemosensitive ovarian cancer models, addition of exosomal DNMT1, miR-6836, and tumor-associated macrophage-derived extracellular vesicles (TAM-EVs) carrying GATA3 increased tumor volume [13, 14, 24]. Moreover, TAM-Evs carrying GATA3 increased tumor weight, and decreased apoptosis and inflammation in the tumor [14]. In addition, the administration of exosomal PANDAR resulted in an increase in ascites and the number of metastatic nodules in the abdomen of chemosensitive ovarian cancer mice [20]. One study in chemoresistant ovarian cancer mice, reported that adding exosomes derived from cisplatin-resistant A2780cis cells resulted in increased tumor volume and weight [47]. These findings reveal a crucial mechanistic link between exosomal content and tumor progression, particularly highlighting how specific exosomal cargo can influence both primary tumor growth and metastatic potential. The consistent observation that multiple exosomal components (DNMT1, miR-6836, GATA3, and PANDAR) can promote tumor growth suggests a complex network of exosome-mediated signaling in the tumor microenvironment [13, 14, 20, 24, 47]. To translate these promising findings into clinical applications, several critical areas require further investigation.

A summary of data regarding the effects of exosomal proteins or genes in mice with ovarian cancer is shown in Supplementary Table 2.

Chemotherapeutic agents, including cisplatin, carboplatin, paclitaxel, and docetaxel, have been used to treat ovarian cancer cells, and the effects of modulating exosomal proteins and genes on chemosensitivity have been extensively reported [8, 9, 13,14,15, 17,18,19,20,21,22,23,24, 26,27,28,29, 34, 35, 37, 39, 50,51,52,53,54]. In chemosensitive ovarian cancer cells, addition of exosomal proteins such as DNMT1, GATA3, TIE-1, circFoxp1, PANDAR, and UCA1 and also exosomal miRNAs, including miR-98-5p, miR-6836, miR-21-5p, miR-21-3p, miR-891-5p, miR-433, and miR-21, and exosomes derived from platinum-resistant cells (CP70 and C30) decreased the antitumor effects of chemotherapy [8, 9, 13, 14, 17, 20, 24, 29, 34, 39, 51, 52]. These effects included an increase in cell survival, proliferation, colony formation, invasion, migration, and IC50, while decreasing the level of apoptosis and DNA damage [8, 9, 13, 14, 17, 20, 24, 29, 34, 39, 51, 52]. Interestingly, miR-181c caused a contrasting effect, increasing the antitumor effects of chemotherapy by decreasing cell viability and IC50, and increasing apoptosis [27]. Conversely, the absence of exosomal PANDAR, miR-6836, miR-21-5p, miR-214, and circ_C20orf11 enhanced the antitumor effect of chemotherapy, causing a decrease in cell viability, colony formation, invasion, and migration, and increasing apoptosis [20,21,22, 24, 54]. However, a lack of exosomal Cdr1as, miR-181c, and miR-146a diminished the antitumor effects of chemotherapy, increasing cell proliferation, viability, and IC50, and decreasing apoptosis [26, 27, 53]. All of these findings suggest that the modulation of exosomal proteins and miRNA plays a crucial role in chemosensitive ovarian cancer cells. The presence of specific exosomal components, such as DNMT1, GATA3, TIE-1, circFoxp1, PANDAR, UCA1, various miRNAs(miR-98-5p, miR-6836, miR-21-5p, miR-21-3p, miR-891-5p, miR-433, and miR-21) and exosomes derived from platinum-resistant cells (CP70 and C30) can decrease the antitumor effects of chemotherapy [8, 9, 13, 14, 17, 20, 22, 24, 29, 34, 39, 51, 52]. Conversely, the presence of certain exosomal components, including Cdrlas, miR-181c, and miR-146a can enhance the antitumor effects of chemotherapy [26, 27, 53].

In chemoresistant ovarian cancer cells, the addition of exosomal Cdr1as, miR-181c, and Bifidobacterium longum increased the antitumor effect of chemotherapy, by decreasing cell proliferation, viability, invasion, migration, and IC50, and increasing apoptosis [26,27,28]. On the other hand, the lack of exosomal UCA1, circPIP5K1A, circ_0007841, miR-548aq-3p, circ_C20orf11, CLPTM1L, and circ_0025033 increased the antitumor effect of chemotherapy, decreasing cell proliferation, viability, colony formation, invasion, migration, and IC50, and increasing apoptosis [15, 17,18,19, 21, 23, 37]. However, the lack of miR-181c resulted in a different effect in this context, the antitumor effect of chemotherapy diminishing as shown by an increase in cell viability and IC50, and decreasing apoptosis [27].

It has been shown that the exosomal protein plasma gelsolin (pGSN) mediates chemoresistance by decreasing apoptosis in chemosensitive ovarian cancer cells [35]. However, the role of pGSN remains controversial, as another study reported that addition of pGSN to ovarian cancer cells did not alter the effects of chemotherapy regards decreasing apoptosis in chemosensitive cells [50]. The discrepancy in these findings may be attributed to the differences in the cell lines used in the experiments. Variations in cell lines can significantly influence their response to chemotherapy and the mechanisms that regulate apoptosis, potentially leading to inconsistent results. To clarify the role of pGSN in ovarian cancer chemoresistance, future studies need to employ standardized cell lines and experimental conditions to ensure comparability and reproducibility of results. Interestingly, the lack of pGSN increased the antitumor effects of chemotherapy by increasing apoptosis in chemoresistant ovarian cancer cells [35, 50]. These findings suggest the complex roles of exosomal proteins and miRNAs in modulating the chemotherapeutic response, potentially contributing to the development of chemoresistance in ovarian cancer. These findings demonstrate the complex roles of exosomal proteins and miRNAs in modulating chemotherapeutic response and reveal critical insights into chemoresistance development in ovarian cancer, including the hierarchical organization of exosomal signaling, resistance thresholds affecting cellular responses, and context-dependent functions. These insights suggest promising therapeutic strategies, such as combination therapies targeting multiple exosomal pathways, smart approaches considering cellular resistance states, personalized treatments based on patient exosomal profiles, and resistance reversal using sensitizing exosomal components. A summary of data regarding the effects of exosomal proteins and genes in chemotherapy treated-ovarian cancer cells is shown in Table 3 and Fig. 1.

In vitro studies (left) demonstrate how exosomal factors, when added/transfected or knocked down, affect cell viability and apoptosis. In vivo studies (right) show the impact of exosomal components on tumor volume and weight in ovarian cancer mouse models under chemotherapy treatment. Red arrows indicate tumor progression, while blue arrows indicate favorable outcomes. Upward and downward arrows denote increase and decrease in the measured parameters, respectively.

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In chemosensitive ovarian cancer mouse models, addition of exosomal UCA1, miR-548aq-3p, CAFs-derived exosomal miR-98-5p, and miR-429 attenuated the antitumor effects of chemotherapy by increasing tumor volume and/or weight [17, 37, 45, 51]. Conversely, the absence of miR-429 reduced the antitumor effect of chemotherapy by resulting in a decrease in tumor volume, while the absence of Cdr1as had the opposite effect, enhancing the antitumor effect of chemotherapy by decreasing both tumor volume and weight [26, 45].

In chemoresistant ovarian cancer mouse models, the absence of circ_C20orf11, circ-PIP5K1A, CLPTM1L, circ_0007841, circFoxp1, and miR-1246 potentiated the antitumor effect of chemotherapy by causing a decrease in tumor volume and/or weight [16, 18, 19, 21, 23, 29]. However, the absence of miR-18a-5p attenuated the antitumor effect of chemotherapy evidenced by increased tumor volume and weight [25]. The addition of miR-18a-5p enhanced the antitumor effect of chemotherapy by reducing tumor volume and weight [25]. Similarly, the addition of miR-181c, derived from bone marrow stem cell extracellular vesicles (BMSCs-EVs), potentiated the antitumor effect of chemotherapy in chemoresistant ovarian cancer mice by decreasing tumor volume and weight and increasing apoptosis [27]. These findings highlight the potential for exosomal proteins and genes to modulate tumor growth and chemotherapeutic response in ovarian cancer. The data suggest that exosomal UCA1, miR-548aq-3p, miR-98-5p, miR-429, circ_C20orf11, circ-PIP5K1A, CLPTM1L, circ_0007841, circFoxp1, miR-1246 may contribute to chemoresistance, while, miR-18a-5p, and miR-181c and Cdrlas may enhance chemosensitivity in ovarian cancer [16,17,18,19, 21, 23, 25,26,27, 29, 37, 45, 51]. The identification of specific exosomal components that contribute to chemoresistance or enhance chemosensitivity provides a foundation for the development of novel therapeutic strategies targeting these proteins and genes. These exosomal proteins and genes may also serve as potential biomarkers for predicting chemotherapy response and monitoring treatment efficacy in ovarian cancer patients. Future studies could focus on validating these findings in a clinical setting and explore the mechanisms underlying the observed effects to facilitate the translation of these discoveries into clinical applications. A summary of data regarding the effects of exosomal proteins or genes in animal models of chemotherapy treated-ovarian cancer is shown in Table 4 and Fig. 1.

Effects of exosomal loaded chemotherapy on chemosensitivity in chemotherapy-treated ovarian cancer: evidence from in vitro studies

Exosomal loaded chemotherapy demonstrated superior anti-cancer effects in comparison to chemotherapy alone in both chemosensitive and chemoresistant ovarian cancer cell lines, as evidenced by in vitro studies. The results are shown in Table 5.

In chemoresistant ovarian cancer cell lines, exosomal-loaded chemotherapy exhibited greater benefits to antitumor effects than conventional chemotherapy [55]. Cisplatin-loaded milk exosomes had a more potent antitumor effect as indicated by a decrease in cell viability, while cisplatin-loaded umbilical cord-derived macrophage exosomes increased apoptosis in those resistant cell lines [56, 57]. Doxorubicin-loaded nanovesicles further reduced cell viability, colony formation, healing rate, and migration in chemoresistant ovarian cells when compared to doxorubicin alone [58]. Milk exosome-loaded anthocyanidins (Anthos) effectively reduced cell survival and IC50 in chemoresistant ovarian cancer cells [59]. Similarly, paclitaxel-loaded lipid nanogels decreased cell viability more effectively in drug-resistant ovarian cancer cells compared to paclitaxel alone [60]. In chemosensitive and chemoresistant ovarian cancer cells, cisplatin-loaded exosomes derived from cord blood (eNK-Exo) decreased cell survival and increased apoptosis, while doxorubicin-loaded lemon-derived extracellular vesicles with heparin-cRGD-EVs loaded doxorubicin (HRED) reduced cell viability and elevated the levels of reactive oxygen species (ROS) compared to their respective chemotherapy agents alone [49, 61].

Furthermore, the combination of exosomal-loaded chemotherapy with other agents showed promising results. EXO-TMP (exosome-loaded tetramethylpyrazine) combined with paclitaxel reduced cell viability more effectively and increased apoptosis in chemoresistant ovarian cancer cells when compared to TMP and paclitaxel alone [62]. In chemoresistant ovarian cancer cells, miR-497 and triptolide (TP) encapsulated in hybrid nanoparticles (miR497/TP-HENPs) caused enhanced antitumor effects by decreasing cell viability and increasing apoptosis when compared to triptolide alone [63].

These findings indicated the potential for exosomal-loaded chemotherapy in combination with other therapeutic agents to overcome chemoresistance and possibly enhance antitumor effects in ovarian cancer cell lines. The superior antitumor effects of exosomal-loaded chemotherapy, when compared to conventional chemotherapy can be attributed to several factors. Exosomes protect the encapsulated chemotherapeutic agents from degradation and enhance their stability, increasing bioavailability and therapeutic efficacy [64]. Moreover, exosomes facilitate targeted delivery of chemotherapeutic agents to tumor cells, reducing off-target effects and minimizing systemic toxicity [65]. The natural composition of exosomes, including lipids, proteins, and nucleic acids, facilitates efficient cellular uptake and intracellular drug release, further enhancing the anticancer effects of the loaded chemotherapeutic agents [66]. Exosomes derived from specific cell types, such as immune cells or mesenchymal stem cells, may also possess intrinsic antitumor properties that can act in synergy with the loaded chemotherapeutic agents to potentiate their anticancer effects [67]. The use of exosomes as drug delivery vehicles, particularly, it appears, when combined with complementary agents, present as a promising strategy for improving the efficacy of chemotherapy in chemoresistant ovarian cancer.

In chemoresistant ovarian cancer mice, milk exosome-loaded cisplatin decreased tumor volume more effectively than cisplatin alone [57]. Similarly, lemon-derived extracellular vesicles with HRED exhibited a more potent antitumor effect when compared to doxorubicin alone evidenced by decreased tumor volume/weight with increased apoptosis [61]. Doxorubicin-loaded nanovesicles also demonstrated superior antitumor effects compared to doxorubicin alone by reducing tumor volume and weight in chemoresistant ovarian cancer mice [58]. Paclitaxel-loaded lipid nanogels showed antitumor effects comparable to paclitaxel alone in reducing tumor volume in chemoresistant ovarian cancer mice [60]. Moreover, miR-497 and triptolide (TP) co-encapsulated in hybrid nanoparticles (miR497/TP-HENPs) exhibited enhanced antitumor effects evidenced by decreasing tumor volume more effectively than triptolide alone [63].

In a chemosensitive ovarian cancer mice model, Anthos-loaded milk exosomes also exhibited a more potent antitumor effect than Anthos alone evidenced by a greater decrease in tumor volume [59]. Treatment with a combination of exosomal-loaded chemotherapy with other agents showed promising results.

The superior antitumor effects of exosomal-loaded chemotherapy in ovarian cancer mouse models can be attributed to several factors. Exosomes protect encapsulated chemotherapeutic agents from degradation, enhance stability, increase bioavailability and therapeutic efficacy, facilitate targeted delivery to tumor cells, and reduce off-target effects and systemic toxicity [64, 65]. They also allow for efficient cellular uptake and intracellular drug release [66]. In addition, exosomes derived from specific cell types may possess intrinsic antitumor properties that act in synergy with loaded chemotherapeutic agents, potentiating their anticancer effects [67]. These unique features highlight the potential of exosomal-loaded chemotherapy, particularly when applied in combined with complementary agents, to overcome chemoresistance and possibly enhance antitumor effects in ovarian cancer mouse models, making exosomes promising vehicles for the delivery of chemotherapeutic agents. A summary of data pertinent to the effects of exosomal-loaded chemotherapy in animal models of chemotherapy-treated-ovarian cancer is shown in Table 6.

Profiles of exosomal protein and gene expression differ between chemosensitive and chemoresistant forms of ovarian cancer, with several exosomal components being upregulated or downregulated in chemoresistant ovarian cancer (Fig. 1). The modulation of specific exosomal proteins and genes can influence ovarian cancer cell phenotypes and chemotherapeutic response. Exosomal delivery of chemotherapeutic agents presents as a promising strategy for targeted drug delivery and the overcoming of chemoresistance in ovarian cancer.