Exosomes, which can be seen as cup-shaped objects under electron microscopy, are vesicles actively produced extracellularly by various live cells (15–17). The cell membrane invaginates to generate endosomes, multiple endosomes merge to form Early-Sorting Endosomes (ESE), and then ESE invaginates once more to wrap intracellular material and form numerous vesicles, which further convert into Late-Sorting Endosomes (LSE) (18, 19). Several tightly controlled mechanisms are involved in producing, sorting, and releasing the exosome’s contents. Several molecules, including the Endosomal Sorting Complex Needed for Transport (ESCRT), four transmembrane proteins (CD9, CD63, and CD81), the apoptosis-linked gene 2-interacting protein X (Alix), and the tumor susceptibility gene 101(TSG101), are involved in the intracellular transport of the exosome (20–22). The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein complex and the family of synaptic binding proteins are necessary for the production of exosomes ( Figure 1 ) (23).

Exosomes are vital in transmitting materials and information between cells (24). They can reach the appropriate target cells or organs by direct fusion, endocytosis, receptor-ligand interaction, and other mechanisms (25, 26). Intercellular communication and biological processes like antigen presentation, immunological response, and cell differentiation are regulated by endometriosis in the body (27, 28). Endometriosis are involved in intercellular communication activities and govern biological processes, including antigen presentation, immunological response, and cell differentiation, thereby partaking in the initiation and progression of diseases (2, 29, 30). Proteomics analyses have shown exosomes from different cellular origins are heterogeneous (31, 32). Exosomes can physiologically affect many cells and tissues because of their various contents (33, 34). Exosomes from a healthy microenvironment may help preserve the target cells’ function. Still, exosomes from a stressful microenvironment might cause damage by sending oxidative and inflammatory signals to the target tissues (35). So, it is suggested that exosomes serve as significant intercellular communication carriers and can transport bioactive chemicals from their source cells, which may be crucial for intercellular communication (36–38).

While exosomes represent a potential tool for endometriosis diagnosis, their efficient purification without cellular contamination is a limiting factor (39). The primary techniques for isolating exosomes are gradient density centrifugation, differential ultracentrifugation, polymer immunoprecipitation, gel exclusion separation, and membrane affinity kits. One of the most popular separation techniques nowadays is ultracentrifugation, and the purest separation can be achieved using ultracentrifugation in combination with sucrose gradient density centrifugation (40). Exosomes have a low level of toxicity, are highly bioavailable, and are biologically stable (41). Consequently, it is anticipated that the identification and isolation of disease-specific exosomes free of cellular exosomes that are typically contaminated will shed new light on the advancement of precision medicine (42). Due to the size and physicochemical characteristics of exosomes, which differ from those of lipoproteins and protein complexes, as well as the fact that a variety of cells secretes exosomes, there is still much to learn about how to isolate and purify exosomes, which is a bottleneck problem in basic research and clinical applications related to exosomes.

LncRNAs are a family of RNAs with transcripts longer than 200 nucleotides frequently present in eukaryotic genomes but do not code for proteins (43, 44). Most lncRNAs can be found in the cytoplasm or nucleus of a cell and are produced from a single strand inside a protein-coding gene sequence (45). Antisense Bidirectional lncRNAs share promoters with protein-coding genes but are transcribed in the opposite direction to protein-coding genes; long intergenic ncRNAs (lincRNAs) are produced from the complementary DNA strand of the protein-coding gene, which is transcribed in the opposite direction and overlaps with at least one exon of the forward gene. Intronic lncRNAs are found in the protein-coding gene’s intron region and do not overlap with its exons (46, 47).

Recent research has shown that lncRNAs are crucial for maintaining intracellular homeostasis when cells or tissues mature (48). This dispels the myth that noncoding RNAs (ncRNAs) are just “transcriptional noise” with no biological purpose (49, 50). It has been demonstrated that LncRNAs have a role in a variety of physiological and pathological processes (51, 52). Via epistasis, transcription, post-transcription, and acting as mediators of biological processes, lncRNAs are implicated in the regulation of apoptosis: epistasis lncRNAs can bind to Pol II to repress DNA expression, bind to DNA to form a triple helix structure to regulate, and can bind to transcription factors or recruit transcription-related factors to target genes to regulate the transcription of target genes (53–55). These lncRNA-specific structures or sequences can be specific sites on genomic DNA and can recruit the chromatin reconstruction complex (56, 57). The post-transcriptional regulation impacts the binding shear body and regulates the shearing process of mRNA by binding to antisense lncRNA at the target region of mRNA ( Figure 2 ) (58, 59).

Before being translated into protein, pre-mRNA is specially spliced in the nucleus to generate mature mRNA, which is subsequently translocated from the heart to the ribosome in the cytoplasm. Only when the structural gene ultimately succeeds in producing an active protein is the gene considered functional (60). Several studies have demonstrated that lncRNAs can control mRNA translation in various ways (61). mRNA transport can be impacted by lncRNAs, which in turn control adipogenesis. In addition to acting as an insulin-sensitizing hormone to lower blood sugar and encourage adipogenesis, lncRNAs are an endogenous bioactive peptide released by adipocytes during lipogenesis. AdipoQ ASlncRNA joins forces with AdipoQ mRNA to create a double-strand in the nucleus, preventing AdipoQ mRNA from moving from the core to the cytoplasm suppressing adipogenesis. In order to play a part in controlling the stability of the target genes, lncRNA often attaches to the relevant mRNA or particular protein to form an RNA-RNA or RNA-protein complex (62). Antisense lncRNAs’ cytoplasmic binding to sense mRNAs is a typical example of this regulation. It has been demonstrated that lncRNAs can associate with RNA-binding proteins (RBPs) to create RNA-protein complexes that subtly control the stability of mRNA (63).

LncRNAs can indirectly regulate the expression of target genes by competing for binding one or more miRNAs with the same response element, thereby promoting or inhibiting the onset or progression of disease (64, 65). This is a critical distinction between lncRNAs and miRNAs: the latter cannot interfere with or activate gene expression. LncRNAs can interact with miRNAs as a competitive endogenous RNA (ceRNA), functioning as a “sponge” for the miRNA molecule and easing its stress (66). This is one of the many ways lncRNAs and miRNAs function in cells. The ceRNA mechanism is a large and delicate method of gene expression control whose expression level is affected by conditions (67). LncRNAs, circRNAs, pseudogenes, synthetic miRNA inhibitors, and viral miRNA inhibitors are currently ceRNAs (68).

LncRNAs can regulate gene expression and immune system responses, demonstrating biological processes’ tissue specificity and complexity (69). Involved in the body’s intrinsic and adaptive immunity, lncRNAs are crucial to many physical and immunological methods. The etiology of autoimmune and inflammatory illnesses is influenced by lncRNAs, such as lincRNA-Cox2 and lncRNA-dendritic cells (DC) (70). Numerous significant pathways connected to endometriosis are enriched in lncRNAs. Transient Receptor Potential (Trp) ion channels and thyroid hormone production were discovered to produce large amounts of inflammatory mediators, which suggests that lncRNAs may regulate the expression of inflammatory and immunological components linked to endometriosis (71). Inflammatory reactions may develop and be controlled in part by lncRNAs. According to immunological research, epigenetic dysregulation of B cells, which includes aberrant lncRNA expression, histone changes, and altered DNA methylation, might result in the body producing pathogenic autoantibodies. Endometriosis and autoimmune disorders share a biological mechanism with lncRNAs. Current hormonal and surgical treatments for endometriosis may be improved if the concept of immunomodulatory therapy for autoimmune illnesses is extended to the treatment of endometriosis (72, 73).

Reverse regulatory RNA, siRNA competitive binding, and target gene stability regulation are techniques that LncRNAs can use to control target genes (74). LncRNAs can work as ceRNAs to control the expression of target genes, altering how well those genes function and becoming a key player in the emergence of disease (75, 76). MiR-199a can compete with vascular endothelial growth factor (VEGF)-A for the binding site on the lncRNA ENST00000465368, which reduces miR-199a’s ability to bind to its target gene VEGF-A and weakens miR-199a (77). Inducing downstream signaling pathways, endothelial cell proliferation and migration, increased microvascular permeability, promotion of neovascularization, and successful ectopic endothelial implantation are all made possible by the angiogenesis-specific regulator VEGF-A, which binds to its receptor (78, 79). A decrease in the expression of Syndecan-1 (SDC1), a cell adhesion molecule, could result from downregulating the expression of lncRNANR 033688. This could enhance the repressive effect of miR-10b on its target gene SDC1, which would reduce cell-cell and cell-matrix adhesion, facilitating the invasion of ectopic endometrial glandular epithelial cells (80). The growth of endometriosis and the interactions between miRNAs and lncRNAs are tightly connected, and endometriosis proliferation, invasion, and metastasis are all significantly impacted by these factors (81, 82).

Endometrial glands and stromal implants, known as endometriosis, are found inside the uterine cavity but develop outside (100). Even though endometriosis is a benign condition, it is frequently described as “benign cancer” due to its local infiltration, implantation, metastasis, and recurrence (101–105). Surgery is an invasive procedure with some dangers, and pathological examinations take too long to diagnose endometriosis. More significant and of theoretical relevance are future investigations into the pathogenesis of endometriosis and the hunt for novel biomarkers and molecular targets for diagnosis and therapy (106). An essential characteristic of endometriosis is the enhanced capacity of endometrial cells to infiltrate and migrate (107). Endometriosis lesions adhere extensively or densely to the tissues around them, and many different lesions exist. lncRNAs play a significant role in controlling human disease, physiology, and cancer (108, 109). As elaborated in section 6.3, more researchers are discovering that lncRNAs are abnormally expressed in endometriosis patients and play a role in controlling the progression of the illness due to the in-depth study of lncRNAs in recent years. Exosome extracellular nucleotidase was discovered to be a diagnostic sign for endometriosis in ovarian endometriosis cysts.

The pathogenesis and pathophysiology of endometriosis, classified as chronic inflammatory illnesses, are significantly influenced by immunological variables. However, only a tiny portion of the population has endometrial fragments that spread, grow, and eventually develop into endometriosis. This is likely because of changes in the internal environment of endometriosis patients, such as immune imbalance, and the ectopic lesions are typically accompanied by inflammatory congestion and inflammatory infiltration (110). Many women experience the “menstrual reflux” phenomenon multiple times. One of the clinical classification indicators of endometriosis is the degree of inflammation. The abnormal immune function in endometriosis patients is primarily exhibited in two ways: on the one hand, it is a compromised immunosurveillance and immunocidal cytotoxic effect, which prevents the body from effectively clearing the endothelium; and on the other hand, it is a compromised immune environment in the abdominal cavity, which interferes with pregnancy and causes spots. Infertility, repeated implantation failure, early miscarriage, and aberrant histogenesis are related to endometriosis worsened by the peripheral circulating immune system and female endometrial autoimmune imbalance ( Figures 3 , 4 ) (111).

Patients with endometriosis frequently experience infertility, and aberrant changes in endometrial status and uterine artery flow resistance can impact endometrial tolerance and, in turn, affect pregnancy and prognosis (130–132). Studies have revealed that the in situ endometrium of endometriosis exhibits a marked reduction in H19 expression (133). H19 usually is abundantly expressed in late-proliferating ESCs, whereas in the situ endometrium of endometriosis, its expression is downregulated. Low levels of H19 raise the activity of miRNALet-7, which in turn suppresses in situ ESC proliferation and survival and inhibits the downstream target insulin-like growth factor 1 receptor (IGF1R) at the post-transcriptional level. This results in situ endometrial defects, which affect endometrial tolerance and obstruct embryo implantation. By interfering with the H19/Let-7/IGF1R regulation system, endometriosis patients may experience spontaneous miscarriage or infertility due to diminished endometrial readiness and pregnancy receptivity. Through controlling miR-124-3p and Integrin beta-3 (ITGB3), lncRNA-H19 downregulation may prevent the proliferation and invasion of ectopic endometrial cells. This gives the treatment of endometriosis a new target (134).

Endometriosis can hinder oocyte growth and maturation, and as endometriosis levels rise, so does the disruption of ovarian reserve function. The expression of lncRNMALAT1 is increased in ectopic endometrial tissue (135). Through increasing the EMT-related transcription factors ZEB1 and ZEB2, MALAT1, a ceRNA of miR-200C, can support ESCs, boosting proliferation, invasion, and ectopic pregnancy. In ovarian granulosa cells of endometriosis, the expression of lncRNA-MALAT1 was markedly downregulated and positively associated with the number of sinus follicles (136). Further in vitro research supported the hypothesis that MALAT1 knock-down could affect follicular granulosa cell proliferation by activating the ERK/MAPK signaling pathway and up-regulating the expression of cell cycle regulatory proteins and that up-regulating the lncRNAENST00000433673 could affect embryo implantation and impair female fertility (137–139).

Exosome lncRNAs have proven to offer promise as non-invasive biomarkers for determining the presence of illness. In endometriosis, lncRNA AC002454.1 is considerably overexpressed, and the expression level is closely associated with cyclin-dependent kinase6(CDK6) levels (140). The biological behavior of endometrial cells may be cooperatively influenced by AC002454.1 and CDK6, which may work in concert to encourage the growth of endometriosis (141). In the endometrial tissues of endometriosis patients and healthy individuals, 86 lncRNAs showed differential expression. KEGG pathway analysis revealed that these lncRNAs were connected to various biological functions and signaling pathways in endometriosis (142). The lncRNA ENST00000482343 in the serum of endometriosis patients could be used as a potential molecular marker, according to earlier studies that examined the differential expression profiles of lncRNAs in 110 serum samples and 24 tissue samples and assessed their diagnostic value using the receiver operating characteristic curve. In ovarian endometriotic tissues, Urothelial Cancer Associated 1 (UCA1) expression was markedly downregulated, and the extent of UCA1 downregulation was positively connected with the severity of ovarian endometriosis (143). UCA1 might be used as a biomarker to evaluate the prognosis and staging of ovarian endometriosis (143). HOXA11-AS1 and HOXA gene mRNA fragments Patients with endometriosis had considerably lower expression levels in their in situ endometrium than in their ectopic endometrium, which raises the possibility that HOXA11-AS1 may be involved in the growth of peritoneal endometriosis (144).

In comparison to in situ and normal endometrium, ectopic endometrium expressed TC0101441 at a greater level. High expression of TC0101441 in ECSCs produced EVs, which were subsequently internalized and absorbed by low-expression ECSCs to achieve TC0101441 transfer in ECSCs and eventually encourage endometriosis migration and invasion (145). Women with endometriosis had less maternally expressed gene 3 (MEG3)-210 in their ectopic endometrium (146). ESC migration and invasion are encouraged by the downregulation of MEG3-210. Through interacting with Galectin-1 via p38MAPK and cyclic AMP-dependent protein kinase A/sarco-endoplasmic reticulum ATPase (PKA/SERCA) signaling, mEG3-210 promotes ESC migration and invasion (147). In endometriosis, miR-145 reduces tumor growth, invasiveness, and stem cell characteristics. Prostate cancer-associated transcript-1 (PCAT-1) lncRNA and siRNA dramatically boosted miR-145 expression, reducing endometriotic stem cell proliferation and invasiveness (148). Normal endometrial tissues had a lower ratio of lncRNA steroid receptor activator (SRA) to steroid receptor activating protein (SRAP) than endometriosis tissues. In contrast to normal endometrial tissue, the expression of SRA and ER-lncRNA in endometriotic ovarian tissue was lower than that of SRAP and ER-lncRNA. Through controlling ER, SRA in ovarian endometriosis may play a significant regulatory function in the development of ESCs (149).