Exosomes are a type of extracellular vesicle (EVs), while ectosomes are the other type (22). Compared with ectosomes, the biological origin and particle diameter of exosomes are different. After forming an outward bud, ectosomes sever the surface of the plasma membrane, and their diameters range from 50 nm to 1 mm (23). However, exosomes are nanoscale vesicles originating from endosomes with diameters of 40–160 nm (average, ~100 nm) (23). All cells secrete exosomes in normal and pathological conditions, which maintain cell homeostasis and mediate intercellular communication (24). Exosomes contain numerous cellular components, including nucleic acids, amino acids, lipids, glycans, metabolites, cytoplasm and cell surface proteins (24). In exosomes from distinct cell types, 9,769 proteins, 3,408 mRNAs, 2,838 miRNAs and 1,116 lipids have so far been discovered (25). Exosomes have been the subject of an increasing number of research in recent years due to their potential use as non-invasive liquid biopsy instruments for the detection and treatment of a variety of disorders as well as their potential for usage in prescription drugs (23,26).

Exosomes were discovered for the first time in sheep reticulocytes by Pan and Johnstone in 1983 (27). Initially considered as cellular debris, exosomes were later found to have independent structures (27). The occurrence of exosomes starts from the vesicles on the cell membrane, which turn inward to form exosomes, and the cytoplasmic membrane invaginates to enclose some specific extracellular biological macromolecules and cell membrane proteins to form intracellular multivesicular bodies (MVBs) (28). After the formation of MVBs, cells may fuse with autophagosomes or lysosomes, during which the previously encapsulated substances may be degraded or released through the fusion of the endosome with the plasma membrane to form exosomes (29). At present, several possibilities have been suggested for cargo sorting into exosomes, but the specific mechanism remains unclear (30). Exosome release and biomolecule packing into exosomes are reportedly regulated by the endosomal sorting complex required for transport (ESCRT) pathway, and ESCRT proteins import ubiquitin proteins into MVBs (30). A total of five protein-protein complexes make up the ESCRT system: i) ESCRT-0; ii) ESCRT-I; iii) ESCRT-II; iv) ESCRT-III; and v) Vps4-Vta1 (31). In summary, ESCRT-0 gathers ubiquitinated cargo to start the process; protein complexes in a saddle shape are created when the ESCRT-I and ESCRT-II complexes bind cargo; the ESCRT-III complex promotes vesicle contraction and maturation; and Vps4-Vta1 promotes membrane fracture (32). In addition, some ESCRT-independent pathways also play important roles in exosome genesis. Lipid rafts, such as flotillins and caveolins, play a key role in ESCRT-independent intraluminal vesicles formation (33,34). Exosome production has also been linked to flotillin, caveolin-1, cholesterol and tetraspanins (Fig. 1) (35–38).

As aforementioned, exosomes were initially considered waste products excreted by cells. However, exosomes can control the proliferation, migration and invasion of tumor cells by information transfer, as more and more studies have demonstrated (39,40). For instance, He et al revealed that pancreatic cancer cells release exosomes that are abundant in FGD5 antisense RNA 1, which facilitates the evolution of pancreatic cancer by way of tumor-associated alternatively activated (M2) macrophage polarization (41). Exosomes have also been revealed to modulate immune responses (42). According to Yang et al, exosomal hsa_circ_0085361 is abnormally expressed in bladder cancer tissues and controls T cell depletion by influencing downstream miRNAs (43). Exosomes can also be crucial in a number of biological processes of the neurological system (44). According to studies, damaging proteins such β amyloid peptide, superoxide dismutase and α synuclein are present in the exosomes of the central nervous system and help advance disorders (44–47). For example, studies have found that α synuclein, which is secreted by cells through exosomal calcium-dependent mechanisms, helps amplify and spread Parkinson's disease-related pathology (47). Exosomes also contribute to the development of metabolic and other disorders, such as cardiovascular ailments (23). Notably, there are several potential uses for exosomes in the treatment, identification and assessment of tumors. According to Xu et al, the exosome-related gene fibroblast growth factor 9 can be downregulated and exploited as a novel diagnostic and prognostic target for ovarian cancer (48). Because a number of components of exosomes are related to diseases, research on exosomes has increased (49,50).

CircRNAs are closed circular RNA molecules found in a variety of specimen types, including bone marrow cells, platelets, white blood cells and red blood cells (51). Unlike conventional linear RNA, circRNA backsplicing joins the upstream 3′ splice acceptor site and the downstream 5′ splice donor site to create a single-stranded covalent closed loop (52). Circular RNA is more durable compared with linear RNA and resistant to exonuclease disintegration because it lacks the 5′ and 3′ ends (52). According to the various genome constituent sequences, circRNAs can be divided into three different categories: Exonic circular RNAs, intronic circular RNAs (ciRNAs) and exon-intron circular RNAs (EIciRNAs) (Fig. 2) (53). The majority of them are present in the nucleus, including ciRNAs and EIciRNAs; however, there are few miRNA targets for ciRNAs (53,54).

Due to its distinctive structure, circRNAs have a wide range of biological roles and are crucial in numerous illnesses, according to recent studies (55,56). CircRNAs can control gene expression by interacting with miRNAs, as a number of studies have demonstrated (57,58). For example, Huang et al has revealed that hsa_circ_104348 can regulate the expression of miR-187-3p, thereby affecting the progression of hepatocellular carcinoma (59). The exonic region of RNase P RNA component H27 is the source of circRNA-002178, which has been shown to be overexpressed in esophageal cancer cells (60). CircRNA-002178 can act as a sponge for miR-34a and miR-28-5p to reduce their inhibitory effects on their target genes PDL1 and PD1 in cancer cells and CD8 T cells (60,61). Circular RNAs can also function by attaching to RNA-binding proteins. A new circRNA has been identified by Chen et al in the friend leukemia virus integration 1 promoter, and it is reported to encourage breast cancer spread by controlling the enzymes methylcytosine dioxygenase TET1 and DNA methyl transferase (62). Due to the absence of the 5′ cap, it has also been proposed that circRNAs translate in a cap-independent manner (54,63).

At present, the following circRNAs that can be translated into proteins have been studied: circ-AKT3 (64), circSHPRH (65) and circ-ZNF609 (66). For example, circ-AKT3 is expressed at a lower level in glioblastoma tissue compared with normal brain tissue, and it can encode AKT3-174aa (64). The tumorigenicity of glioblastoma can be affected by influencing the expression of circ-AKT3 and AKT3-174aa (64). As circRNA research advances, these types of molecules may be employed as tumor diagnostic markers. For example, Lu et al demonstrated that hsa_circ_0001789 is underexpressed in GC tissues and plasma, with an area under receiver operating curve (AUC) of 0.82; this circRNA may become a novel diagnostic biomarker for GC, and its efficacy is better compared with that of traditional tumor markers (67). According to a previous study, the hepatocellular carcinoma diagnostic biomarkers hsa_circ_0004001, hsa_circ_0004123, hsa_circ_0075792 and the combination of the three exhibit greater sensitivity and specificity compared with the three circRNAs separately (68).

According to previous studies, circRNAs influence various biological processes, are persistent and are concentrated in exosomes (69,70). Exosomal circPRRX1, as the competing endogenous RNA of miR-596, has been revealed to promote the proliferation, migration and invasion of GC cells, and decreases their radiation sensitivity through the upregulation of NF-κB-activated protein (71). Since a number of cell types can receive exosomes, exosomes can act as messengers in intercellular communication (72). In the occurrence and development of tumors, circRNA can be packaged into exosomes and sent to receptor cells to play a certain role, affecting the tumor microenvironment and thus influencing the progression of the disease (73). As shown in Fig. 1, exosomes transfer circRNAs into recipient cells mainly via three processes: Receptor-ligand interaction, membrane fusion and endocytosis (23). However, the specific mechanism of selective packaging of circRNAs into exosomes is still unclear. According to Yang et al, the exosome circ-133 produced by hypoxia cells is substantially expressed in the plasma of CRC patients and can be transferred to healthy cells to advance the disease (74). Notably, numerous other studies have found a connection between exosomes and the removal of intracellular circRNAs (75,76). For example, it has been revealed that exosomes can be further eliminated by the reticuloendothelial system or produced by the kidney and liver (75). Moreover, previous research has revealed that, compared with healthy cells, CRC cells can actively release more circ-rho-related BTB domain-containing 3 (circRHOBTB3) to sustain colorectal cancer cell fitness (76). In another study, Chen et al demonstrated that circRHOBTB3 inhibits the progression of CRC by regulating intracellular reactive oxygen species and metabolic pathways (76). In addition, this study advanced a novel theory of tumor escape known as ‘the tumor exosome escape mechanism’, which postulates that tumor cells secrete tumor inhibitory circRNAs in order to maintain the fitness of cancer cells. The mechanism of tumor exosome escape is of great significance for understanding and treating cancer (76). Furthermore, the expression levels of circRNA in some patients with tumors are significantly different compared with that of the healthy population, such as hsa_circ_001783 and circRNA_102231, and because of its strong stability, long half-life and anti-degradation, circRNA can be used as a tumor diagnosis and molecular marker (77,78).

Exosomal circRNAs have been implicated in the emergence and progression of gastrointestinal cancer in a growing number of studies over the past several years (79,80). By binding to miRNA, receptor proteins, or other regulatory mechanisms, exosomal circRNAs influence tumor growth, metastasis, stemness, angiogenesis, the immunological microenvironment and treatment resistance (Fig. 3 and Table I).

Exosomal circRNAs have been shown to control the microenvironment and surrounding tissue cells, which has been demonstrated to have an impact on how gastrointestinal cancer progresses (81). It has been reported that exosomal circRNAs promote the occurrence and development of gastrointestinal cancer by affecting tumor proliferation, metastasis, stemness and angiogenesis (81). Sang et al demonstrated that circRNA RELL1 is significantly downregulated in GC tissues and transmitted by exosomes (82). CircRELL1 inhibits GC progression through the miR-637/ephrin type-B receptor 3 axis, which may be a novel diagnostic marker and therapeutic target for GC (82). Yu et al revealed that circRNA NIMA-related kinase 9 accelerates GC progression by targeting the miR-409-3p/microtubule associated protein 7 axis, which can be reflected in malignant behaviors such as migration and invasion (83). A possible therapeutic target for CRC has been identified in research as the cancer-derived exosomal hsa_circRNA_001046, which plays an oncogenic role in the progression of the disease (84). According to Gao et al, circRNA component of oligomeric Golgi complex 2 (COG2) may be transported from cancer cells with a high metastatic potential to cancer cells with a low metastatic potential via exosomes (85). circCOG2 has been demonstrated to be enhanced in CRC tissue and plasma exosomes. By controlling downstream miRNA and associated proteins, circCOG2 aids in the development of the malignant phenotype of CRC. According to this, circCOG2 may be both a therapeutic target and a predictive factor for CRC (85).

In addition, there is growing evidence that exosomes released by various living cells promote the metastasis of gastrointestinal cancer by delivering circRNAs (86,87). For example, circ-RanGAP1 is found in plasma exosomes from preoperative patients with GC, according to the research of Lu et al (86). In addition, the ability of GC cells to migrate and invade is improved by the plasma exosomes that were obtained from these individuals. This research raises the possibility that circ-RanGAP1 might serve as a predictive biomarker and a therapeutic target for the treatment of GC (86). Hui et al demonstrated that circNHSL1 knockdown represses migration, invasion and glutaminolysis and inhibits tumor growth by downregulating the miR-149-5p/tyrosine 3-monooxygenase axis in GC, implying an underlying therapy target for GC treatment (87). Shen et al also revealed that hsa_circ_0000437 regulates malignant behaviors such as migration of human lymphatic endothelial cells by targeting serine and arginine rich splicing factor 3 and inhibiting programmed cell death factor 4, as well as lymph node metastasis (LNM) in the popliteal LNM model (88). In CRC, circLONP2 is abnormally highly expressed in metastatic primary CRC tissues and can be transferred between cells by regulating miR-17 (89). This study suggests that circLONP2 may be a potential anti-metastatic therapeutic target for CRC (89). The findings of Chen et al determine that CRC cells are rich in exosomal circTUBGCP4, which promotes CRC metastasis through upregulation of pyruvate dehydrogenase kinase 2 (90). Additionally, Yu et al revealed that the exosomal circ_FMN2 is abundant in CRC cells and that its overexpression can encourage the spread of CRC cells and the development of colorectal tumors (91).

The incidence, invasion, metastasis and treatment resistance of gastrointestinal cancer are all assumed to be influenced by epithelial-mesenchymal transition (EMT), a fundamental cellular process (92). CircRNAs are crucial to EMT in gastrointestinal cancer (93,94). Exosomal circ670 from the tissues of patients with GC has been demonstrated to alter the EMT process of GC stem cells, hence boosting the growth of GC, according to a previous study (95). According to Miao et al, exosomal circRNA collagen type I α 2 chain (circCOL1A2) is significantly expressed in CRC cells, and miR-665 can impact EMT and other cellular properties when combined with circCOL1A2 or LIM and SH3 Protein 1 (96). Moreover, this study indicated that circCOL1A2 is a potential novel therapeutic target for CRC (96).

Additionally, it has been shown that a number of exosomal circRNAs are associated with the stemness and angiogenesis of gastrointestinal tumor cells (97). Zhao et al demonstrated that the exosomes of CD133 cells are rich in hsa_circ_0000677, which can mediate the stemness of CRC cells and promote the progression of CRC, and is expected to become a potential therapeutic target for this cancer (97). Liu et al also revealed that the expression of circ_0001190 in the exosome source of GC is low, and overexpression of circ_0001190 can inhibit the angiogenesis ability of cells, thus inhibiting the development of GC (98). Additionally, Zeng et al demonstrated that circFNDC3B has a low expression level in CRC tissues and cells and that it has the ability to stop the growth of the disease by preventing the angiogenic features of the disease (99). These studies indicate that exosomal circRNAs can promote or inhibit the progression of gastrointestinal cancer.

Exosomal circRNAs can affect the function of immune cells in the tumor microenvironment and then affect the occurrence and development of gastrointestinal cancer. For instance, exosomal hsa_circ_0017252 secreted by GC cells slows the growth of the disease by inhibiting M2-like polarization of macrophages (100). Exosome-derived circPACRGL is significantly expressed in CRC cells. By controlling downstream miRNAs, circPACRGL promotes the malignant activity of CRC cells and the differentiation of N1 to N2 neutrophils. To the best of our knowledge, this research is the first to demonstrate that exosomal circPACRGL contributes to CRC carcinogenesis and may have promise as a biomarker (101). These findings suggest that exosomal circRNAs can affect the progression of gastrointestinal cancer through immune cells.

It has been revealed that circRNAs cannot only affect the progression of gastrointestinal cancer, but also participate in their chemoresistance (102). A number of circRNAs have a role in drug resistance in GC, such as circ 0008253 and circ_0091741 (103,104). According to a recent study, circ 0008253 is abundant in M2-polarized exosomes that are produced by macrophages and can be delivered to GC cells via exosomes to increase their resistance to oxaliplatin (OXA) (103). Chen et al also demonstrated that the exosomal circ_0091741 derived from GC cells increases the expression of tripartite motif containing 14, thereby enhancing OXA resistance (104). In addition, circ_0063526 is highly expressed in GC tissues and cells, and cisplatin resistance is enhanced by regulating the expression of serine hydroxymethyltransferase 2 (105). Moreover, exosome-derived circ-PVT1 is underexpressed in GC cells and serum, and contributes to DDP resistance by regulating miR-30a-5p; therefore, Exosomal circ-PVT1 may be a potential therapeutic target for GC (106). In CRC, a novel support for a possible therapeutic target for oxaliplatin resistance is provided by the exosomal circATG4B, which contributes to the lower chemosensitivity of CRC cells (107). Zhang et al revealed that circ_0006174 is upregulated in exosomes of doxorubicin (DOX)-resistant CRC cells and can enhance their resistance through the intercellular transfer of exosomes (108). Another study has revealed that hsa_circ_0005963 can be transferred from chemotherapy-resistant CRC cells to sensitive cells via exosomes, enhancing drug resistance in sensitive cells (109). A study suggests that hsa_circ_0005963 may be a potential therapeutic target for drug-resistant CRC (109). Moreover, Zhao et al revealed that miR-217 and miR-485-3p are controlled by exosome-mediated circ_0000338 transfer, which increases 3-fluorouracil resistance in CRC (110). These results suggest that exosomal circRNAs can enhance the resistance of oxaliplatin, 3-fluorouracil, cisplatin and DOX in gastrointestinal cancer. The application of antitumor drugs and specific circRNA inhibitors can improve the therapeutic effect of gastrointestinal tumors.