Temporomandibular joint osteoarthritis (TMJOA) is a degenerative temporomandibular arthropathy characterized by progressive cartilage degeneration, abnormal subchondral bone remodeling and obvious synovitis (Scrivani et al., 2008; Toller, 1973). Due to the severe concomitant symptoms such as difficulties in chewing, acute or chronic pain, and even maxillofacial deformities, it severely deteriorates the quality of patient life and leads to the large resultant socioeconomic burden. Joint cartilage is composed of chondrocytes and extracellular matrix like collagen fibers, proteoglycans, and hyaluronic acid. Feature of avascular structure of cartilage is detrimental to the exchange of available signaling molecules, migration of progenitor cells, and adequate supply of nutrients and oxygen, resulting in the inability of damaged cartilage tissue to regenerate effectively (Chen et al., 2020). Because of the limited self-healing ability of cartilage, it has become one of the most difficult joint diseases to treat. Compared with other joints in the body, temporomandibular joint has its own characteristics (Macedo et al., 2017; David and Roberts, 2018). Besides, the layer of hyaline cartilage covering generalized joints mainly contained type II collagen, but the cartilage of TMJ is fibrocartilage, which is a kind of cartilage composed of both type I collagen and type II collagen. Because of the structural differences, there will be some differences in treatment strategies when the disease occurs. The cartilage of TMJ has better multidirectional bearing capacity and more dense fibers, which are not easy to degrade and are less affected by aging (Schwartz et al., 2015; Chandrasekaran et al., 2021). However, when it is damaged, the difficulty of restoring normal structure (Kuo et al., 2011). Numerous studies have confirmed that it is a pathological state affected by multiple factors (Figure 1). Excessive mechanical stress is a major factor leading to cartilage rupture in TMJ (Su et al., 2014; Huang et al., 2021; Ootake et al., 2021). Uneven stress distribution in TMJ caused by occlusal disorder was reported to induce the hyperactivity of osteoclasts in subchondral bone. Researchers have demonstrated that inflammation is one of the risk factors of TMJOA (Li et al., 2019a; Li et al., 2019b; Luo et al., 2019; Lei et al., 2022). Liu detected synovial fluid from TMJOA patients and found that the level of inflammatory cytokines was significantly increased.16 Moreover, genetic factors and age-related reduction of host-adaptive capacity are also vital in TMJOA (Xu et al., 2003; Yamaguchi et al., 2014). It is because of the specificality of TMJ structure and the ambiguity of etiological mechanism that the treatment of TMJOA has been set up a huge obstacle.

To date, treatment strategies for TMJAO are symptomatic and limited (Figure 1), only to reduce inflammation and relieve pain (Thie et al., 2001). Traditional clinical treatments can stop the progression of the disease to some extent, but they cannot actively restore degraded cartilage or damaged subchondral bone (Derwich et al., 2021; Liu Q. et al., 2022; Matheus et al., 2022). Novel radical therapies for osteoarthritis are urgently required. In recent years, cell-based disease treatment strategies have raised considerable concerns, especially mesenchymal stem cells (MSCs) -based therapies (Matheus et al., 2022). Abundant native MSCs are present in multiple niches in the joint, including subchondral bone, synovial fluid, and adipose tissue. In the last decade, increasing evidence has suggested that MSCs have great potential in the treatment of osteoarthritis. BMSCs have suggested promising therapeutic efficacy for TMJ cartilage repair (Ciocca et al., 2013). Although the role of MSCs in the field of disease treatment cannot be ignored, we still need to comprehensively understand its non-negligible bottlenecks as cell therapy strategies. The host exhibited immunological tolerance toward implanted MSCs and had a potential risk for malignancies, which might also pose a risk to immunological cells for controlling an inflammatory milieu (Lalu et al., 2012). Therefore, it is inevitable to find an alternative approach to solve the dilemma faced by MSC-based therapy. Numerous studies have summarized the bio-effect of MSCs is increasingly attributed to paracrine signaling to transfer its cargo to the body, among which exosomes are a vital carrier for message in many biological and pathological processes. Exosomes provide new perspectives for the development of cell-free and ready-to-use therapy for treatment of cartilage lesions and TMJOA.

Herein, the present review was aimed at discussing the therapeutic potential and corresponding mechanism of MSCs, the biological properties of exosomes derived from diversified cell sources, and advances in our knowledge of their emerging roles in managing TMJOA. We also discussed the detailed exosome-based tissue engineering strategies of TMJOA therapy in the hope of providing inspiration for future investigations. Particularly, we proposed novel perspectives for the development and implementation of exosomes as a cell-free regenerative medicine therapeutic strategy for cartilage repair in TMJOA and discussed future opportunities and challenges in this exciting field.

Since MSCs first discovery by Friedenstein (Friedenstein et al., 1982), they are commonly used in the treatment of various diseases, including TMJOA. We conducted a literature review and found that the application of MSCs in osteoarthritis was first reported in 1995, and more and more related research is being carried on, with over 89% of the published in the recent 10 years (Figure 2).

When TMJOA occurs, the dynamic balance between chondrocyte matrix anabolism and catabolism is disrupted, accelerating the progression of the disease (Weng et al., 2017). Zhang et al. (2017) reported BMSCs reversed the loss of cartilage matrix associated with osteoarthritis and enhanced scavenging activity of the degraded matrix in deep zone chondrocytes. Lu et al. (2015) also found that the implanted GFP-BMSCs differentiated into COL2-positive cells and relieved matrix degradation in TMJOA. It was indicated that human umbilical cord matrix-mesenchymal stem cells (hUCMSC) showed prominent cartilage protective effect and effective cartilage regeneration potential (Kim et al., 2019). Moreover, Maria revealed scaffolds loaded with dental pulp mesenchymal stem cells (DPSCs) effectively supported abundant fibrocartilaginous tissue formation. Besides, other MSCs, such as adipose-derived mesenchymal stem cells (ADMSCs) (Ahtiainen et al., 2013) and synovial fluid derived mesenchymal stem cells (SFDMSCs) (Koyama et al., 2011), have also been indicated to alleviate TMJOA by participating in cartilage matrix metabolism.

Uncoupled remodeling of subchondral bone is another pathological feature contributed to TMJOA (Jiao et al., 2011; Yang et al., 2014; Zheng et al., 2018; Ibrahim et al., 2019). Human exfoliated deciduous teeth stem cells (SHED) markedly improved surface smoothness and bone integrity of the destroyed condylar in TMJOA mice (Chen et al., 2013). Chen K investigated MSC-treated groups demonstrated pronounced micro-architectural changes of the subchondral bone (Tanaka et al., 2008). In addition, it was reported that the migration of BMSCs restored subchondral bone loss in mice with TMJOA (Lu et al., 2015).

Evidence has suggested that sustained inflammation is involved in the onset and progression of TMJOA (Liu W. et al., 2017). When stimulated, immune cells in inflammatory microenvironment release inflammatory factors to affect the matrix metabolism of chondrocytes to deteriorate TMJOA (Tanaka et al., 2008) and are also in close correlation with sensory neuron hyperexcitability to induce the pain of TMJOA (Magnano et al., 2007; Ou et al., 2021). Buul et al. found the decreased expression of IL-1β, MMP-1 and MMP-13 in synovial explants when cultured with MSCs conditioned medium (Van Buul et al., 2012). It was recently shown that BMSCs injection into the bilateral TMJ region significantly reversed high levels of TNF-α and IL-1β in TMJOA (Lu et al., 2015). This is further supported by Hyunjeong Kim’s study (Kim et al., 2019). The self-assembled peptide hydrogels accelerated tissue regeneration by anti-inflammatory modulation (Kim et al., 2016).

Inflammation and immunity go hand in hand (Bartholomew et al., 2002; Koliaraki et al., 2020; Lim et al., 2021; Pham et al., 2021). In the pathogenesis of inflammatory diseases, dysregulation of the host immuno-inflammatory response is one of the important predisposing factors (Theill et al., 2002; Hernández et al., 2011). Similarly, Monasterio proposed cytokines, CCLs and CCRs of the Th1/Th17/Th22 axis were involved in TMJOA pathogenesis (Monasterio et al., 2018). A large number of studies have shown that MSCs regulate innate and acquired immunity in the treatment of OA (Yu et al., 2016). Tang et al. (2021a) reported that hUCMSCs protected cartilage from injury by regulating the macrophages polarization and affecting the joint immune microenvironment, but notably, there was a stronger regulation ability of immune effector process in hUCMSCs-exosomes treatment group.

In recent years, although the efficacy of MSCs in treating TMJOA has been widely studied in animal studies and human clinical trials, in fact, the problems encountered in clinical application have been deeply troubling researchers (Table 1). Donor’s age affects the intrinsic activity and functionality of obtained cells (Kim et al., 2020). The lack of standardization for large-scale cell production results in inconsistent cell quality after expansion. Additionally, the senescence and dedifferentiation of cells during the expansion in vitro will also affect potential and increase the risk in the application (Siddappa et al., 2007). More cautiously, there is a potential of tumorigenicity (Le et al., 2012; Waterman et al., 2010). Moreover, the issue of cell storage is also a bottleneck of MSC-based strategy. Whether the biological activity of MSCs will be affected after repeated cryopreservation is a great question to be considered in future. It is noteworthy that there is a paradigm shift that, rather than direct differentiation to cells of the target tissue, the therapeutic efficacy of MSCs in tissue repair and regeneration is predominantly attributed to paracrine signaling, particularly exosomes (Mayourian et al., 2018; Li et al., 2019; Mori et al., 2019; Zhang et al., 2019; Zhou Q.-F. et al., 2020). Therefore, exosome-based therapeutic strategy of TMJOA may be a promising substitute for MSC-based therapy.

It was not until 2006 that Ratajczak proposed for the first time that mRNA could be delivered by membrane-derived vesicles (MV) released from the surface of activated eucaryotic cells and exert positive effects on surrounding cells (Ratajczak et al., 2006). Exosome-mediated transfer of RNAs was suggested as a novel mechanism of genetic exchange between cells (Waterman et al., 2010), occurring within the microenvironment or at a distance by traffic of exosomes. Exosomes are the smallest in size ranging from 40 to 160 nm in diameter among the three main subcategories of extracellular vesicles (EVs). Exosomes of different cell origin carry their own various bioactive molecules, containing different types of proteins, DNAs, mRNAs, microRNAs, lipids, metabolites and so on. It is the diversity of contents that illustrates the diversity of exosome functions (Valadi et al., 2007). They are ubiquitously involved in the basic processes of innate and adaptive immunity and immune-mediated disease processes (Garikipati et al., 2018). It was shown that miR-21-5, as a lead cardioactive MSC-exosomal-microRNA, mediated effects on increasing engineered cardiac tissues contractility and was suggested as a specific molecular target for optimizing cardio-therapies (Mayourian et al., 2018). In recent years, increasing studies have been conducted on the application of exosomes in the treatment of neurological diseases (Budden et al., 2021; Xu et al., 2017; Rufino-Ramos et al., 2017). More attention should also be paid to bottlenecks in exosome treatment, including the limitation of increasing exosome production, the difficulty of analyzing the effective components of exosomes and the better improvement of the functions of the active component. Encouragingly, the problems of exosomes faced in the diseases therapy have been gradually handled via various biotechnology modifies. The composition and secretion of exosomes are affected by the environment and signals of donor cells, including hypoxia, heat, and pharmacological intervention (Pegtel et al., 2010; Fan et al., 2020). Therefore, changing the culture conditions of donor cells can meet the clinical needs of exosomes in treating diseases. Because exosomes are excellent carriers, the direct insertion of miRNA mimics or siRNAs into exosomes through electroporation (Ma et al., 2018) and electric pulses (Yang et al., 2020) has attracted the attention of many researchers. By modifying exosomes membrane through genetic manipulation strategy by biotechnology, exosomes can reach the target cells and tissues according to the predetermined route and play a more specific role (Kanki et al., 2011; Wang et al., 2018). The intersection between different cells exosomes and chondrocytes offered a new insight into the pathogenesis and treatment of degenerative joint diseases. Many studies have proposed that exosomes play an irreplaceable role in the treatment of TMJOA. In the following section, we summarized the current studies on the therapeutic effects of exosomes from various cells in TMJOA.

The different responses of recipient cells to exosomes are mainly due to the heterogeneity of exosomes, including their inconsistent expression of cell surface receptors and different contents. It means that exosomes from different cells have different effects on the same type of cell and the same exosome may also have inconsistent or even contradictory effects on different target cell types or target tissues66 (Table 2). More and more researchers attempt to obtain diversified exosomes and apply them in OA treatment to have a deeper understanding of the occurrence and development of OA and hope to find more novel targets in molecular mechanisms of TMJOA treatment (Figure 3). To date, an increasing amount of literature has indicated that exosomes from different sources (Figure 2), such as MSCs, chondrocytes, and synovial fluid in TMJ cavity, are reportedly important in the treatment of TMJOA. In recent years, researchers have focused on identifying effective constituents in exosomes, such as miRNA, for the treatment of TMJOA, with a view to obtain a more direct, effective, and targeted therapeutic strategy.

Owing to the uniqueness and complexity of the TMJ, it is a great challenge to achieve complete restoration of its anatomical, structural, and functional integrity. The optimization of exosome-based strategy is a necessary step for TMJOA treatment. Bioengineering is constantly developing and provides an optimized solution in regenerative medicine (Table 3). Helgeland made a systematic review to answer the question of whether scaffold based TMJ tissue regeneration have better outcomes in TMJOA treatment. The overall preclinical evidence indicated that biomaterial scaffolds combined with biological components enhanced the potential for cartilage regeneration in TMJOA (Bellio et al., 2020). Additionally, the optimization of bioengineering technology in exosome based TMJOA therapeutic strategy has aroused the hot interests of researchers. There might be several disadvantages with direct administration of exosome-containing suspension in cartilage regeneration, especially, the difficulty of local exosome retention. Liu developed a photoinduced hydrogel exosome scaffold for a better retention of cargo exosome (Helgeland et al., 2018). In the system, they demonstrated that it retained stem cell-derived exosomes and showed an excellent biocompatibility and cartilage-integration by positively regulating both chondrocytes and BMSCs in vitro and promoting cartilage matrix and cell deposition at cartilage injury site. Using a crosslinked network of chondroitin sulfate, alginate-dopamine, and regenerated silk fibroin, an injectable hydrogel with encapsulated exosomes was exploited in superficial cartilage regeneration. Exosomes released by the hydrogels recruited BMSCs into defects via the chemokine pathway (Liu X. et al., 2017). These findings revealed the hydrogel coated with exosomes as a promising approach for accelerating cartilage regeneration in situ and neo-cartilage extracellular matrix remodeling. Chen designed a 3D printed cartilage extracellular matrix-gelatin methacrylate-exosome delivery scaffold (ECM/GelMA/Ex scaffold) with radial channels and superior cell recruitment capacity. The scaffold not only enhanced cartilage regeneration but also facilitated recovery of subchondral bone. Furthermore, they also found that MSCs exosomes enhanced mitochondrial biogenesis and rescued the mitochondrial dysfunction in degenerated cartilage (Zhang et al., 2021). The controlled exosome release platform with histological biological scaffolds solves the problems of insufficient local exosome concentration and short half-life of exosomes after injection to a large extent, optimizing the exosome based TMJOA treatment strategy.

The dense matrix biological barrier of cartilage makes chondrocyte-targeted drug delivery difficult. Exosomes enter the cell mainly via endocytosis, direct membrane fusion, or pinocytosis, 66 and the released contents could exert biological effects. It indicates exosomes have a great potential as a vehicle for drug delivery. Hence, it is an innovation and optimization in TMJOA treatment to modify surface structures for improving the efficiency of exosomes entering cells and to modulate encapsulated contents for strengthening therapeutic effects by genetic engineering technology or direct physicochemical loading. A study demonstrated that exosomes gained MSC targeting capability after fusing exosomal membrane protein Lamp 2b with MSC-binding peptide E7 (Chen et al., 2019). SFMSCs with E7-exosomes entered the middle zone of the cartilage more easily. Additionally, BMSCs-derived exosomes loading with KGN (a small molecule that can induce MSCs differentiation to chondrocytes) by electroporation efficiently increased COL2 and ACAN and induced higher cartilage differentiation of SFMSCs. In vivo, it showed best cartilage repair. ATF4-overexpressing exosomes were developed by introducing the mRNA of ATF4 into exosomes via electroporation. It showed these exosomes alleviated inflammation and cartilage degeneration in osteoarthritis mice by promoting chondrocytes autophagy and inhibiting apoptosis (Xu et al., 2021). To achieve a more predictable and desirable clinical response, specific therapeutic miRNA enrichment could be performed through the overexpressing genetic technique. It was suggested that miR-140-5p-overexpressing hSDMSCs derived exosomes enhanced the proliferation and migration abilities of chondrocytes (Wang Z. et al., 2021). They observed the exosomes highly expressed miR-140-5p blocked this side-effect in ECM via targeting RalA to enhance SOX9 and ACAN. Exosomes derived from miR-92a-3p-overexpressing MSCs targeted WNT5A to elevate chondrogenesis in MSCs and suppress cartilage degradation in primary chondrocytes (Tao et al., 2017). Besides, hBMSC-derived overexpressing miR-26a-5p exosomes relieved OA and were served as a repressor to retard damage of SFs via PTGS2 downregulation in vitro (Mao et al., 2018). Generally, utilizing a specific exosomal-miRNA mainly involves these proposed mechanisms, the overexpression of miRNA in cells, the isolation of exosomes containing miRNA, then delivery to chondrocytes in inflammatory microenvironment or TMJOA animal models, and finally targeting a pathogenic gene via miRNA. Some studies have shown that the effect of hypoxia-preconditioned exosomes on cartilage repair are superior to that of normoxia-preconditioned exosomes, manifesting in the promotion of chondrocyte proliferation and migration and the inhibition of chondrocyte apoptosis (Jin et al., 2020). TGF-β1-stimulated BMSCs-derived exosomes highly expressed miR-135b and polarized synovial macrophages (SMs) into M2 type to alleviate cartilage destruction. M2 polarization of SMs was significantly reversed by increase of MAPK6 (Zhang B. et al., 2022). Pretreating exosomes with physical or chemical stimulation optimizes exosome-based therapeutic strategies.

Although exosomes were originally regarded as useless metabolic byproducts, it is well recognized that exosomes, as various carrier of signaling mediators, play a vital role in mediating cell-to-cell communication and in activating immunomodulatory activity. Certainly, numerous studies have shown exosomes are sufficient to treat degenerative diseases, including systemic OA and TMJOA. A correct view of the prospects and existing problems of exosome-based therapeutic strategy is the basis for further research.

Emerging as a trending research area, exosome-based therapeutic strategy in TMJOA has gained much interest because of its unique regulatory ability in TMJ inflammation as well as the low immunogenicity (Wang Y. et al., 2021). Some studies have reported that MSCs show a certain degree of immunogenicity in mediating disease treatment (Qi et al., 2016; Gregory et al., 2005). Compared with MSCs, exosomes have been reported not to express class II human leukocyte antigens and have lower immunogenicity when applicated in vivo (Krampera et al., 2006; Stagg et al., 2006; Sun et al., 2009; Geiger et al., 2015; Qi et al., 2016; Yaghoubi et al., 2019; Kang et al., 2020). TMJ is a complex system, and the immune privilege of exosomes maximally ensures it not to be cleared by immune cells when playing the therapeutic role in TMJOA. In addition, at present, few studies have reported the tumorigenic effect of exosomes in vivo, which might occur in the MSC-based therapy (Wislet-Gendebien et al., 2012; Funes et al., 2014; Li et al., 2022). Because cartilage is a dense biological barrier staggered by collagenous fiber, the transport property of exosomes is advantageous in TMJOA treatment. Being nano-sized and biocompatible, exosomes can be served as nanocarriers, easily reaching to the cartilage to fuse with chondrocytes. Certainly, the side effects associated with cell-based therapy, such as vascular embolism and pulmonary embolism (De Boeck et al., 2013; Jung et al., 2013), are also rare when exosomes are injected systematically. Furthermore, the less strict storage condition also gives exosomes greater possibilities for therapeutic application. Low temperature cold storage or repeated freezing and thawing does not influence exosome sizes and bioactivities, which shows higher clinical application value compared with cell-based therapies. It takes more time to resuscitate frozen cells to normal functional state, and the activity of resuscitated cells cannot be predicted (Mäkelä et al., 2015). Most importantly, many studies have shown that cell-cell interactions are mainly dependent on exosomes. MSCs-derived exosomes share the same or even more powerful biological effects than MSCs (Zhou X. et al., 2020), such as metabolic regulation of cartilage matrix, inhibition of inflammatory factors, relief of TMJOA pain, and homing of cells to the cartilage defect. Moreover, exosomes modified by genetic engineering have higher organotropism and cartilage-targeting capability. It has involved the comparison of exosomal differences in organs or systems between healthy and sick populations. High-throughput sequencing has confirmed that exosomes in the joint system differ between normal state and TMJOA, which indicates exosomes can be used as biomarkers for the early diagnosis of TMJOA. MiRNA is one of the important cargoes of exosomes. Through literature review, we noticed some exosome-derived miRNAs related with TMJOA treatment. RNAhybrid and miRanda databases were used to predict the target genes of the miRNAs, and Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed for the identified target genes (Figure 4). It showed 22 biological processes enriched in the GO analysis, including endocytosis, actin cytoskeleton organization, protein polymerization, and other processes. And it displayed 20 signaling pathways obtained by the KEGG analysis, including osteoclast differentiation, inflammatory mediator regulation of TRP channels, apoptosis, and other pathways. The information of enrichment analysis suggested the mechanism and related targets of exosomes in the treatment of TMJOA, which will help us further study the pathogenesis of TMJOA and find out more effective TMJOA therapeutic strategy in the future.

Despite the excellent therapeutic effects of exosomes, there are many issues that need to be addressed. Unlike TMJOA cell-therapy, although results from preclinical studies have demonstrated the chondroprotection role of exosomes, explorations into the exosomes efficacy in treatment are still in the start-up stage. Currently, the research on TMJOA treatment mainly focused on small animals. There is almost no large animal studies or human clinical trials to evaluate exosome-based therapeutic strategy in TMJOA. Insufficient evidence from preclinical research and clinical trials significantly hindered the elucidation of mechanisms and the clinical translation applications. Therefore, future studies are recommended to bridge this knowledge gap and validate the safety and efficacy of exosomes therapy. Meanwhile, the difficulties encountered in the acquisition and the preparation of exosomes are inescapable. Various methods of exosomes separation in vitro have been developed, such as ultracentrifugation-based technique, size-based technique, and immuno-affinity action-based technique (Lőrincz et al., 2014). However, the most standardized and optimal operational procedure has not yet been established. The comparability between different studies is poor due to the differences of yield and purity of exosomes. Extracting homotypic exosomes with consistent contents is crucial in precisive therapy and in reduction of adverse effects caused by unintended unknown by-products (Ding et al., 2021). It is urgent to develop an optimal isolation procedure, which maximizes yield and purity of exosomes and minimizes changes of contents and sizes during extraction. In addition, due to the quick turnover of synovial fluid in TMJ cavity, more studies are needed to determine the effective dose and frequency of exosomes injection. Like cell-based therapy, exosome-based therapeutic strategy is also limited by rapid clearance in vivo and short effective period in direct injection. Therefore, it is particularly critical to optimize the therapeutic strategy of exosomes in TMJOA via tissue engineering approaches. Notably, the cartilage of TMJ is fibrocartilage, which is different from the hyaline cartilage of the most joints of the body. It is made up of various proportions of both cartilaginous tissue and fibrous and has a more complex tissue structure and tensile and compressive strength. Although there are many studies on the treatment of OA, it is still questionable whether these treatment measures are also effective for TMJOA. We should explore the effectiveness of these treatments on TMJOA in a more scientific and rigorous manner. ‘A one size fits all’ therapeutic scaffold may not achieve the best treatment effects in TMJOA (Embree et al., 2016; Jiang et al., 2021; Jiang et al., 2021; Fan et al., 2022). According to the characteristics of different fibrocartilage tissue types, layered scaffolds loaded with exosomes exhibit outstanding advantages in the formation of layered tissue structure in cartilage regeneration to simulate the normal fibrocartilage to the maximum extent. Though faced with challenges, exosome-based therapeutic strategy is promising in TMJOA and worthy of further investigations in vivo and in vitro.

In this review, we summarized the roles of MSCs and exosomes in TMJOA, manifesting in the regulation of cartilage matrix metabolism, the balance of subchondral bone homeostasis, the relief of inflammation, and the effects of immune regulation. Currently, MSC-based therapy is facing many challenges, while exosome-based therapeutic strategy can be a promising novel alternative because of its advantages in cell-to-cell communication in TMJ system. Exosomes, as mini vesicles, deliver nucleic acids and proteins to target tissues or cells and exert therapeutic efficacy in TMJOA. The pathogenesis of TMJOA is complicated and multifactorial. The optimization of the existing exosome-based strategies, such as the combination of tissue engineering scaffolds or genetic modification, more effectively reduce the side effects involved in exosomes treatment and improve cartilage repair and regeneration. However, the translation from experimental research to clinical application of exosomes has been hindered due to insufficient evidence of preclinical and clinical trials. Further research is needed to identify effective constituents of TMJO-target exosomes and explore underlying mechanisms, to investigate therapeutic targets, to evaluate the safety of exosomes application, and finally to establish a consensus in the therapeutic potency of exosome-based therapeutic strategy.