The reparative role of exosomes in myotrauma has garnered considerable scrutiny, with findings affirming their ability to instigate muscular tissue regeneration through multifarious mechanisms. Predominantly, exosomes expedite myotrauma remediation and restoration by stimulating myogenic proliferation, catalyzing the phenotypic maturation of tendinous cells, fostering neurite outgrowth, and facilitating the proliferation of Schwannian cells (51). Exosomes derived from platelet-enriched plasma and mesenchymal stromal cells have been observed to significantly expedite the recuperation of muscular functionality (51).

Exosomes exert their influence by attenuating cellular pyroptosis and ameliorating ischemic myopathy. Empirical evidence suggests that exosomes sourced from mesenchymal stromal cells (MSCs) harbor the therapeutic potential for myopathic injuries, endorsing myoblastic differentiation in patients with Duchenne Muscular Dystrophy and in murine models of MDX (52). Furthermore, exosomes emanating from C2C12 myoblasts have been implicated in the promotion of myofibrillar regeneration, expediting lipogenesis within injured myocytes, mitigating myofibrosis, and accelerating reparative processes, which are attributed to the exosomal mediation of satellite cell proliferation and fibro-adipogenic progenitor cell differentiation (53).

Exosomes isolated from human adipose-derived mesenchymal stromal cells (AD-MSCs) have demonstrated promising therapeutic implications for myogenic regeneration. These exosomes are postulated as efficacious modalities for regenerative therapy, potentially inaugurating novel avenues for myotrauma remediation (54). Additionally, exosomes from bone marrow stromal cells (BMSCs) have been documented to enhance muscular healing by promoting M2 macrophagic polarization, whereas pro-inflammatory C2C12-derived exosomes have been associated with M1 macrophagic polarization and the suppression of myogenic repair mechanisms (12, 27, 55).

Adhesive Capsulitis (AC), commonly manifested as Shoulder Stiffness (SS), is a pervasive affliction characterized by aggravated pain and a diminished range of articular motion (56). Pathologically, AC is classified as an inflammatory and fibrotic disorder. Investigations have unveiled that exosomes from Bone Marrow Stromal Cells (BMSCs) can suppress the expression of TGFBR1 through the mediation of let-7a-5p, consequently impeding the progression of AC (14, 28). Exosomes have emerged as a significant therapeutic entity in the management of diverse fibrotic maladies, with exosomes from various sources and their molecular cargoes—such as miRNAs, lncRNAs, and proteins—being contemplated as targeted therapeutic interventions. These entities can influence an array of cellular types and signal transduction pathways implicated in fibrosis (57, 58).

Exosomes hold significant potential in the treatment of tendon injuries, encompassing Achilles and rotator cuff injuries. In the realm of tendon injury therapy, exosomes function through multiple mechanisms. These primarily include the suppression of inflammatory responses, modulation of macrophage polarization, regulation of gene expression, remodeling of the cellular microenvironment, restructuring of the extracellular matrix, and promotion of angiogenesis (59).

In the context of rotator cuff injury repair, exosomes exhibit considerable therapeutic potential. Studies have found that Mesenchymal Stem Cells (MSCs) can enhance healing post-rotator cuff repair through the release of exosomes (60). Additionally, purified exosome products are being explored to improve the surgical outcomes of rotator cuff tendon-bone healing and to reduce postoperative re-tear rates. This is achieved by focusing on biological and biomechanical factors (61).

In the treatment of Achilles tendon injuries, exosomes have also demonstrated the ability to promote the healing of injured tendons. Specifically, exosomes from tendon stem cells have been found to facilitate tendon injury healing through mechanisms that balance the synthesis and degradation of the tendon extracellular matrix (62). Concurrently, given that poor outcomes in many soft tissue injuries (such as Achilles tendon ruptures, rotator cuff tears, and flexor tendon injuries) are attributed to macrophage-induced inflammation, researchers are investigating exosome-based therapies to suppress inflammation and thereby improve the treatment outcomes of tendon injuries (10).

Exosomes have demonstrated significant therapeutic potential in tendon-bone healing, particularly in the healing process following Anterior Cruciate Ligament Reconstruction (ACLR). Research indicates that exosomes derived from Bone Marrow Stromal Cells (BMSCs) can facilitate tendon-bone healing by modulating the polarization of M1/M2 type macrophages, a mechanism that has been validated in rat models of ACLR (63). Typically, ACLR may fail due to the inability to regenerate normal tissue at the tendon-bone junction and the formation of fibrous scar tissue at this interface (64). However, the combination of BMSC-derived exosomes with cartilage fragments has been shown to enhance healing at the tendon-bone interface, thereby increasing the success rate of ACLR (65).

The role of exosomes in facilitating tendon-bone healing primarily encompasses (1) inhibition of inflammatory responses and regulation of macrophage polarization, (2) control of gene expression, remodeling of the cellular microenvironment, and restructuring of the extracellular matrix, and (3) promotion of angiogenesis (59). Although studies have observed the effects of BMSC-derived exosomes (BMSC-Exos) on tendon-bone healing post-ACLR in rats, both in vivo and in vitro, elucidating the possible mechanisms, it remains unclear whether BMSC-Exos can facilitate tendon-bone healing in humans post-ACLR. Additionally, some studies have explored the effects of exosomes on tendon-bone healing and osteogenesis at the tendon-bone junction using rat ACLR models. For instance, by locally injecting IONP-Exos, BMSC-Exos, or PBS into the surgical knee joint, the retention of exosomes at the surgical site was observed. It was found that exosomes can promote bone formation at the tendon-bone junction (66).

Exosomes have demonstrated potential value in the treatment of arthritis, primarily manifesting in alleviating cartilage damage, inhibiting bone overgrowth, and modulating immune responses. Certain types of exosomes show potential advantages in reducing inflammation and regulating immune responses, which could be significant for the treatment of disease models including Rheumatoid Arthritis (RA). Exosomes can inhibit the proliferation of T lymphocytes indicative of inflammation and induce other anti-inflammatory effects (67, 68). Additionally, exosomes are involved in numerous physiological and pathological processes, influencing the development of various diseases, including Osteoarthritis (OA), by regulating intercellular communication (69).

In the treatment of Rheumatoid Arthritis, exosomes can act as therapeutic carriers. These extracellular vesicles from mice cells affect biological mechanisms and signal transduction by transporting genetic and proteomic components (67). Exosomes also play a role in RA-related arthritis, where these specialized function extracellular vesicles are responsible for transporting autoantigens and mediators to distant cells (68).

Firstly, exosomes can promote cartilage repair and regeneration by regulating cell migration, proliferation, differentiation, and extracellular matrix synthesis. For example, exosomes from Mesenchymal Stem Cells (MSCs) can modulate immune responses, reduce cell apoptosis, enhance cell proliferation, and initiate the proliferation and migration of chondroprogenitor cells (19, 38). Additionally, exosomes can alleviate cartilage injury, reduce bone overgrowth, inhibit the production of M1 macrophages, and promote the generation of M2 macrophages, while also decreasing levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, and increasing levels of the anti-inflammatory cytokine IL-10 (70).

In the treatment of rheumatoid arthritis, exosomes can be used as therapeutic carriers; they are extracellular vesicles in mice that influence biological mechanisms and signaling and can play a role by transporting genetic and protein components (67). Exosome also plays a role in rheumatoid arthritis, these specialized functioning extracellular vesicles are responsible for transporting self-antigens and mediators to distant cells (68).

Exosomes, small vesicles originating from the endoplasmic reticulum, circulate through blood and other bodily fluids, providing a unique platform for intercellular communication. Recent research highlights the pivotal role of exosomes in metabolic regulation during physical activity, especially in endurance exercises (39, 71, 72). Here is an overview of the role of exosomes in exercise-induced metabolic regulation.

Bioactive Molecules in Exosomes: During exercise, the bioactive molecules within exosomes, such as peptides and nucleic acids (collectively termed exerkines), undergo alterations. Studies indicate that endurance exercise induces the release of exosomes, particularly peptides and nucleic acids from skeletal muscle and other tissues (73, 74). These bioactive molecules can exert endocrine-like effects, impacting the pathophysiology of conditions like obesity and Type 2 Diabetes (73–75).

Intercellular Communication Role of Exosomes: Functioning as endocrine-like vesicles, exosomes can carry proteins, microRNAs, and other nucleic acids, facilitating communication between cells and tissues, and even among organs. This contributes to the formation of a coordinated metabolic network within the body (72, 74, 76).

Future Therapeutic Potential of Exosomes: Researchers hypothesize that future therapies for obesity and Type 2 Diabetes might involve the use of modified exosomes enriched with exerkines. These exosomes, through their contained bioactive molecules, could positively regulate metabolic health, offering new therapeutic possibilities for these metabolic diseases (73, 74, 76).

Release of Exosomes and Exercise Intensity: Interestingly, studies have also discovered that with increasing exercise intensity, the concentration of exosomes in circulation correspondingly rises. This further suggests a critical role of exosomes in metabolic regulation during exercise (73, 77).

Recent research has unveiled the significance of exosomes in combating fatigue and oxidative stress (78–81). In the realm of anti-fatigue, exosomes are believed to improve cellular energy metabolism and enhance cells’ resistance to fatigue and damage. The mechanistic repertoire of exosomes in cellular bioenergetics encompasses the enhancement of mitochondrial efficacy, the amplification of adenosine triphosphate (ATP) synthesis, and the optimization of oxidative phosphorylation efficiency (78, 79). Additionally, the exosomal content of select RNA species and proteins may actuate specific metabolic cascades, thereby underpinning recuperative processes subsequent to physical exertion (78, 80, 81).

In the context of antioxidative activity, exosomes possess proficiency in the sequestration and neutralization of reactive oxygen species (80–82). This antioxidative mechanism is predominantly ascribed to the presence of enzymatic constituents within exosomes, such as catalases, sulfiredoxins, and an array of redox-modulating molecules. These enzymes are adept at obliterating surplus free radicals, thereby mitigating oxidative stress and attenuating cellular damage. Moreover, exosomes exert a modulatory effect on intracellular antioxidant pathways, including the Nrf2 axis, thereby reinforcing the cellular defense against oxidative insults (82). The exosomal complement of bioactive RNA and proteins also fine-tunes the redox equilibrium, which bolsters their antioxidative properties.

Empirical investigations have corroborated that exosomal antioxidants, for instance, glutathione and superoxide dismutase, are capable of neutralizing excessive reactive species, ameliorating oxidative detriment (82, 83). This plays an instrumental role in diminishing muscular fatigue post-exercise and decelerating cellular senescence. Furthermore, exosomal antioxidants are pivotal in sustaining intracellular redox homeostasis, thus endorsing normative cellular operations (84, 85). Additionally, exosomes harbor an ensemble of anti-fatigue molecular entities such as heat shock proteins and antioxidative enzymes, orchestrating the cellular stress response and fostering recuperation (82, 86). In response to fatigue-inducing stimuli, cellular systems can escalate the release of these anti-fatigue proteins via exosomes, thereby enhancing endurance and resilience.

Exosomes are implicated as pivotal entities in the mediation of myocyte repair, a process of particular pertinence to athletes undergoing rigorous training regimens (12, 52, 53, 87). In the aftermath of high-intensity exercise, athletes frequently endure microtraumas within muscular tissues, precipitating inflammation and consequent discomfort. Investigations have substantiated that exosomes possess the capability to encapsulate and convey growth factors, microRNAs, and an array of other bioactive compounds to myocytes experiencing trauma. This facilitates a cascade of cellular activities inclusive of proliferation, motility, and morphological specialization, thereby expediting the restoration and rejuvenation of compromised tissues. In addition, exosomes have been observed to potentiate athletic stamina. The myriad bioactive molecules harbored within exosomes are known to initiate a spectrum of metabolic processes that amplify the efficacy of mitochondrial oxidative phosphorylation (39, 88, 89). This suggests that in the milieu of sustained and intensive exertion, the myocytes of athletes are equipped to uphold an elevated rate of adenosine triphosphate (ATP) synthesis, thereby augmenting endurance.

In addition, exosomes can augment athletes’ antioxidative capabilities. During exercise, increased oxygen consumption leads to the production of reactive oxygen species (ROS), which can cause cellular damage (8, 48, 82, 83). However, antioxidative enzymes and other molecules within exosomes can effectively scavenge these free radicals, protecting cells from damage and expediting the recovery process. Lastly, exosomes can modulate immune responses, reducing post-exercise inflammatory reactions. Specific proteins and RNA molecules within exosomes can influence the activation and secretion of immune cells, thereby inhibiting the production and release of inflammatory cytokines and reducing post-exercise inflammation ( Figure 1 ) (50, 90, 91).