Exos encompass a diverse array of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell-derived neurotrophic factor (GDNF) (48, 49) (Figure 2). These neurotrophic elements are capable of activating intracellular survival signaling pathways, such as the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathways. Such activation inhibits the initiation of apoptotic processes and enhances the survival capacity of neuronal cells (50). In addition, Exos contain anti-apoptotic proteins, including members of the B-cell lymphoma-2 (Bcl-2) family and heat shock proteins (HSPs) (Figure 2). These proteins modulate mitochondrial function, stabilize mitochondrial membrane potential, and inhibit the release of cytochrome C, thereby obstructing the apoptotic cascade and reducing neuronal apoptosis (51–53).

Fu et al. (54) demonstrated that Exos derived from human adipose tissue mesenchymal stem cells (MSCs) inhibit neuronal apoptosis and promote neurogenesis via the miR-21a-3p/PI3K/Akt signaling pathway. Zhu et al. developed a nanofiber scaffold composed of a hyaluronic acid hydrogel patch designed to deliver Exos and methylprednisolone to the injured spinal cord in a non-invasive manner. This approach effectively inhibited inflammation and neuronal apoptosis while enhancing neuronal survival through the modulation of TLR4/MyD88/NF-κB, MAPK, and Akt/mTOR pathways (55). Furthermore, Maresin 1 (MaR1), recognized as an anti-inflammatory and pro-resolving mediator, exhibits potential for tissue regeneration. Wei et al. (56) found that MaR1 suppresses astrocyte activation via the PI3K/Akt/mTOR signaling pathway, reduces the production of pro-inflammatory cytokines in the spinal dorsal horn of mice, and facilitates the regeneration of injured nerves. Neuregulin-1 (Nrg1) is crucial for the differentiation of oligodendrocytes. Ding et al. demonstrated in a study involving SCI in rats that intravaginal administration of Nrg1 can induce the transformation of reactive astrocytes into oligodendrocyte lineage cells, a process mediated by the PI3K/Akt/mTOR signaling pathway. This pathway inhibits astrocyte proliferation, promotes myelin regeneration, and protects axons (57). Furthermore, natural compounds such as resveratrol, 7,8-dihydroxyflavones, propofol, and cephalin have been shown to exert neuroprotective effects through modulation of the PI3K/Akt/mTOR signaling pathway (58). The potential for combining Exos with these substances to treat SCI and achieve a synergistic therapeutic effect presents a promising strategy for the regulation of nerve damage, warranting further investigation.

In recent years, a breakthrough has been made in the mechanism research of Exos in the field of neuroprotection. Pay, etc. confirmed that the high expression of BDNF nasal delivery non-greeks secrete body (MSCs–sEV) can be targeted enrichment in SCI, its concentration of neurotrophic factor is a natural body secretion of eight times, in the rhesus monkey model, to realize motor function recovery rate was 67% (46). Sun et al. also found that nasal delivery of a specific subset of MSC-derived small extracellular vesicles, CD146+CD271+ ucmsc-sev, could target and enrich at the site of SCI and inhibit DLL4 through the transfer of miR-27a-3p to regulate inflammation, inhibit apoptosis, and promote nerve regeneration. It can effectively reduce traumatic SCI and improve neurological function recovery (59). In addition, Exos have shown remarkable potential for inhibiting iron death and thus promoting neuroprotection (60, 61). Exos can play a role by transferring specific proteins, miRNAs, and other molecules, regulating iron metabolism, enhancing antioxidant capacity, and regulating related signaling pathways. These mechanisms, on the one hand, reduce the accumulation of iron ions in neurons, on the other hand, alleviate oxidative stress and lipid peroxidation, and ultimately inhibit ferroptosis (62, 63). Zhang et al. (64) were the first to show that in vitro Exos therapy activates mitochondrial phagocytosis via the PINK1/Parkin pathway, thereby reducing ferroptosis in neuronal cells, which plays a crucial role in neuroprotection following trauma. Similarly, Chen et al. (65) demonstrated that mesenchymal stem cell-derived Exosomes (MSC-Exos) alleviate ferroptosis in microglia through the Nrf2/GCH1/BH4 signaling pathway, indicating their promising potential in protecting and restoring neural function after SCI.

Consequently, Exos exhibit anti-apoptotic and neuroprotective properties through the transmission of anti-apoptotic signaling molecules, modulation of intracellular signaling pathways, and inhibition of ferroptosis. These mechanisms suggest a wide range of potential applications for Exos in the treatment of neurological disorders.

Exos play a crucial role in axon regeneration and synaptic remodeling (66). They are enriched with various axon growth factors, including neurofilament and microtubule-associated proteins (MAPs) (Figure 2), which are instrumental in facilitating axonal growth and extension (67, 68). Concurrently, the transfer of RNA is critical in tissue formation. Exos are rich in diverse miRNAs that can modulate gene expression to enhance axon regeneration and myelination (69) (Figure 2). In a study by Gao et al. (70) the delivery of miR-26a to damaged neurons via an in vivo regenerative system led to decreased astrocyte activation at the injury site and promoted neuronal axon growth. Furthermore, research by Huang et al. demonstrated that Exos derived from endothelial cell (EC) culture medium can activate the PI3K/Akt/PTEN signaling pathway by upregulating miR-199-5p, thereby facilitating nerve regeneration. Their findings also indicated that EC-derived Exos exhibit strong neuronal affinity both in vitro and in vivo (71). In a study utilizing the SCI model, Sun et al. successfully isolated Exos characterized by CD271+CD56+ markers from a specific CD271+CD56+ bone marrow stromal cell (BMSC) subgroup through on-site implantation. Their findings indicated that miR-431-3p plays a crucial role in the mechanism by which CD271+CD56+ BMSC-derived Exos facilitate functional recovery and axonal regeneration post-SCI (72). Similarly, Fan et al. identified that BMSC-derived Exos modulate M2 polarization of microglia via the NF-κB signaling pathway, resulting in a marked decrease in CD68-positive microglia, enhanced recruitment of local neural stem cells (NSCs), and increased axonal growth through the PTEN/PI3K/Akt/mTOR pathway. This process significantly contributes to early functional recovery in mouse models of SCI (73). Additionally, other research has demonstrated that exercise training may work synergistically with BMSC-derived Exos to regulate neuronal apoptosis via the JNK1/c-Jun signaling pathway, thereby reconstructing neural circuits, promoting synaptic formation and axonal regeneration, and ultimately enhancing neural function recovery (74).

In recent years, breakthroughs have been made in the molecular mechanism of Exos in synaptic remodeling, which has become the core strategy for SCI repair by regulating the dynamic balance of synaptic structure and function at multiple levels. Postsynaptic density (PSD) is a key structure in synaptic plasticity, and its dynamic assembly depends on protein phase separation. The study by Zhang's team found that the scaffold protein SAPAP carried by mesenchymal stem cell Exos regulates the fusion and separation of PSD core and PSD pallium through phosphorylation: when the phosphorylation level of SAPAP increased, PSD core fused with PSD pallium to form a homogeneous concentrated phase, which enhanced the aggregation of NMDA receptors on the postsynaptic membrane. Under low phosphorylation, the PSD structure dissociates to maintain synaptic stability. In the SCI rat model, exosome intervention increased the PSD volume by 2.1 times and the synaptic transmission efficiency by 40% (75). Another study confirmed that the postsynaptic density protein 95 (PSD-95) carried by Exos of neural stem cells could participate in the assembly of PSD and promote the recovery of synaptic connection strength in the injured area (76). In addition, RVG-BDNF-Exos (BDNF-targeted delivery Exos modified by rabies virus glycoprotein) developed by Cheng's team penetrated the BBB after tail vein injection, specifically bound to nicotinic acetylcholine receptors on the surface of neurons, and delivered the BDNF gene to postsynaptic neurons. The Exos significantly up-regulated the expression of PSD95 and Syn-1 in the hippocampus and the injured area of the spinal cord, restored the synaptic density to 68% of the normal level, and reversed the synaptic loss by activating the TrkB/ERK pathway. A similar strategy improved axonal regeneration to 58% in a macaque model of SCI, demonstrating the clinical potential of targeted delivery for the first time in a non-human primate (77). According to Piette et al. (78) neural energy metabolism is closely related to synaptic plasticity. Kochan et al. found in animal experiments that there will be a transient surge in mitochondrial fusion dynamics when newborn neurons enter the critical period. This process can stabilize the elongated mitochondrial morphology in dendrites and provide energy support for synaptic plasticity, which is crucial for the plasticity of new synapses and the improvement of existing brain circuits (79).

In addition, neural precursor cells expressing developmentally down-regulated protein 4 (NEDD4) combined with Exos may play an important role in the treatment of SCI. After wrapping NEDD4 in Exos, NEDD4 can be transported to related cells at the site of injury, such as neurons and glial cells. Thus, it can play a more effective role in relieving the inhibition of nerve regeneration and regulating the microenvironment of nerve regeneration (80, 81). NEDD4, as an E3 ubiquitin ligase, is involved in the regulation of axon guidance during neural development. NEDD4-1 and NEDD4-2 were found to be required for axon guidance at the spinal commissural, and they regulate Roundabout (Robo) receptor endocytosis, ubiquitination, and degradation by interacting with Ndfip1 and Ndfip2 proteins to form a complex. Robo receptor is an axon guidance receptor that plays an important role in axon growth cone guidance (82, 83). Ding et al. (84) discovered that Nedd4 is required for developmental myelination by stabilizing the E3 ligase VHL through K63-linked ubiquitination, revealing a new role for Nedd4 in glial biology. Fimiani et al. (85) demonstrated in animal experiments that Nedd4 is required for the correct accumulation of differentiated oligodendrocytes and can promote myelination in the central and peripheral nervous systems of mice. Sullivan and Bashaw et al. (86) demonstrated that commissuless (Comm) promotes the growth of the axon midline by promoting Robo1 ubiquitination of Nedd4 and eventually leading to its degradation. Shi et al. (87) also found in animal experiments that NEDD4 may control the molecular mechanism of the endocytosis pathway and play an important role in the initiation stage of demyelination and axon regeneration. After SCI, NEDD4 may regulate related receptors through a similar mechanism, affect the regeneration and growth direction of axons, and promote the correct extension of axons at the injury site. In addition, it has been found that MiR-155-5p overexpression inhibits nuclear PTEN expression by targeting Nedd4 family interacting protein 1 (Ndfip1), which in turn aggravates astrocyte activation and glial scarring in SCI models (88). NEDD4 may regulate the expression and function of related proteins in glial cells, inhibit the over-expressed proteins that hinder nerve regeneration in the glial scar, and promote the secretion of some factors that are beneficial to nerve regeneration, thereby improving the microenvironment of nerve regeneration.

Exos have exhibited tremendous potential and diverse mechanisms in promoting nerve regeneration; however, there remain numerous unexplored areas that require further investigation to fully harness their role in nerve regeneration and disease treatment while advancing their development and application in clinical settings.

The occurrence of inflammation is a prominent pathological process following SCI, and effective management of both local and systemic inflammation plays a pivotal role in enhancing patient prognosis (89, 90). SCI triggers a robust inflammatory response, leading to the release of numerous inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) (91, 92), thereby exacerbating neuronal damage (Figure 2).

In the event of SCI, macrophages accumulate at the injury site and play a pivotal role in the subsequent immune response (93). Macrophage-derived Exos significantly influence the immune microenvironment in SCI, with the miR-23a-3p/PTEN/PI3K/Akt signaling pathway potentially playing a critical role (94). Exos can modulate macrophage polarization by promoting the M2 subtype while inhibiting the activation of the M1 subtype. M2 macrophages exhibit anti-inflammatory properties and facilitate tissue repair, whereas M1 macrophages release pro-inflammatory cytokines that intensify inflammation (95–97). Ren et al. demonstrated that spinal cord-derived Exos can mitigate inflammation following SCI by suppressing M1 polarization and promoting M2 polarization. The SOCS3/STAT3 signaling pathway is essential in enhancing the inflammatory microenvironment and inhibiting neuronal apoptosis (98). Additionally, reactive oxygen species (ROS) can induce M1 macrophage polarization via the MAPK/NF-κB P65 signaling pathway. Liu et al. (99) reported that Exos derived from dental pulp stem cells ameliorate SCI by reducing M1 macrophage polarization through the ROS/MAPK/NF-κB P65 signaling pathway. Peng et al. (100) also observed that histone demethylase UTX deletion (UTX–/–EC) in endothelial cells promotes neural recovery mainly through Exos from UTX–/–EC polarizing macrophages toward an M2 subtype after SCI.

Moreover, bioactive molecules such as miRNAs and proteins within Exos may contribute to the modulation of inflammatory responses. Yuan et al. (101) reported that endothelial cell-derived Exosomes (EC-Exos) enhanced the prognosis of SCI via the SOCS3/JAK2/STAT3 signaling pathway, while the upregulation of miR-222-3p in EC-Exos led to a reduction in pro-inflammatory macrophages and an increase in anti-inflammatory macrophages. Liu et al. further demonstrated the potential involvement of miR-216a-5p in the polarization of microglial cells. Additionally, it has been observed that MSC-Exos produced under hypoxic conditions exert a more pronounced effect on neurological function recovery compared to normoxic MSC-Exos (24). Regulatory T (Treg) cells, recognized as potent anti-inflammatory agents, play a crucial role in mitigating neuroinflammation following SCI. Kong et al. (102) demonstrated that Exos derived from Treg cells can encapsulate and deliver miR-2861 to modulate IRAK1 expression, thereby influencing BSCB integrity and reducing neuroinflammation in murine models of SCI. Furthermore, Xiong et al. (103) confirmed through animal studies that Treg cells target NKAP with miR-709, leading to decreased microglial apoptosis and enhanced motor function recovery post-SCI. These findings suggest that by strategically designing and applying specific combinations of these miRNAs, synergistic effects could potentially enhance the effectiveness of SCI repair.

In addition, the activation of Bruton's tyrosine kinase (BTK) is associated with microglia/astrocytes and B-cell neuroimmune response mechanisms. Ibrutinib is a BTK inhibitor in innate immune cells. Torabi et al. (104) found that ibrutinib can reduce neutrophil infiltration, protect nerve tissue, and enhance the recovery of motor ability in SCI model mice. Yu et al. (105) also found in animal experiments that ibrutinib blocked excessive neuroimmune responses and promoted neuroprotection in SCI rat models through BTK-mediated activation of microglia/astrocytes and B cell/antibody responses. Therefore, Exos combined with ibrutinib may provide a new strategy for the treatment of SCI.

Effective angiogenesis is essential for the reparative processes following SCI. Exos contain a variety of angiogenesis-related factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) (106, 107). These factors facilitate the proliferation and migration of vascular endothelial cells and support the formation of vascular lumens at the site of injury, thereby ensuring an adequate supply of nutrients and oxygen necessary for the survival and regeneration of nerve cells (19, 108). Li et al. demonstrated that cerebrospinal fluid-derived Exosomes (CSF-Exos) can activate the PI3K/Akt signaling pathway, promoting vascular regeneration and enhancing motor function recovery post-SCI. This discovery indicates a potential novel therapeutic strategy for acute SCI (109). Additionally, Luo et al. (36) reported that Exos derived from M2 macrophages (M2-Exos) augment angiogenic activity in vitro by activating the Wnt/β-catenin signaling pathway through the transfer of OTULIN protein, thereby promoting vascular regeneration and functional recovery in murine models of SCI. Li et al. (23) on the other hand, effectively repaired neural tissue in mice by stimulating angiogenesis using Exos derived from human umbilical vein endothelial cells (HUVEC) through hypoxia pretreatment.

Furthermore, Exos exhibit the potential to facilitate the repair of the BSCB and preserve its integrity. In a study conducted by Gao et al. (110) the administration of Exos into mice with SCI demonstrated that miR-210 activates the JAK1/STAT3 signaling pathway, thereby modulating endothelial barrier function, enhancing BSCB integrity, and promoting the recovery of motor function. In another animal experiment conducted by Xie et al. (111) CD146+CD271+ MSC-Exos were found to upregulate tight junction protein expression and promote BSCB repair through the miR-501-5p/MLCK signaling pathway.

Although there is some understanding of how Exos promote angiogenesis and BSCB repair, further investigation is necessary to elucidate their mechanisms for better therapeutic efficacy.

The ECM is integral to the reparative processes following SCI (112). The lack of nerve regeneration is largely due to the absence of intrinsic nerve growth programs and the development of glial scars (113, 114). Exos, as essential mediators of intercellular communication, possess significant potential in facilitating ECM remodeling post-SCI (115, 116).

Exos play a crucial role in maintaining spinal stability by modulating the synthesis and degradation of collagen, regulating fibronectin levels, and influencing other components of the ECM. This modulation leads to alterations in both the structure and function of the ECM, while simultaneously inhibiting the release of inflammatory mediators and reducing the formation of glial scars. As a result, a conducive microenvironment for nerve regeneration is established (117, 118). Additionally, Exos can transport matrix metalloproteinases (MMPs) or their inhibitors, such as tissue inhibitors of metalloproteinases (TIMPs) (119), thereby managing ECM degradation and reconstruction by regulating the balance of these molecules (120). During tissue repair and regeneration, Exos enhance pathological microenvironments by preventing or mitigating scar tissue formation, thereby promoting repair (116). Liu et al. (121) demonstrated through animal studies that bone marrow mesenchymal stem cell-derived Exosomes (BMSC-Exos) effectively suppress inflammation following traumatic SCI, inhibit the activation of A1 neurotoxic reactive astrocytes, reduce glial scar formation, and facilitate nerve regeneration. In another animal experiment, Cheng et al. also found that human umbilical cord mesenchymal stem cells (HucMSC-EX) exosomes-embedded gelatin foam delivered miRNAs or proteins to inhibit the expression of chondroitin sulfate proteoglycan (CSPG) synthesis-related genes, while upregulating the activity of metalloproteinases such as ADAMTS to promote their degradation. On the other hand, it directly blocked the activation of CSPG receptors PTPσ and NgR, inhibited the downstream RhoA/ROCK pathway, and released the inhibition of axon growth. Gelatin sponge scaffolds can enhance the regulatory effect by sustained-release Exos and guide their directional distribution, and ultimately improve the microenvironment of nerve regeneration (122). Singh et al. found that Rab27a could mediate the release of CSPG-containing EVs from astrocytes, increase CSPG expression through the Rho/ROCK pathway, affect pAkt and β-tubulin III levels, and promote axonal degeneration and glial scar formation. This suggests that Rab27a-related mechanisms in Exos affect the content and distribution of CSPG in the ECM, which in consequence affects the repair process after SCI. Inhibition of Rab27a-mediated EVs release may reduce CSPG deposition, inhibit glial scar formation, and create a better ECM environment for nerve regeneration (123). Another team found that Exos secreted by UTX-depleted vascular endothelial cells carried miR-467b-3p, which transferred to macrophages, inhibited PTEN expression, activated PI3K/AKT/mTOR signaling pathway, and promoted macrophage polarization to anti-inflammatory M2 type, reducing inflammatory response. It can reduce the destruction of ECM by inflammation, and at the same time may promote the repair and remodeling of ECM, providing a more favorable microenvironment for nerve regeneration (100). In addition, some Exos can regulate the expression and function of BBB-related proteins in the blood. For example, arginine-glycine-aspartic acid (RGD) -modified Exos derived from CD163 + macrophages can deliver transforming growth factor β (TGF-β) to the neovascularization in the center of SCI, promote angiogenesis and stability of the blood-brain spinal barrier, and reduce the invasion of inflammatory cells and harmful substances. Maintaining the stability of ECM is beneficial to nerve regeneration (124).

Overall, Exos influence cellular behavior and tissue repair processes by modulating the composition, structure, and functionality of the ECM. These regulatory mechanisms are essential for the maintenance of normal tissue and recovery following injury.

Firstly, hydrogel, as a scaffold material, exhibits excellent biocompatibility and possesses loose and porous structural characteristics. It can serve as a carrier for Exos, thereby prolonging their residence time in specific areas and facilitating controlled release (106). Numerous studies have demonstrated that the combination of Exos with hydrogels promotes the survival and regeneration of nerve cells while reducing inflammatory responses (72, 73). Han et al. (125) utilized Exos combined with hydrogel to treat SCI, ensuring more reliable, convenient, and effective delivery of Exos to targeted regions. Guan et al. (126) combined M2-Exos with hydrogel, while Li et al. (127) combined MSC-Exos with hydrogel; both treatment approaches resulted in accelerated neuron and axon regeneration as well as significantly enhanced functional recovery in SCI rats. Secondly, bioscaffolds composed of natural polysaccharides, protein polymers, self-assembled peptides, and biocompatible polymers such as polylactic acid (PLA) and polyvinyl alcohol (PVA) have been extensively utilized in the repair of spinal cord injuries (128). Liu et al. (129) incorporated collagen scaffolds with Exos' surface to facilitate the retention of miR21-loaded Exos at the lesion site and ensure a sustained release of miR21 into cells. Zhang et al. (130) fused umbilical cord MSC-Exos with multifunctional collagen scaffolds to offer a versatile therapeutic approach for various diseases including SCI. The combination of Exos with these scaffold materials can augment the biological activity of the scaffold and promote nerve regeneration.

Exos is a natural nanocarrier secreted by a variety of cells. It has the characteristics of high stability, targeting, low immunogenicity, and good biocompatibility, and is suitable for various drug delivery and therapeutic applications (26, 28, 35, 131). Through genetic engineering and chemical modification techniques, drugs can be encapsulated inside or attached to the surface of Exos to construct targeted drug delivery systems (NDDS) that can specifically deliver drugs to certain types of cells or tissues (27, 132). The most common bioactive molecules loaded in Exos include miRNA, mRNA, proteins, and small molecules (39, 133). Moreover, engineered Exos can also be combined with metal nanoparticles, graphene, and other nanomaterials to enhance their targeting ability and bioavailability (134, 135). In the treatment of nervous system diseases specifically, Exos have emerged as promising carriers for delivering drugs due to their inherent capability to cross the BBB and BSCB (111, 136). Guo et al. (137) delivered Exos loaded with phosphatase and tenin homologous siRNA to SCI rats and found that Exos could cross the BBB and migrate to the injured spinal cord area, improving motor function, sensory function, and faster recovery of urinary reflex. Cui et al. (138) on the other hand, utilized immune Exos loaded nano micelles capable of crossing the BBB for treating glioblastoma, which not only exhibited improved efficacy but also prevented postoperative recurrence. In another study conducted by Gao et al. (139) M2-Exos loaded with berberine were employed for treating mice with SCI, resulting in significant improvement in motor function. As carriers for NDDS, Exos exhibit great potential and application prospects. With further research advancements, Exos-based therapies will find wider utility in precision medicine, personalized therapy, and other related fields.

In the progress of researching Exos-based SCI therapies, despite significant achievements, the field still faces numerous challenges and unanswered questions. Firstly, a major issue lies in the source and quality control of Exos (32, 131). Exos derived from different cell origins may exhibit substantial variations in composition, function, and therapeutic effects (148). Currently, various Exos separation technologies have been developed based on size, density, compatibility, and surface protein characteristics (149), but large-scale mass production (13) and ensuring the purity, stability, and biological activity of Exos remain crucial issues that need to be addressed. Additionally, during storage and transportation processes, Exos are prone to aggregation and degradation, which can impact their therapeutic efficacy (150, 151). Secondly, the therapeutic mechanism of Exos is not fully understood. While it is known that Exos can exert therapeutic effects by delivering bioactive molecules, little is known about their specific signaling pathways or cell-cell interactions among other mechanisms (16, 115). This lack of understanding makes it challenging to optimize and personalize Exos therapy. Furthermore, targeted delivery of Exos also poses a challenge. Despite improvements in targeting ability through combining with biological scaffolds, the presence of BSCB at the SCI site, along with the complex microenvironment, still presents significant obstacles for efficient targeted delivery (152). Lastly, long-term efficacy and safety concerns regarding Exos therapy cannot be ignored. Although short-term animal experiments have shown certain effectiveness of Exos treatment (122, 153), further investigation is required to assess long-term effects and potential complications such as tumor formation and neurodegeneration (34, 154). Designing well-designed clinical trials to evaluate the safety and effectiveness of Exos therapy is an important step toward the clinical translation of the therapy.

Future research should focus more on these issues, pushing the field forward through technological innovation and rigorous scientific validation, ultimately providing more effective treatment options for SCI patients.

With the ongoing advancement of Exos research, significant breakthroughs are expected in the treatment of SCI. The future research directions mainly focus on optimizing the methods for the separation and purification of Exos to enhance both yield and quality. Furthermore, investigating the underlying mechanisms of Exos will provide a solid theoretical foundation for their clinical application. Additionally, developing targeted therapeutic strategies for Exos and improving their efficacy aims to boost treatment outcomes. Lastly, carrying out large-scale clinical trials is essential to validate the safety and effectiveness of Exos in treating SCI.