Yuanhu Shi
Zhilong Li1,2†
Qinghua Wang
Yuyu Sun- 1School of Medicine and Affiliated Nantong Hospital 3 of Nantong University, Nantong, Jiangsu, China
- 2School of Medicine, Nantong University, Nantong, Jiangsu, China
- 3Laboratory Animal Center, Nantong University, Nantong, Jiangsu, China
- 4Department of Spine Surgery, Nantong City No.1 People's Hospital and The Affiliated Hospital 2 of Nantong University and Research Institute for Spine and Spinal Cord Disease of Nantong University, Nantong, Jiangsu, China
- 5Department of Science and Education in Affiliated Nantong Hospital 3 of Nantong University and Nantong Third People's Hospital, Nantong, Jiangsu, China
- 6Department of Orthopedics in Affiliated Nantong Hospital 3 of Nantong University, Nantong, China
Spinal cord injury (SCI) is a devastating disorder of the central nervous system. It is characterized by primary mechanical damage and secondary pathological cascades. These lead to persistent sensory and motor deficits, substantial socioeconomic burdens, and limited therapeutic efficacy. Exosomes are nanoscale vesicles secreted by various cells that serve as key mediators of intercellular communication by delivering bioactive molecules, particularly microRNAs (miRNAs), which regulate gene expression in target cells. This review explores how exosomal miRNAs contribute to neural repair in SCI. These contributions include inhibiting neuroinflammation via pathways such as NF-κB and TLR4; suppressing neuronal apoptosis through PTEN/PI3K/Akt signaling; promoting axonal regeneration via the ERK1/2/STAT3 and NGF/TrkA pathways, enhancing angiogenesis by targeting SPRED1 and integrin α5, and modulating of the immune microenvironment toward M2 polarization, and multifaceted neuroprotection involving alleviating autophagy and endoplasmic reticulum stress. Drawing on recent preclinical studies from 2024–2025, including those utilizing mesenchymal stem cell–derived exosomes loaded with miRNAs such as miR-124-3p, miR-338-5p, and miR-216a-5p, the review highlights promising innovations, such as bioengineered exosomes and biomaterial integrations. Recent preclinical advancements, such as exosome-based therapies that have shown reduced lesion volumes and improved motor function in rodent models, highlight the potential for translation to clinical applications. Ongoing efforts are anticipated to lead to clinical trials in the near future. Despite challenges in standardization, delivery efficiency, immunogenicity, and long-term safety, exosomal miRNA therapy offers a cell-free, multitargeted approach with strong potential for clinical translation in SCI management.
1 Part I: Introduction to spinal cord injury
1.1 Epidemiology and pathophysiology of spinal cord injury
SCI is a central nervous system injury that is usually caused by traumatic events such as traffic accidents, falls, sports injuries, or violence (Silva et al., 2014). Each year, approximately 10.4–83 per million worldwide suffer from SCI. Moreover, the mortality and morbidity rates are on the rise every year (GBD Spinal Cord Injuries Collaborators., 2023; Yu et al., 2024). The pathological process of SCI can be divided into two stages: primary and secondary injury. Primary injuries are caused by mechanical forces acting directly on the spinal cord, resulting in physical destruction of neurons, axons, and blood vessels (Ahuja et al., 2017). Secondary injury usually occurs within hours to weeks, the pathological process of secondary spinal cord injury is complex and covers a few aspects including hemorrhage and hematomas formation, inflammatory response, ischemia and hypoxia, toxic effects of excitatory amino acids, apoptosis and glial scar formation (Hu et al., 2023; Anjum et al., 2020). After the SCI, blood vessel rupture leads to hemorrhage and hematomas formation, which compresses the nerve tissue and hinders the blood supply, aggravating the local ischemia and hypoxia (Alizadeh et al., 2019); in the inflammatory response, the damage of vascular endothelial cells destroys the blood-spinal cord barrier (BSCB), which leads to the exudation of inflammatory cells and release of inflammatory mediators (Liu et al., 2021), and at the same time, the injured neuronal cells also release cytokines and chemokines, attracting more inflammatory cells, thus forming a vicious circle (Hellenbrand et al., 2021); the energy metabolism of nerve cells is impaired by ischemia and hypoxia, which leads to dysfunction of ion pumps and overloading of intracellular ions, resulting in oedema and rupture of cells (Anjum et al., 2020; Okada, 2016; Ortega et al., 2023; Li et al., 2022b); the release of large amounts of excitatory amino acids excessively activates cell membrane receptors, leading to inward flow of calcium ions and activation of calcium-dependent enzymes to destroy the cellular structure and function (Zrzavy et al., 2021); apoptosis is triggered by a variety of factors, affecting the number of nerve cells surviving; glial scarring has the role of isolating the damaged area, but overgrowth hinders the regeneration and extension of nerve axons (Zrzavy et al., 2021; Orr and Gensel, 2018). In addition, oxidative stress also plays an important role in secondary damage, where excess Reactive Oxygen Species (ROS) can trigger lipid peroxidation, protein denaturation and DNA damage, leading to apoptosis and necrosis (Visavadiya et al., 2016). These secondary reactions further exacerbate neuronal damage and lead to irreversible loss of function (Gris et al., 2008). This complex pathological process ultimately leads to long-term dysfunction and severely reduced quality of life in patients with SCI (Hagen, 2015).
1.2 Current treatments and emerging therapies for spinal cord injury
SCI is a devastating condition leading to permanent functional deficits, with current treatments focusing on acute stabilization through surgical decompression, methylprednisolone for polarization, and hemodynamic management to mitigate secondary damage, alongside rehabilitation therapies like physical training and assistive devices to preserve remaining function and prevent complications (Karsy and Hawryluk, 2019). Emerging regenerative approaches include stem cell transplantation, nanomaterials, and gene therapies to promote neural repair (Bartlett et al., 2020; Sugai et al., 2025). Recent advances in exosome-based RNA therapy for SCI highlight its potential as a cell-free therapy (Hwang et al., 2023). From 2024 to 2025, studies showed that exosomes derived from mesenchymal stem cells (MSCs) and neural stem cells can effectively deliver therapeutic RNAs, such as miR-21, miR-124-3p and miR-145-5p, to the site of SCI by crossing the BSCB. In rodent models, these RNAs have been shown to inhibit inflammation through pathways such as NF-κB, reduce neuronal apoptosis, promote axonal regeneration, enhance angiogenesis, and significantly improve motor recovery (Ralph et al., 2024). Innovations include bioengineered exosomes with enhanced miRNA loading (e.g., miR-26a, miR-133b) and integration with biomaterials, such as scaffolds, to optimize delivery and retention (Sousa et al., 2025). For instance, a study demonstrated that bone marrow-derived mesenchymal stem cell exosomes containing miR-338-5p reduced cell apoptosis via the Cnr1/Rap1/Akt axis (Zhang et al., 2021). Another study reported that hypoxia-pretreated bone marrow-derived mesenchymal stem cell exosomes containing miR-216a-5p promoted M2 macrophage polarization (Shao et al., 2024; Liu et al., 2020). Despite challenges such as low yield and standardization, bibliometric analysis indicates a robust trajectory toward clinical translation, with ongoing trials exploring safety and efficacy. To further illustrate the translational potential, recent preclinical studies from 2024–2025 have paved the way for clinical applications. For example, a 2025 study on exosome-based therapy for SCI in rodent models demonstrated nerve regeneration and functional recovery, with plans for human clinical trials announced for 2026. These developments, combined with interdisciplinary efforts in bioengineering, suggest exosomal miRNA therapy could soon enter broader clinical testing.
2 Part II: Introduction to exosomes and exosomal miRNAs
2.1 Biogenesis and composition of exosomes
Exosomes are nanoscale, membrane-bound vesicles that are actively secreted by nearly all cell types into the extracellular space under physiological or pathological conditions. They typically range in diameter from 30 to 150 nanometers. They act as “messengers” for intercellular communication, stably carrying and transporting various bioactive molecules from source cells within their lipid bilayer membranes. The contents of exosomal vesicles are particularly important and include proteins, lipids, and nucleic acids, especially functional RNAs such as messenger RNA (mRNA), miRNA, and lncRNA (Kalluri and Lebleu, 2020). These exosomal RNAs are not passively loaded, but rather are products of cellular sorting mechanisms. After being delivered to recipient cells, they can directly participate in and regulate gene expression networks, thereby playing a crucial role in remodeling the microenvironment and regulating cellular function.
2.2 Advantages of exosomes as delivery vehicles in spinal cord injury treatment
Exosomes' unique property as natural information carriers gives them unparalleled advantages in the treatment of SCI (Tan et al., 2024; Li et al., 2024). The pathological microenvironment following SCI is extremely complex. RNA molecules, which can regulate multiple key pathways, such as inflammation, apoptosis, angiogenesis, and axonal regeneration, simultaneously, are considered highly promising therapeutic tools (Figure 1) (Gaudet and Popovich, 2014). However, naked RNA molecules are highly unstable in vivo. They are prone to rapid degradation by nucleases and struggle to penetrate physiological barriers. This severely limits their clinical application. Exosomes effectively address these challenges. First, their natural membrane structure provides robust protection for the internal RNA, shielding it from degradation. Second, they exhibit excellent biocompatibility and low immunogenicity, ensuring the safety of the delivery process. More critically, they can cross the blood-brain barrier, enabling them to deliver RNA directly to the central nervous system's core injury site (Luan et al., 2017). Therefore, using exosomes as RNA delivery carriers is a strategic “empowerment” that significantly amplifies the therapeutic efficacy of RNA. This opens up a promising path for developing efficient, safe, new strategies for spinal cord injury repair.
Figure 1. Biogenesis and functional regulation of exosomes in the spinal cord microenvironment.
2.3 Role of exosomal non-coding RNAs with a focus on miRNAs
Exosomes carry a variety of RNA molecules that form a complex regulatory network which participates in the repair process following spinal cord injury. Key non-coding RNA molecules include miRNAs, lncRNAs, circRNAs, and others. LncRNAs and circRNAs can act as “molecular sponges” to absorb miRNAs or participate in other complex regulatory mechanisms, playing a role in neural regeneration and functional remodeling (Wu et al., 2022). However, miRNAs are undoubtedly the most studied and mechanistically well-understood class of molecules in current research (Silvestro and Mazzon, 2022). They precisely “silence” the expression of specific genes at the post-transcriptional level by binding to the mRNA of target genes (Bartel, 2018). This efficiently regulates key pathological processes, such as inflammatory responses, cell apoptosis, and axonal growth (Yang et al., 2022; Pan et al., 2021). Due to significant breakthroughs in the study of miRNAs in spinal cord injury repair and relatively clear mechanisms, this review will focus on miRNAs delivered via exosomes (Table 1). It will systematically elucidate their mechanisms of action and application prospects in spinal cord injury treatment.
Table 1. Mechanisms and therapeutic potential of different miRNAs in spinal cord injury.
3 Part III: Functions of exosomal miRNA in the treatment of spinal cord injury
3.1 Inhibition of neuroinflammatory responses
Neuroinflammation is the primary mechanism that drives secondary pathological cascade reactions following SCI. Following injury, the release of numerous pro-inflammatory cytokines, such as IL-1β and TNF-α, activates signaling pathways, including NF-κB and TLR4 (Ransohoff, 2016; Wang et al., 2015). This exacerbates neuronal damage and deteriorates the local microenvironment. Exosome-derived miRNAs can target these pathways precisely or directly regulate pro-inflammatory transcription factors, such as IRF5 (Gong et al., 2024). This effectively inhibits excessive activation of microglia and macrophages, mitigating the inflammatory response (Yuan et al., 2023). The therapeutic value of exosomes lies in breaking the vicious cycle of inflammation, reducing secondary neural damage, and creating favorable conditions for tissue repair and functional recovery (Nakazaki et al., 2021). For instance, Jiang et al. showed that Neural stem cells (NSC) exosome-derived miR-124-3p inhibits the PI3K/AKT/NF-κB pathway by targeting MYH9. This significantly reduces pro-inflammatory factor levels and improves motor function in SCI rat models (Jiang et al., 2020). From a systems biology perspective, miRNAs like miR-124-3p interact with multiple pathways and cell types in the SCI microenvironment, forming competing endogenous RNA (ceRNA) networks that modulate inflammation across microglia, astrocytes, and macrophages. Integrated multi-omics profiling in rat models has revealed miRNA-guided regulatory networks post-SCI, where miRNAs orchestrate gene expression hubs involving inflammation, apoptosis, and regeneration, highlighting their role as central nodes in dynamic cellular interactions (Klassen et al., 2025). Similarly, Liu et al. (2020) found that hypoxia-pretreated MSC exosomes regulate the TLR4/NF-κB pathway via miR-216a-5p, inducing microglia to polarize from the pro-inflammatory M1 type to the anti-inflammatory M2 type. Recent evidence indicates that hypoxia-preconditioned bone marrow mesenchymal stem cell (BMSC)-derived exosomes enriched with miR-146a-5p can promote M2 polarization of macrophages by modulating the IRAK1-TRAF6-NF-κB signaling axis. This alleviates neuroinflammation and improves the post-injury microenvironment (Liang et al., 2024). Together, these studies underscore the significant potential of exosome miRNA therapy in precisely regulating the immune microenvironment.
3.2 Inhibition of neuronal apoptosis
Neuronal apoptosis is a key factor in permanent functional loss following SCI, involving mitochondrial dysfunction, oxidative stress, and abnormal upregulation of pro-apoptotic genes, such as PTEN and Bax (Liu et al., 2019). Exosomal miRNAs can reduce neuronal apoptosis by targeting and inhibiting these pro-apoptotic genes or by activating key cell survival pathways (Feng et al., 2021), such as the PI3K/AKT pathway (Huang et al., 2022; Xiao et al., 2022). Maintaining the survival of neural networks is essential for axonal regeneration and functional reconstruction; therefore, inhibiting apoptosis is crucial for extending the therapeutic window (Huang et al., 2020). Zhang et al. (2021) demonstrated that BMSC-derived miR-338-5p regulates the Cnr1/Rap1/Akt axis by upregulating the anti-apoptotic protein Bcl-2 and downregulating Bax, significantly reducing neuronal apoptosis in SCI rats. Systems biology analyses indicate that miRNAs such as miR-338-5p engage in multifaceted interactions, regulating apoptosis through interconnected pathways involving neurons, endothelial cells, and immune cells, as evidenced by whole transcriptome sequencing revealing miRNA-mRNA networks that balance pro- and anti-apoptotic signals in the SCI niche (Klassen et al., 2025). Additionally, Huang et al. found that plasma exosomal miR-429 can reduce neuronal loss during the acute SCI phase by inhibiting the PTEN/PI3K/Akt pathway (Huang et al., 2022). Furthermore, endothelial progenitor cell-derived exosomes loaded with miR-210 were shown to decrease the Bax/Bcl-2 ratio and cleaved caspase-3 levels. This led to improved BBB scores from days 7 to 28 post-injury (Wang et al., 2024). These findings suggest that exosomal miRNA therapies targeting apoptosis offer significant neuroprotective advantages.
3.3 Promoting axonal regeneration
Axonal regeneration forms the structural basis for the recovery of motor and sensory function following SCI. However, the glial scar formed after injury and the accumulation of inhibitory molecules (Hesp et al., 2015), such as Repulsive Guidance Molecule A (RGMA) (Nakagawa et al., 2019), in the microenvironment, are the primary obstacles to axonal growth. Exosomal miRNAs can effectively promote axonal extension and reconstruction of functional neural circuits by regulating signaling pathways critical for axonal growth, such as the PTEN/AKT/mTOR and NGF/TrkA pathways (Li et al., 2018). Wang et al. discovered that human umbilical cord MSC exosomal miR-145-5p can significantly promote axonal growth in SCI rat models by activating the NGF/TrkA pathway (Wang et al., 2021). Similarly, (Li et al. 2018) confirmed that miR-133b, when delivered by modified MSC exosomes, activates the ERK1/2/STAT3 pathway, thereby stimulating nerve fiber regeneration. Incorporating a systems biology lens, miR-133b and similar miRNAs interact with diverse cell types (e.g., neurons and oligodendrocytes) via regulatory networks, as shown in multi-omics studies where miRNA hubs coordinate axonal guidance, myelin repair, and extracellular matrix remodeling in the SCI microenvironment (Klassen et al., 2025). Additionally, a study demonstrated that epidermal growth factor receptor (EGFR)-positive neural stem cell-derived exosomes carrying miR-34a-5p promote axonal growth and enhance functional recovery after spinal cord injury by silencing histone deacetylase 6 (HDAC6). This finding confirms the critical role of neural exosomes in axonal regeneration (Qin et al., 2024). While these studies highlight the immense potential of exosomal miRNAs in overcoming regenerative barriers, addressing the complexity and persistence of glial scar formation remains a key challenge in optimizing therapeutic outcomes.
3.4 Promoting angiogenesis
Vascular reconstruction in the injured area is crucial for improving local ischemia and hypoxia, supporting neuronal survival, and removing metabolic waste. It is also a prerequisite for optimizing the neuro-repair microenvironment (Xin et al., 2013). Exosomal miRNAs can promote endothelial cell proliferation, migration, and tubular structure formation by targeting and regulating genes related to angiogenesis (e.g., integrin α5 and SPRED1) (Anderson et al., 2016; Zhang et al., 2015). Umezu et al. (2013) demonstrated that miR-92a, delivered by K562 cell exosomes, significantly increased neovascular density in a SCI model by targeting integrin α5. Huang et al. (2020) found that miR-126 in modified MSC exosomes increases the expression of angiogenesis markers [e.g., vascular endothelial growth factor (VEGF)] by regulating the SPRED1/PIK3R2 pathway, thereby promoting functional recovery. In systems biology terms, miR-126 forms part of integrated networks linking endothelial cells with neurons and immune cells, modulating angiogenesis through feedback loops identified in omics-based models of the SCI vascular niche (Klassen et al., 2025; Zhang et al., 2023). Furthermore, it was found that exosomes secreted by human urine-derived stem cells are enriched in miR-216a-5p. This microRNA targets PTEN and activates the AKT signaling pathway, promoting angiogenesis and enhancing cell survival. This provides new mechanistic insight into exosome-mediated vascular reconstruction (Zhang et al., 2020). These findings underscore the pivotal role of exosomal miRNAs in angiogenesis.
3.5 Regulating the immune microenvironment
An imbalance in the immune microenvironment after SCI, particularly the excessive activation of M1-type pro-inflammatory macrophages/microglia, exacerbates inflammatory damage and disrupts the integrity of the BSCB (Milich et al., 2019). Exosomal miRNAs can regulate key signaling pathways to induce polarization of macrophages/microglia toward an M2-type reparative phenotype (Liu et al., 2020). This protects the structural integrity of the BSCB and reshapes the immune microenvironment from “damaging” to “reparative” (Noble and Wrathall, 1989). Qing et al. demonstrated that miRNAs in BMSC exosomes (e.g., miR-125a) promote M2 polarization by regulating the PI3K/AKT/NF-κB pathways (Chang et al., 2021). Additionally, Gao et al. (2023) found that pericardial cell exosomal miR-210-5p can protect the BSCB's integrity through the JAK1/STAT3 pathway. These findings underscore the pivotal role of exosomal miRNAs in immune regulation.
3.6 Multifunctional neuroprotective effects
In addition to their specific functions, certain exosomal miRNAs have broad-spectrum neuroprotective effects. These effects are achieved through multiple mechanisms, including regulating cellular autophagy, alleviating endoplasmic reticulum (ER) stress, and promoting neuronal differentiation (Zhang and Han, 2022b; Li R. Y. et al., 2023; He et al., 2022). These multifaceted, multitargeted effects provide a foundation for improving the overall neural microenvironment following SCI and supporting long-term functional recovery (Chang et al., 2024). For instance, Ke et al. discovered that neural stem cell exosomes enhanced by IGF-1 exert neuroprotective effects through the miR-219a-2-3p/YY1 axis (Ma et al., 2019). Xu et al. (2019b) demonstrated that miR-92b-3p in astrocyte exosomes provides early protection during the acute phase of SCI by alleviating endoplasmic reticulum stress. Additionally, a study published in the journal Pain revealed that exosomal miRNAs modulate neuropathic pain following SCI by affecting neuronal hyper-excitability pathways. This finding expands our understanding of exosome-mediated neuroregulation (Picco et al., 2025). Together, these studies reveal the broad neuroprotective potential of exosomal miRNAs and offer new insights for comprehensive SCI treatment. However, their long-term efficacy and reproducibility in human clinical trials must be validated.
4 Part IV: Conclusion
In summary, SCI remains a significant clinical challenge, involving complex pathophysiological processes that result in permanent neurological impairment. Exosomal RNAs, particularly miRNAs, may emerge as transformative therapeutics, modulating intercellular communication, and orchestrating multifaceted repair processes. As detailed in this review, exosomal miRNAs exert profound effects on SCI pathophysiology by attenuating neuroinflammation through pathways such as NF-κB and TLR4, inhibiting neuronal apoptosis via PTEN/PI3K/Akt signaling, promoting axonal regeneration and angiogenesis, and reshaping the immune microenvironment toward a reparative phenotype (Figure 2) (Zha, 2025). Recent advancements highlight the potential of exosomes derived from MSCs and neural stem cells. Engineered variants of these exosomes can enhance miRNA delivery, leading to better outcomes in preclinical models, such as reduced lesion volumes and improved motor function (Wang et al., 2025; Lin et al., 2025). However, there are still some challenges to overcome before this can be translated into clinical practice, such as standardizing exosome production, optimizing delivery strategies, and mitigating immunogenicity. This requires rigorous GMP-compliant protocols and long-term safety evaluations (Chen et al., 2025; Ma Y. et al., 2025).
Figure 2. The main pathways of the roles of miRNAs in spinal cord injury.
From a broader perspective, based on the comprehensive evidence presented in this review, exosomal miRNA therapy represents a paradigm shift in SCI treatment, offering a non-invasive, multitargeted strategy that could bridge the gap between preclinical promise and clinical reality. Its ability to integrate with emerging technologies, such as bioengineered scaffolds and CRISPR-based enhancements, underscores the need for accelerated interdisciplinary collaboration to refine scalability and personalize interventions, which may gradually contribute to more effective and patient-centered regenerative strategies in the future.
5 Part V: Challenges and future perspectives for clinical translation
5.1 Current challenges in exosomal miRNA therapy for SCI
Exosomal miRNA therapy shows significant potential for repairing SCI, but its clinical translation still faces multiple technical and biological challenges. First, there are prominent standardization issues in exosome preparation, including separation purity, miRNA loading efficiency, and batch-to-batch variability, which may lead to inconsistent therapeutic effects (Li et al., 2024; Zha, 2025). Second, delivery efficiency is limited. Intravenous administration often results in rapid hepatic clearance and insufficient BSCB penetration. Local injection enhances targeting but increases the risk of invasiveness and infection. Dose optimization is also challenging because excessive doses may trigger immune responses or off-target effects that affect gene regulation in non-neural tissues (Singh et al., 2024). In addition, safety considerations are critical as well, including the immunogenicity of donor-derived exosome sources, which may induce inflammation or rejection reactions (Alvi et al., 2024). Long-term risks, such as tumorigenesis, must be monitored vigilantly, as miRNA regulation may interfere with cell proliferation pathways (Wei et al., 2025). Strategies to mitigate these risks encompass the use of autologous or hypoimmunogenic exosomes, surface modification with targeting moieties to enhance specificity, and comprehensive post-treatment monitoring via advanced imaging and biomarker assays to detect any adverse events early (Ma Y. et al., 2025; Wu et al., 2025). Additionally, preclinical studies often neglect gender differences and long-term outcome assessments, limiting their applicability to humans (Shang et al., 2025). Notably, studies have revealed gender differences in the response of extracellular vesicles following chronic spinal cord injury. These differences correlate with neuroinflammation and neurodegenerative changes in the aging brain. Consequently, overlooking gender variations may limit the universality of therapeutic outcomes (Li Y. et al., 2023). To overcome these obstacles, GMP-compliant protocols and biomarker monitoring systems must be developed to ensure the therapy's reliability and safety (Ma Y. et al., 2025).
5.2 Future directions and innovations in exosomal miRNA-based treatments
Looking ahead, exosomal miRNA therapy shows promise for making breakthroughs in SCI treatment through multidisciplinary integration. One emerging trend is the optimization of engineered exosomes through hormone pretreatment or induction with specific factors to enhance the anti-inflammatory and regenerative efficacy of miRNAs. Melatonin-pretreated plasma exosomes, for instance, have been shown to significantly enhance anti-inflammatory function by delivering miR-138-5p, thereby inhibiting microglial activation and promoting spinal cord repair. This demonstrates their potential to reduce lesion volume and improve motor function in animal models (Chen H. et al., 2024). Similarly, IL-4-pretreated human umbilical cord mesenchymal stem cell-derived exosomes loaded with miR-125a promote M2 macrophage polarization and downregulate IRF5 expression. Recent studies have reported their effective mitigation of inflammatory cascades in SCI models (Li M. et al., 2025; Liao et al., 2025). Combination strategies are also emerging. For instance, the co-administration of exosomes with biomaterials, such as hydrogel scaffolds, or CRISPR tools can promote synergistic repair mechanisms and sustained release. Studies using GelMA/HA-NB hydrogels for local exosome delivery demonstrated sustained exosome release and nearly doubled functional recovery compared to free exosome administration. These results highlight the potential of biomaterial-integrated delivery strategies for SCI (Cheng et al., 2021). Ultrasound-targeted microbubble destruction enhances the targeted delivery of platelet-rich plasma-derived exosomes to injured peripheral nerves, promoting Schwann cell proliferation and nerve regeneration in rat models (Yi et al., 2023). Recent advances include NT3-loaded, exosome-degradable, conductive scaffolds, which a 2025 study demonstrated to have advantages in promoting axonal regeneration and functional recovery, offering a novel SCI repair platform (Ma L. et al., 2025). Additionally, scalable, off-the-shelf exosome-mimicking nanoparticles will accelerate the translation of research from the laboratory to the clinic, and a surge in clinical trials is expected by 2030 (Kim et al., 2024; Ke et al., 2024). Future research should prioritize the development of personalized exosomal miRNA therapies tailored to individual patient profiles, such as miRNA expression patterns post-injury. Combination therapies integrating exosomal miRNAs with stem cell transplants, biomaterials, or pharmacological agents could synergistically enhance repair mechanisms (Guo et al., 2026). Fostering interdisciplinary collaboration among neuroscientists, bioengineers, and clinicians will be essential to accelerate clinical translation, potentially through multi-center trials and shared databases for real-time data integration.
Author contributions
YuaS: Writing – original draft. ZL: Writing – original draft. YP: Writing – original draft. QW: Writing – original draft. ZC: Writing – review & editing. LQ: Writing – original draft, Writing – review & editing. YuyS: Writing – original draft, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Nantong Science and Technology Project (JC2023040), Nantong University Special Research Project in Clinical Medicine (2023HY016, 2023JZ028), and Jiangsu Provincial Health Commission (Z2024066).
Acknowledgments
Thanks for Figdraw.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The reviewer SL declared a shared affiliation with the author(s) YP and QW to the handling editor at the time of review.
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Keywords: axonal regeneration, exosomes, microRNA, neuroinflammation, spinal cord injury
Citation: Shi Y, Li Z, Pu Y, Wang Q, Cui Z, Qi L and Sun Y (2026) The potential mechanisms and regulatory roles of exosomal miRNA in neural repair after spinal cord injury. Front. Cell. Neurosci. 19:1711454. doi: 10.3389/fncel.2025.1711454
Received: 23 September 2025; Revised: 23 December 2025;
Accepted: 26 December 2025; Published: 20 January 2026.
Edited by:
Haruyuki Kamiya, Hokkaido University, JapanReviewed by:
Luis B. Tovar-y-Romo, National Autonomous University of Mexico, MexicoShiying Li, Nantong University, China
Paramita Basu, University of Pittsburgh, United States
Copyright © 2026 Shi, Li, Pu, Wang, Cui, Qi and Sun. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Longju Qi, cWlsb25nanVudEAxNjMuY29t; Yuyu Sun, c3VueXV5dW50QDEyNi5jb20=
†These authors have contributed equally to this work