MSC-derived extracellular vesicles for spinal cord injury: inflammatory microenvironment modulation, stage-dependent...

Spinal cord injury is not only an acute mechanical insult but also the beginning of a prolonged secondary pathological process dominated by inflammatory microenvironmental imbalance. Because the primary traumatic event occurs within minutes and offers a narrow therapeutic window, persistent post-traumatic inflammation, blood-spinal cord barrier disruption, edema, oxidative stress, complement activation, inflammasome signaling, astrocyte reactivity, vascular dysfunction, and extracellular matrix remodeling represent more realistic therapeutic targets. In accordance with the Minimal Information for Studies of Extracellular Vesicles recommendations, this review uses the term MSC-derived extracellular vesicles, abbreviated as MSC-EVs, to describe MSC-derived vesicle preparations reported in the cited studies, including small extracellular vesicles and exosome-like vesicles, unless endosomal biogenesis has been strictly demonstrated. Existing preclinical studies suggest that MSC-EVs may attenuate the inflammatory microenvironment after spinal cord injury by suppressing complement activation, inhibiting NLRP3 inflammasome signaling, modulating heterogeneous microglia/macrophage states, reducing neurotoxic inflammatory astrocyte responses, improving blood-spinal cord barrier integrity, and decreasing inflammatory cytokine production. These anti-inflammatory and barrier-protective effects are closely linked to downstream neuroprotection, angiogenesis, axonal plasticity, remyelination, and tissue repair. Mechanistically, MSC-EVs regulate multiple signaling pathways, including NF-κB, PI3K/Akt, ERK, RhoA/ROCK, PTEN/PI3K/Akt, and Wnt/β-catenin, and deliver regulatory microRNAs such as miR-133b, miR-21, miR-29, miR-126, and miR-486-5p. However, available evidence is uneven: some claims are supported by gain- and loss-of-function experiments, whereas others remain correlative or based on limited animal studies. Beyond microRNAs, MSC-EVs also contain mRNAs, long non-coding RNAs, circular RNAs, tRNA-derived fragments, proteins, and lipids, but their specific roles in spinal cord injury remain less well defined. Reactive astrogliosis is heterogeneous and stage-dependent; A1/A2 terminology may be useful descriptively but should not be treated as a complete classification of astrocyte states. Although MSC-EVs may reduce some risks associated with live-cell transplantation, their clinical translation remains limited by inefficient lesion delivery, biodistribution uncertainty, cargo heterogeneity, storage instability, lack of standardized potency assays, incomplete time-dose-response data, and evolving regulatory requirements. This review summarizes MSC-EVs as modulators of the spinal cord injury inflammatory microenvironment, integrates their actions into an acute-subacute-chronic stage-based model, and discusses the major preclinical and translational barriers that must be addressed before clinical application.