The Pivotal Roles of Macrophages and Microglia in Mesenchymal Stromal/Stem Cell-Derived Small Extracellular Vesicle-Mediated Tissue Repair After Spinal Cord Injury.

macrophages. This interaction initiates a multifaceted therapeutic program. First, MSC-sEVs not only reprogram myeloid cells toward an anti-inflammatory, M2-like phenotype but also sustain this reparative state, thereby stabilizing a pro-resolving immune environment, attenuating the production of proinflammatory cytokines such as TNF-α and IL-6, and enhancing the expression of anti-inflammatory mediators, including Interleukin-10 (IL-10) and Transforming growth factor-beta (TGF-β). This polarization is partly driven by transferred microRNAs that suppress central inflammatory signaling hubs, notably the Toll-like receptor 4 (TLR4)/Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome pathways. Second, MSC-sEVs augment macrophage phagocytic capacity, facilitating the removal of myelin debris and apoptotic cells and thereby creating a permissive microenvironment for regeneration. Third, soluble factors released from reprogrammed myeloid cells confer neuroprotective and trophic support to neurons and oligodendrocytes, mitigating secondary degeneration. Finally, these cells contribute to the re-establishment of BSCB integrity by promoting tight junction protein re-expression, reconstituting pericyte-endothelial interactions, and enhancing microvascular remodeling. Collectively, these coordinated mechanisms suppress neuroinflammation, preserve neural tissue, and support functional recovery. The therapeutic benefits of MSC-sEVs in SCI, therefore, depend substantially on the reprogramming of macrophages and microglia. Elucidating this bidirectional communication between MSC-sEVs and myeloid cells provides critical insight into SCI pathophysiology and identifies macrophage and microglial modulation as a strategic target for next-generation sEV-based neuroregenerative interventions.