Inflammation is a major driver of retinal degeneration in disorders such as dry age-related macular degeneration, yet effective therapies that can simultaneously suppress inflammatory damage and protect neural tissue remain limited. Small extracellular vesicles (sEV) derived from mesenchymal stem cells (MSCs) have emerged as a promising cell-free therapeutic option, but their baseline efficacy may be insufficient in highly inflammatory microenvironments.
In this study, the authors developed small extracellular vesicles derived from TNF-α-preconditioned mesenchymal stem cells (T-sEV) and evaluated their therapeutic potential in inflammatory retinal injury. The results showed that TNF-α priming remodeled the miRNA cargo of sEV, with marked enrichment of anti-inflammatory miRNAs, particularly miR-146a-5p. T-sEV were efficiently internalized by macrophages and showed stronger inhibition of M1 macrophage polarization than control sEV, accompanied by reduced expression of pro-inflammatory genes and cytokines.
Mechanistically, integrated analysis of vesicle miRNA profiles and macrophage transcriptomes indicated that T-sEV miRNAs target key inflammatory regulators such as Cd86, Il1r1, and Nos2, thereby modulating pathways related to cytokine signaling and MAPK activity. In a NaIO₃-induced murine retinal degeneration model, intravitreal administration of T-sEV significantly preserved retinal function and structural integrity, reduced macrophage infiltration, and showed favorable local and systemic safety.
These findings suggest that inflammatory preconditioning can enhance the therapeutic capacity of MSC-derived extracellular vesicles and support T-sEV as a promising cell-free strategy for retinal degenerative diseases associated with inflammation. The work titled “Extracellular vesicles derived from TNF-α-preconditioned mesenchymal stem cells mitigate inflammatory retinal injury” was published in Extracellular Vesicles and Circulating Nucleic Acids (published on March 17, 2026).

DOI：10.20517/evcna.2025.159