Critical limb ischemia (CLI), an advanced stage of peripheral arterial disease, is identified by severe ischemia, rest pain, and tissue necrosis, and possibly leads to amputation if untreated. Cell therapies offer a treatment for CLI by alleviating resting pain and improving the condition of damaged tissue. However, it may mediate immune rejection reactions after cell transplantation and cell activities are susceptible to environmental influences. Small extracellular vesicles (sEV) have emerged as a promising approach for the treatment of CLI, as these carry a lot of the active substances of cells during their formation process. In this study, we investigated the potential of small extracellular vesicles secreted by interstitial cells (IC-sEV) to restore tissue function and repair ischemic tissue. Our results demonstrated that IC-sEV could effectively promote the proliferation, migration and tube formation of HUVECs. Moreover, IC-sEV had a more pronounced effect on promoting the expression of angiogenic factors in HUVECs compared to ASC-sEV. The therapeutic effect of IC-sEV was further investigated using an in vivo animal model of limb ischemia. These data demonstrated that IC-sEV significantly improved blood perfusion in ischemic limbs, promoted the recovery of limb function, and reduced the extent of ischemic tissue damage. Further analysis revealed that IC-sEV promoted microvascular densities, markedly decreased infiltration, cell apoptosis and fibrosis in the ischemic limbs. In conclusion, IC-sEV transplantation is expected to become a new alternative for the treatment of CLI.

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