Injectable Alginate-Based\nHydrogels Encapsulating\nEngineered Endothelial Extracellular Vesicles for the Treatment of\nCritical Limb Ischemia

Critical limb ischemia (CLI) is a peripheral arterial\ndisease resulting\nfrom chronic inflammation of vascular systems. Recent studies have\nshown that inhibiting macrophage inflammation has the potential to\ntreat CLI, and extracellular vesicles (EVs) from endothelial cells\ncan inhibit macrophage activation. However, the limited cell-targeting\ncapabilities and rapid clearance of EVs from the injection site limit\nthe in vivo application of the EVs. Here, we modified endothelial\nEVs with platelet membranes (pM/EVs) to boost the inhibition effects\non macrophage inflammation and developed an injectable alginate-based\ncollagen composite (ACC) hydrogel for localized delivery of pM/EVs\n(pM/EVs@ACC) for CLI treatment. We found that pM/EVs can effectively\ninhibit macrophage inflammation in vitro. Furthermore, pM/EVs@ACC\ntreatment significantly promotes the recovery of limb functions, restoring\nthe feet’ blood supply and relieving inflammation. Our findings\nprovide compelling evidence that the pM/EVs@ACC injectable system\nmediating delivery of pM/EVs is a promising strategy for CLI treatment.