Engineering stem cell exosomes promotes the survival of multi-territory perforator flap in diabetes via regulating anti-inflammatory and angiogenesis

Abstract The versatile multi-territory perforator flap remains a cornerstone of reconstructive surgery for diabetic ulcerations, yet its clinical efficacy faces significant challenges in hyperglycemic conditions. The diabetic milieu significantly exacerbates tissue ischemia through augmented chronic inflammation and impaired angiogenesis, which collectively harm flap perfusion and compromise its overall viability. A major postoperative complication is distal flap necrosis, which is closely associated with the critical “Choke zone,” a hypoperfused transitional area that exhibits delayed vascular recruitment and suboptimal angiogenesis. This vascular bottleneck creates a precarious balance between tissue oxygen demand and supply, ultimately compromising flap viability. To address this issue, we have developed the engineering stem cell exosomes by encapsulating metformin-loaded Mesoporous silica nanoparticles into BMSC exosomes (M-MS@EXO NPs), enabling the release of metformin. Compared to traditional oral medication, delivering metformin through engineered exosomes allows for precise administration in diabetic wounds. The multifunctional M-MS@EXO NPs exhibit dual pharmacological activity by reducing the secretion of inflammatory cytokines while effectively remodeling the vascular niche within the diabetic microenvironment. Additionally, the M-MS@EXO NPs show anti-inflammatory and angiogenesis effects by inhibiting TNF/apoptosis and enhancing VEGF signaling pathways in vitro. In the dorsal multi-territory perforator flap model of type 2 diabetes, the M-MS@EXO NPs demonstrate the ability to alleviate inflammation and promote neovascularization of the Choke zone, reducing distal necrosis, which holds great promise for improving flap survival in diabetes.