Exosomes orchestrate immune homeostasis in acute ischemia-reperfusion flap injury and chronic wounds: the TLR4/NF-κB-STAT3 R-ratio balance decision model, engineering optimization and translational clinical strategy.

Flap ischemia-reperfusion injury (IRI) and chronic refractory wounds are intractable clinical challenges in the field of wound repair. Both pathological conditions share a core pathological hallmark: disrupted homeostasis of the local wound inflammatory immune microenvironment, yet they exhibit distinct patterns of inflammatory dysregulation. Mesenchymal stem cell-derived exosomes exert bidirectional immunomodulatory effects. They inhibit the TLR4/NF-κB signaling pathway to alleviate the acute inflammatory storm triggered by IRI, whereas they activate the STAT3 pathway to reinitiate tissue repair in chronic wounds. Nevertheless, a unified theoretical framework explaining the environment-dependent functional switch of exosomes remains absent in current research, hindering the development and clinical translation of targeted engineered exosomes. To fill this research gap, we perform a systematic review integrating five pivotal inflammatory signaling pathways, including TLR4/NF-κB, STAT3, TGF-β/Smad, NLRP3 and MAPK. We establish a TLR4/NF-κB-STAT3 signal ratio balance decision model to uniformly interpret inconsistent findings from existing