Luyu Li, Chenli Si, Xue Wang, Xiaojin Wu, Ying Shang, Shengfang Ge, Yong Wang, Yong Zuo, Zhen Zhang
Hypertrophic scars (HS) are fibroproliferative lesions arising from aberrant wound healing, their high incidence is countered by a lack of effective interventions owing to an incomplete understanding of pathogenesis. Here, we identify dysregulated mitochondrial dynamics as a key driver of HS and develop a new targeted therapy. Specifically, excessive mitochondrial fission was observed in macrophages derived from both human and murine HS tissues. In vitro and in vivo experiments revealed that this imbalance is governed by AURKB-mediated phosphorylation of DRP1 at Ser616 site. Through machine-learning coupled with biological validation, we identified the natural small-molecule Asiaticoside (AS) as a potent AURKB inhibitor. However, AS has limited targeting accuracy and poor bioavailability. To overcome these challenges, we developed cRGD-decorated extracellular vesicles (EVs) loaded with AS (AS@cRGD-EVs), enabling targeted delivery of AS to macrophages within wound tissue. In vitro and in vivo studies showed that AS@cRGD-EVs effectively restrained macrophage mitochondrial fission, rebalanced the inflammatory milieu, and conferred significant anti-scarring efficacy in murine HS models. This work establishes mitochondrial dynamics as a therapeutic axis for HS and delivers a targeted nanotherapeutic ready for translational evaluation.