Bio-recruiting hydrogel targeting mitochondrial homeostasis under neutrophil extracellular traps for diabetic wound repair.

Diabetic wound healing is a complex process that requires precise coordination among functional cells, with endothelial cells (ECs) playing a critical role in tissue vascularization. We begin by identifying neutrophil extracellular traps (NETs) as one of critical stressors that disrupts mitochondrial homeostasis in ECs. In addition, inadequate recruitment of ECs often leads to unsatisfactory regenerative outcomes. To address these issues, we developed a composite hydrogel formulation co-encapsulating C-X-C motif chemokine ligand 12 (CXCL12) mRNA-loaded exosomes to promote pro-regenerative endothelial cell homing, and leonurine (Leo) to regulate cellular functionalities, thereby preserving endothelial function essential for neovascularization. By pairing exosomal mRNA delivery with the MS2 coat protein (MCP)-MS2 tethering system for mRNA payload multiplication, we achieved sustained CXCL12 production and cascade-amplified recruitment of CXCR4-positive cells. Moreover, Leo released from the composite hydrogel protectively rescued mitochondrial dysfunction. Further, application of this hydrogel to full-thickness skin defects led to significantly improved wound regeneration in diabetic mice. In summary, this study establishes a therapeutic "recruit-reinforce" platform based on a dual-delivery hydrogel armed with CXCL12 mRNA-enriched exosomes and Leo, thereby precisely targeting mitochondrial homeostasis under NETs stress for efficient diabetic wound repair.