Light up the mitochondria: Smart tungstate-oligosaccharide nanoplatform orchestrates mitochondrial transfer from M2 macrophages to restore endothelial function for adaptive diabetic wound regeneration

Diabetic wound (DW) complications, driven by persistent oxidative stress, unresolved inflammation, and vascular dysfunction, present a critical clinical challenge. Given mitochondria's pivotal role in inflammatory regulation, intercellular mitochondrial transfer emerges as a promising therapeutic target for DW management. In this study, we engineered a ROS/glucose/pH-triple responsive nanoplatform (WOC) via coordination-driven assembly of tungstate anions (WO 4 2− ) and chitosan oligosaccharide (COS) to synchronize immunomodulation and angiogenesis for adaptive DW regeneration. The WOC platform demonstrated glucose/pH-triggered release of bioactive components with moderate ROS scavenging capacity, enabling real-time monitoring via visible colorimetric transition. By enhancing mitochondrial bioenergetics, WOC polarized macrophages to M2 phenotype and orchestrated vesicles-dependent mitochondrial transfer to injured endothelial cells, restoring vascular function through upregulated angiogenesis genes, enhanced migration, and tube formation. In diabetic rat models, WOC accelerated wound closure evidently, resolving inflammation and promoting scarless regeneration via balanced collagen deposition. This work establishes mitochondrial transfer as a promising strategy, offering a tunable nanotherapeutic approach to recalibrate cellular cross-talk and microenvironment dynamics in DW healing. The WOC nanoplatform orchestrates multi-stage diabetic wound (DW) repair through three synergistic mechanisms: (1) Microenvironment-Responsive Bioactivity: Exhibiting ROS-triggered colorimetric signaling and glucose/pH-dependent release of bioactive W element and COS, enabling spatiotemporal drug delivery; (2) Metabolic Reprogramming: WOC-enhanced mitochondrial bioenergetics drive macrophage M2 polarization, establishing an anti-inflammatory milieu; (3) Vascular Restoration: Vesicles-mediated mitochondrial transfer from M2 macrophages to endothelial cells rescues OXPHOS and angiogenesis, while suppressing hypertrophic scar. By synchronizing immunomodulation, mitochondrial transfer, and vascular repair, WOC achieves faster wound closure.