Unraveling Bone-Skin Crosstalk Enables miRNA Nanoformulation for Cutaneous Neurovascular Reconstruction in Diabetic Mice.

The clinical intractability of diabetic foot ulcers stems from a profound uncoupling of cutaneous neurovascular networks, rendering standard metabolic and topical interventions largely palliative. Paradoxically, remote orthopedic trauma robustly accelerates distal skin repair, yet the systemic molecular mediators driving this "bone-skin crosstalk" remain undefined, precluding its translation into non-invasive therapies. Here, we establish that macroscopic bone fracture expedites diabetic wound healing through the systemic release of exosomal miR-130b-3p, a potent orchestrator of coupled angiogenesis and neurogenesis. To recapitulate this physiological axis non-invasively, we engineered a self-assembling, cholesterol-modified agomir-130b-3p nanocomplex that could bypass endolysosomal degradation. For sustained spatial delivery, these carrier-free nanoassemblies were incorporated into an in situ photocrosslinkable methacrylated collagen/silk fibroin hydrogel, creating a bio-instructive extracellular matrix that prolongs microRNA bioavailability. In streptozotocin-induced diabetic mice, hydrogel-mediated agomir delivery achieved 97.2% full-thickness wound closure. Advanced volumetric light-sheet imaging of chemically cleared whole-mount skin confirmed the robust spatiotemporal reconstruction of deep vascular and neural networks. These findings decode a distinct exosome-mediated inter-organ repair mechanism and demonstrate that biomimetic microRNA nanoformulations can effectively translate systemic physiological cues into localized, high-efficacy therapeutics for ischemic neuropathic wounds.