NOX2‐Driven Oxidative Stress Promotes EndMT and Uncouples Angiogenesis–Osteogenesis at the Bone–Implant Interface in Diabetes

Abstract Diabetes undermines implant integration, yet how the bone–implant interface (BII) can be rationally re‐engineered remains unclear. Here endothelial NOX2–driven oxidative stress is identified as a mechanistic switch that triggers endothelial‐to‐mesenchymal transition (EndMT), depletes type‐H (CD31 ⁺ EMCN ⁺ ) vessels, and uncouples angiogenesis from osteogenesis. In a diabetic titanium‐implant model, type‐H endothelium and adjacent osteoprogenitors declined early (≈40% loss at 2 weeks), and peri‐implant bone volume is reduced at 8 weeks (BV/TV 40.98 ± 3.96%). Pharmacologic NOX2 inhibition or endothelial‐specific Nox2 deletion restored endothelial identity, suppressed EndMT and apoptosis, rebuilt type‐H networks, and improved bone formation (BV/TV 53.15 ± 4.97%), yielding higher BV/TV and histological indices. In vitro, on titanium surfaces, NOX2 blockade rescued endothelial proliferation, migration, and adhesion architecture and re‐enabled osteogenesis in EC–OB co‐culture. Bulk RNA‐seq demonstrated pathway reversals (TGF‐β, NF‐κB/MAPK, Wnt/Notch, TNF) and attenuated EC to OB ephrin/plexin edges, consistent with guidance/adhesion rewiring. These findings position NOX2 as an actionable vascular target at the BII and suggest interface‐focused delivery (drug coatings, anti‐EndMT functional surfaces, responsive hydrogels) to re‐establish vessel–bone coupling and strengthen osseointegration in diabetes.