Osteogenic peptide-engineered Coptis chinensis-derived extracellular vesicles promote immuno-osteogenic repair of diabetic bone defects.

Diabetic bone defects are difficult to repair because chronic hyperglycemia creates a hostile inflammatory and oxidative microenvironment that impairs osteogenesis, enhances osteoclast activity and compromises vascular ingrowth. Plant-derived extracellular vesicle-like nanoparticles can transfer source-related biological signals to mammalian cells and are attractive for immune regulation, but native vesicles usually lack defined osteogenic instruction for diabetic bone regeneration. Here, we engineered Coptis chinensis-derived extracellular vesicle-like nanoparticles (Cc-EVs) with a BMP-2-derived osteogenic peptide (OP) through copper-free click chemistry, generating OP-Cc-EVs that combine the immunoregulatory potential of Cc-EVs with osteogenic peptide surface presentation. As a vesicle-only treatment in vitro, OP-Cc-EVs shifted inflammatory macrophages from a pro-inflammatory M1 phenotype toward a reparative M2 phenotype, with transcriptomic changes consistent with inflammatory resolution and repair-oriented tissue regulation. This macrophage response enhanced mesenchymal stromal cell osteogenesis, suppressed osteoclast formation and actin-ring maturation, and generated paracrine signals that promoted endothelial migration and tube formation. For in vivo application, GelMA hydrogel was used as a local carrier to retain OP-Cc-EVs within the diabetic bone-defect site. In a diabetic femoral condyle defect model, local delivery of OP-Cc-EVs promoted vascularized bone regeneration while reducing inflammatory and osteoclastic signals. These findings establish OP-Cc-EVs as a chemically engineered plant-derived vesicle platform with translational potential for immuno-osteogenic repair of diabetic bone defects.