Carbon Dots Enhance Efferocytosis via MSC-Macrophage Crosstalk: A New Strategy for Diabetic Bone Regeneration

The repair of diabetic bone defects (DBDs) is confronted by the dual challenge of a disrupted immune microenvironment and compromised bone regeneration capacity. Current therapeutic approaches remain limited to unilateral strategies focusing primarily on either immunomodulation or osteogenic induction, failing to achieve comprehensive functional restoration. To address this critical issue, we developed a bifunctional carbon dot (GFCDs) derived from gentamycin and folic acid, which demonstrates multi-mechanistic synergistic efficacy in DBDs models. Our findings reveal that GFCDs restore mesenchymal stem cell (MSC) function by reactivating autophagic flux, thereby simultaneously enhancing osteogenic differentiation and immunomodulatory capacity. Furthermore, GFCDs reestablish macrophage efferocytosis through modulation of MSC paracrine activity, creating a reciprocal MSC-macrophage regulatory circuit that systematically restructures the pro-regenerative microenvironment. GFCDs also exhibit broad-spectrum antimicrobial activity against prevalent pathogens in DBDs, including Staphylococcus aureus and Pseudomonas aeruginosa. This work advances the field by both elucidating a GFCDs-mediated crosstalk mechanism between stem and immune cells and proposing a translational therapeutic strategy for diabetic bone regeneration.