Immunoregulatory GelMA microspheres loaded with Th2 cell-derived exosomes for vascularized repair of diabetic bone...

Diabetic bone defects remain challenging to repair because chronic hyperglycaemia establishes a persistent inflammatory microenvironment that impairs angiogenesis and osteogenesis while accelerating osteoclast-mediated bone resorption. Th2 cells are key mediators of inflammation resolution and tissue repair, yet the therapeutic potential of Th2-cell-derived exosomes for diabetic bone regeneration remains largely unexplored. Here, we developed gelatin methacryloyl microspheres loaded with Th2-cell-derived exosomes (T2E@GM) as a local, cell-free immunoregulatory platform for diabetic bone-defect repair. In lipopolysaccharide-challenged macrophages, T2E@GM attenuated pro-inflammatory activation and promoted a reparative phenotype, as evidenced by reduced inflammatory cytokine production and increased Arg1 and IL-10 expression. Transcriptomic profiling further revealed coordinated suppression of inflammatory and osteoclastogenesis-related programmes, together with enrichment of tissue-repair and oxidative-metabolism pathways. This macrophage reprogramming generated a pro-regenerative paracrine milieu that enhanced endothelial migration and tube formation, promoted osteogenic differentiation and matrix mineralization, and inhibited osteoclast formation in vitro. In a diabetic rat calvarial-defect model, local implantation of T2E@GM promoted vascularized bone regeneration, accompanied by increased reparative macrophage polarization and osteogenic activity, as well as reduced inflammatory and osteoclastic signals. These findings provide preclinical evidence that Th2-cell-derived EVs incorporated into GelMA microspheres support immunomodulation and vascularized bone regeneration in diabetic calvarial defects.