Ternary mTOR-targeted conductive nanofibrous scaffolds with bioactive peptides orchestrate immune-metabolic-fibrotic balance for diabetic bone regeneration.

Abstract

Diabetic bone defects (DBD) are difficult to heal because persistent inflammation, metabolic dysfunction and fibrotic repair disrupt the transition from injury to regeneration. Here, we report PP@IL^ES, a peptide functionalized electroconductive nanofibrous scaffold that combines local electrical cues with immobilized and gradually released bioactive peptide signals to remodel the diabetic defect niche. Single cell RNA sequencing and mechanistic analyses showed that PP@IL^ES reshaped macrophage and fibroblast states at the early repair stage. In macrophages, PP@IL^ES was associated with reduced mTORC1 activity, enhanced mitochondrial oxidative metabolism and fatty acid oxidation, increased CD206 expression, and decreased iNOS, TNF alpha and glycolytic output. In fibroblasts, PP@IL^ES attenuated activation through KLF4 associated downregulation of alpha SMA, limiting scar like fibrotic remodeling. In diabetic rats with 5 mm cranial defects, PP@IL^ES promoted bone regeneration and mature lamellar bone formation with reduced fibrotic tissue compared with conductive scaffold alone or peptide scaffold alone. These findings suggest that coordinated regulation of immune metabolism, fibrotic remodeling and osteogenesis through an electrobiochemical scaffold may provide a promising strategy for diabetic bone repair.