Integrated apoptotic extracellular vesicle-recruitment peptide coating reprograms the diabetic bone microenvironment and orchestrates enhanced implant osseointegration.

Abstract

Achieving stable prosthetic fixation remains a formidable challenge under diabetic conditions, primarily due to deficient osseointegration driven by impaired macrophage polarization and persistent inflammatory dysregulation within the bone microenvironment. To overcome these challenges, apoptotic extracellular vesicles (ApoEVs) harvested from osteogenically induced bone marrow mesenchymal stem cells (BMSCs) were further modified with the stem cell-recruiting peptide EPLQLKM (E7). By leveraging mussel-inspired adhesive peptides and bio-orthogonal click conjugation, we achieved mild but stable immobilization of the modified ApoEVs onto titanium (Ti) surfaces. The ApoEV/E7-modified surface effectively inhibited the formation of M1 macrophages and the expression of pro-inflammatory cytokines, while promoting the formation of M2 macrophages and the expression of anti-inflammatory cytokines, thereby improving the inflammatory microenvironment at the diabetic bone-implant interface. Simultaneously, the modified surface stimulated angiogenesis under diabetes-induced inflammatory conditions and enhanced osteogenic activity. <i>In vivo</i> experiments demonstrated that implants with this modified surface enhanced bone tissue regeneration and bone structure restoration at the bone-implant interface in a diabetic inflammatory environment, effectively regulating inflammation at the bone-implant interface and promoting angiogenesis. Collectively, this study suggests that the 3,4-dihydroxyphenylalanine-ApoEV/E7 biomimetic coating effectively enhances interfacial osseointegration via immunomodulation and provides a promising strategy for the design of implant coatings aimed at enhancing osseointegration under diabetic conditions.