α-Ketoglutarate-loaded extracellular vesicles restore OPA1-mediated mitochondrial function to reprogram macrophages and promote periodontal regeneration

Periodontitis is a persistent inflammatory disorder marked by gradual destruction of alveolar bone. Targeting macrophage polarization and mitochondrial metabolism represents a promising strategy for its treatment. Here, we developed engineered extracellular vesicles (AKG-EVs) by encapsulating α-ketoglutarate (AKG) into periodontal ligament stem cell–derived EVs (PDLSCs-EVs) to enhance AKG bioavailability and modulate macrophage function. AKG-EVs were further incorporated into a calcium-crosslinked oxidized sodium alginate/gelatin (OSA/Gel) hydrogel to construct an injectable sustained-release system (OG@AE hydrogel). The prepared hydrogel exhibited a uniform porous structure, good stability, and controlled release behavior. In vitro, AKG-EVs reprogrammed macrophages, driving their polarization from the M1 pro-inflammatory phenotype to an anti-inflammatory M2 state by restoring mitochondrial membrane potential and enhancing oxidative phosphorylation. Mechanistically, AKG-EVs upregulated the expression of optic atrophy protein 1 (OPA1), thereby improving mitochondrial fusion and energy metabolism. Moreover, AKG-EVs enhanced osteoblast proliferation, migratory capacity, and osteogenic differentiation under inflammatory conditions. In vivo, the OG@AE hydrogel significantly alleviated periodontal inflammation, enhanced M2 macrophage polarization, promoted angiogenesis, and promoted alveolar bone repair in rats with periodontitis. This study presents a multifunctional EVs-based hydrogel delivery platform that integrates anti-inflammatory, metabolic regulatory, and pro-regenerative properties, providing a promising therapeutic strategy for periodontitis.