Antiaging Metabolite-Based Polymeric Microparticles for Intracellular Drug Delivery and Bone Regeneration

α-ketoglutarate (AKG), a key component of the tricarboxylic acid cycle, has attracted attention for its antiaging properties. In the recent study, it is indicated that locally delivered cell-permeable AKG significantly promotes osteogenic differentiation and mouse bone regeneration. However, the cytotoxicity and rapid hydrolysis of the metabolite limit its application. In this study, novel AKG-based polymeric microparticles (PAKG MPs) are synthesized for sustained release. In vitro data suggest that the chemical components, hydrophilicity, and size of the MPs can significantly affect their cytotoxicity and pro-osteogenic activity. Excitingly, these biodegradable PAKG MPs are highly phagocytosable for nonphagocytic pre-osteoblasts MC3T3-E1 and primary bone marrow mesenchymal stem cells, significantly promoting their osteoblastic differentiation. RNA-Sequencing (RNA-Seq) data suggest that PAKG MPs strongly activate Wnt/β-catenin and PI3K–Akt pathways for osteogenic differentiation. Moreover, PAKG enables poly(L-lactic acid) and poly(lactic-co-glycolic acid) MPs (PLGA MPs) for efficient phagocytosis. In this data, it is indicated that PLGA–PAKG-MPs-mediated intracellular drug delivery can significantly promote stronger osteoblastic differentiation compared to PLGA-MPs-delivered phenamil. Notably, PAKG MPs significantly improve large bone regeneration in a mouse cranial bone defect model. Thus, the novel PAKG-based MPs show great promise to improve osteogenic differentiation and bone regeneration and enable efficient intracellular drug delivery for broad regenerative medicine.