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

作者：Zhuozhi Wang, Jue Hu, Jeffrey S. Marschall, Ling Yang, Erliang Zeng, Shaoping Zhang, Hongli Sun · 发表于：Small Science · 年份：2024 · DOI：10.1002/smsc.202400201 · 被引用次数：5 · 研究领域：Nanoparticle-Based Drug Delivery、Advanced Drug Delivery Systems、Bone Tissue Engineering Materials

Alpha-ketoglutarate (AKG), a key component of the tricarboxylic acid (TCA) cycle, has attracted attention for its anti-aging properties. Our recent study indicates 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, we synthesize novel AKG-based polymeric microparticles (PAKG MPs) 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 (BMSCs), significantly promoting their osteoblastic differentiation. RNAseq 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 (PLLA & PLGA MPs) for efficient phagocytosis. Our data indicate 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, bone regeneration...