Configuration-Dependent Nanoarchitectonic Effects of Linear and Cyclic Calcium Polyphosphates on Mitochondrial Energy Metabolism and Osteogenic Differentiation

Bone regeneration is an energy-intensive process requiring coordinated regulation of ionic microenvironments and cellular metabolism. Yet, current biomaterials rarely address the dynamic energy requirements of osteogenesis. Inorganic calcium polyphosphates (CPPs), featuring high-energy phosphoanhydride bonds and tunable degradation profiles, offer a promising bioenergetic strategy for metabolically responsive bone repair. Herein, three CPPs with distinct configurations: linear Ca-TPP, cyclic Ca-TMP, and Ca-HMP were synthesized, and their osteogenic effects were systematically investigated by integrating molecular dynamics (MD) simulations with experimental approaches. The results indicate that the configuration-dependent nanoarchitectonic features of CPPs, including phosphate-unit number, charge density, and molecular configuration, govern their stability, solubility, and ion-release behaviors. Specifically, Ca-HMP forms stable assemblies that support sustained phosphate release and long-term energy supply; Ca-TMP displays faster hydrolysis kinetics, preferentially enhancing mitochondrial functional activation and oxidative phosphorylation (OXPHOS); Ca-TPP contributes primarily to extracellular matrix maturation. Importantly, all CPPs exhibit superior pro-osteogenic efficacy compared with crystalline calcium phosphate (Ca–P). CPPs can reprogram cellular metabolism by elevating intracellular ATP levels, increasing mitochondrial membrane potential, and upregulating metabolic and osteogenic genes (including GAPDH, ATP5F1A, ALP, and BMP-2), which is mediated via the activation of AMPK, mTOR, and PI3K-AKT signaling pathways, collectively improving osteogenic differentiation over Ca–P controls. These findings establish CPPs as a class of “smart” metabolic materials that synchronize energy availability with osteogenic demands, providing a promising paradigm for bone regeneration.