ALP-Mimetic Cyclic Peptide Nanotubes: A MultifunctionalStrategy for Osteogenesis and Bone Regeneration

Alkaline phosphatase (ALP) plays a crucial role in bone mineralization by hydrolyzing organophosphates and releasing inorganic phosphate ions, facilitating hydroxyapatite formation. The imidazole ring in the functional domain of ALP is critical for its catalytic activity and bone mineralization. However, the therapeutic application of native ALP is hindered by instability, short half-life, immunogenicity, and variable efficacy. This work presents the development of ALP-mimetic cyclic-octapeptide (ALAKHKHP) nanotubes to promote osteogenic differentiation and bone mineralization. The incorporation of imidazole-rich histidine residues in close proximity gives enzyme-mimetic characteristics. The nanotubes effectively catalyzed <i>para</i>-nitrophenyl phosphate (<i>p</i>NPP) hydrolysis, promoting <i>in vitro</i> calcium deposition and ALP activity, which stimulated osteogenic differentiation of MC3T3-E1 preosteoblasts, as evidenced by the upregulation of osteogenic marker genes. The nanotubes demonstrated excellent cell migration, reactive oxygen species (ROS) scavenging, and anti-inflammatory properties. This biomimetic nanoscaffold provides a promising alternative for bone regeneration, without relying on native enzymes, growth factors, or drugs.