A Novel Lipopeptide–Functionalized Metal–Organic Framework for Periodontitis Therapy through the Htra1/FAK/YAP Pathway

Periodontitis is a chronic inflammatory disease characterized by plaque accumulation, resulting in immune microenvironment disorders and resorption of alveolar bone. To promote bone healing under inflammatory environments, a functional biomaterial based on disease pathophysiology is designed. A novel fatty acid C10-modified polypeptide, C 10 -KR8, is discovered to have excellent abilities in modulating macrophage repolarization and promoting bone regeneration in periodontitis. To build a multifunctional material localized drug delivery system, C 10 -KR8@ZIF-8 (C 10 -KR8-loaded zeolitic imidazolate framework-8) nanoparticles are constructed to sustainedly release the C 10 -KR8 peptide and Zn elements. By synergistic effects of providing a dynamic immuno-modulatory environment and promoting osteogenesis under pathological conditions, the obtained pH-responsive nanoparticles display excellent bone regeneration capability. Furthermore, coimmunoprecipitation/liquid chromatography-tandem mass spectrometry analysis and proteomics analysis revealed that the C 10 -KR8 peptide directly interacts with the high-temperature requirement protein A1 (Htra1), and C 10 -KR8@ZIF-8 nanoparticles promote the osteogenic differentiation of bone mesenchymal stem cells by activating the focal adhesion kinase (FAK)/phosphatidylinositide 3-kinase (PI3K)/AKT pathway and enhancing the nuclear localization of Yes-associated protein (YAP). Taken together, this study demonstrates C 10 -KR8 peptide regulate osteoimmunology and bone regeneration by Htra1/FAK/YAP pathway and that ZIF-8-based peptide loading platform is a promising strategy for periodontitis.