A multifunctional composite hydrogel promotes treatment of bisphosphonate-related osteonecrosis of the jaws

The growing use of bisphosphonates (BPs) is a great challenge to the treatment of bisphosphonate-related osteonecrosis of the jaws (BRONJ), however effective treatment methods are currently lacking. Here, modified citraconic amide-functionalized chitosan (CAS) was selected to encapsulate the zeolite imidazolate framework 8 (ZIF-8) loaded with gold nanoparticles (Au NPs) to prepare Au@ZIF-8/CAS. Characterizations confirmed the successful synthesis of Au@ZIF-8/CAS. Mass spectrometry-based metabolomics detected the effects of Au@ZIF-8/CAS on significant metabolic pathways of macrophages in the presence of zoledronic acid (ZA). Twenty-three candidate key metabolites were identified, mainly focusing on the phenylalanine/tyrosine/tryptophan biosyn-thetic metabolic pathway in the amino acid metabolic pathway. In vitro experiments further confirmed that Au@ZIF-8/CAS could promote the polarization of macrophages from M1 pro-inflammatory phenotype to M2 anti-inflammatory phenotype, so as to produce a good immune microenvironment. In the co-culture system, Au@ZIF-8/CAS could also promote the expression of alkaline phosphatase (ALP), Osteocalcin (OCN), and Runt -related transcription factor 2 (Runx2), and synergistically increased the osteogenic differentiation ability of MC3T3-E1 cells through immunomodulatory effects and direct osteogenic stimulation. Furthermore, the anti-bacterial properties of Au@ZIF-8/CAS were also investigated. In vivo experiments further verified the potential role of Au@ZIF-8/CAS in treatment of BRONJ. These results will provide new directions and ideas for the treatment of inflammatory diseases.