Simultaneously boosting inflammation resolution and osteogenic differentiation in periodontitis using folic acid-modified liposome-thermosensitive hydrogel composites

Currently, the antibiotics-loaded hydrogels have not shown an over standard of clinical effects on periodontitis treatment. Abnormal crosstalk between macrophages and periodontal ligament stem cells (PDLSCs) is a key factor for unexpected clinical efficacy. Here, we reported a therapeutic strategy for the programmed intervention of macrophages and PDLSCs based on folic acid-modified liposome hydrogel composites loaded with genistein (FA-GEN-Lip@Gel). FA-GEN-Lip@Gel exhibited excellent thermos-sensitivity and injectability, could sustained-release genistein for more than 120 h. Flow cytometry showed that FA-GEN-Lip@Gel shifted macrophages from the M1 to M2 phenotype. We further confirmed the anti-inflammatory mechanisms that FA-GEN-Lip@Gel regulate TLR4/MyD88/NF-κB axis in macrophages. In addition, FA-GEN-Lip@Gel could promote osteogenic differentiation of PDLSCs via remodeling of cytokine secretion of IL-6, IL-17, TNF-α and IL-10 in macrophages, as verified by conditioned culture system. Therefore, FA-GEN-Lip@Gel significantly reduced periodontal inflammation in vivo according to ELISA, H&E and immunofluorescence staining. Meanwhile, FA-GEN-Lip@Gel promoted alveolar bone regeneration by remodeling RANKL/OPG balance and increasing osteogenic markers of ALP, BMP2 and RUNX2. Altogether, this study develops a novel liposome-hydrogel composites that can be efficiently simultaneously boost inflammation resolution and osteogenic differentiation in periodontitis via modulating the crosstalk between macrophages and PDLSCs.