A multifunctional nanotherapeutic strategy based on exosome-liposome hybrid nanoparticles for comprehensive periodontitis management

Periodontitis is a formidable chronic inflammatory disorder, marked by pathological oxidative stress, persistent inflammation, and alveolar bone resorption. The simultaneous management of these interrelated pathological processes poses significant challenges to conventional therapeutic modalities. In this study, we developed a multifunctional nanotherapy, EXO@Lip-Res, constructed from exosome-liposome hybrid nanoparticles. By synergistically integrating resveratrol-loaded liposomes with exosomes derived from dental pulp stem cells, this approach was designed to address the multifaceted nature of periodontitis. The synthesized EXO@Lip-Res exhibited favorable physicochemical properties and retained distinct exosomal markers, facilitating a reactive oxygen species (ROS)-responsive to trigger programmed drug release. In vitro evaluations demonstrated that EXO@Lip-Res exhibited superior antioxidant and anti-inflammatory activities. Specifically, EXO@Lip-Res treatment significantly scavenged H2O2-induced intracellular ROS in both RAW264.7 cells and PDLSCs (p < 0.05). In the context of inflammation, the nanoplatform markedly downregulated the expression of pro-inflammatory cytokines in lipopolysaccharide (LPS)-stimulated PDLSCs compared to the LPS-only group. Quantitative analysis revealed a 50% reduction in the mRNA expression of IL-6 and IL-1β, while the protein levels of TNF-α and IL-1β were decreased by approximately 40% (p < 0.05). Mechanistic studies elucidated that its potent anti-inflammatory effects were governed by the inhibition of pivotal signaling pathways, including the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and p38 mitogen-activated protein kinase (MAPK) pathways. Furthermore, EXO@Lip-Res significantly facilitated the polarization of macrophages from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype. In vivo experiments utilizing a rat model of experimental periodontitis demonstrated that EXO@Lip-Res treatment reduced alveolar bone loss by 30%, diminished inflammatory infiltrates, reduced osteoclast numbers. Consistent with the in vitro results, a significant shift in macrophage polarization from the M1 to M2 phenotype was observed within periodontal tissues in vivo. Collectively, this research delineates a comprehensive nanotherapeutic strategy targeting oxidative damage, inflammation, and bone remodeling, providing a potential avenue for the clinical management of periodontitis and related chronic inflammatory diseases.