Nanohydrogel-mediated delivery of Resolvin D1 for periodontitis therapy via immuno-osteogenic crosstalk modulation

Periodontitis is a chronic inflammatory disease characterized by microbial dysbiosis, oxidative stress, and progressive alveolar bone loss. Macrophage mitochondrial dysfunction and cuproptosis—a copper-dependent form of cell death—are emerging contributors to periodontal immune dysregulation. However, effective therapeutic platforms that simultaneously mitigate oxidative stress, suppress inflammation, and promote tissue regeneration remain lacking. Herein, we developed a reactive oxygen species (ROS)-responsive hydrogel (PVA-TSPBA) integrating PEGylated germanene nanosheets (GeNSs-PEG) and the pro-resolving lipid mediator Resolvin D1 (RvD1) to promote immune modulation and osteoimmune regeneration (GeNSs-PEG@G/R). GeNSs-PEG exhibited high RvD1-loading loading and potent ROS-scavenging ability, while the dynamic boronic ester hydrogel enabled inflammation-responsive degradation and controlled drug release. We demonstrated that GeNSs-PEG@G/R effectively reduced intracellular ROS, restored mitochondrial membrane potential, decreased copper accumulation, and contributed to M2 macrophage polarization. Transcriptomic analyses revealed suppression of TNF and IL-17 signaling and activation of antioxidant pathways. Furthermore, conditioned medium from treated macrophages also enhanced osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs). In a rat periodontitis model, GeNS-PEG@G/R attenuated alveolar bone loss and modulated immune cell infiltration via inhibiting cuproptosis and inflammasome related pathways. This multifunctional hydrogel system offers a promising strategy for periodontitis therapy by restoring mitochondrial function and copper homeostasis while promoting immune resolution and tissue repair.