Multifunctional Inorganic-Nanosheets-Based Nanohydrogel for Periodontal Bone Regeneration via Antibacterial and Anti-Ferroptotic Immunomodulation

Periodontal disease is characterized by microbial infection, excessive reactive oxygen species (ROS), and dysregulated inflammatory responses, posing a persistent clinical challenge. Emerging evidence suggests that bacterial infection and ferroptosis─an iron-dependent form of cell death─jointly contribute to inflammation-driven periodontal tissue damage. Here, we present a multifunctional, thermosensitive hydrogel integrating black phosphorus nanosheets (BP NSs) and resveratrol (RSV) for synergistic periodontitis therapy. BP NSs confer near-infrared (NIR) activated photothermal and photodynamic antibacterial properties, along with potent ROS-scavenging capacity. Meanwhile, RSV inhibits ferroptosis by reducing lipid peroxidation and intracellular Fe²⁺ accumulation. The BP-RSV@gel-L system modulates both pro-inflammatory and regenerative cytokine expression, reshapes the inflammatory microenvironment, and promotes the osteogenic differentiation of human periodontal ligament stem cells. In a rat periodontitis model, nanohydrogel markedly attenuated alveolar bone loss and enhanced collagen deposition, which was associated with the suppression of ferroptosis and inflammatory infiltration. This study highlights a nanotherapeutic strategy that integrates antibacterial action, ROS clearance, and ferroptosis-regulating immunomodulation, offering a promising platform for treating chronic inflammatory oral or other diseases.