In situ injectable chemico-biological cascade-driven antioxidant nanoparticles for periodontitis treatment

Oxidative stress in the periodontal microenvironment intensifies inflammation and accelerates alveolar bone destruction. Consequently, strategies that effectively suppress oxidative stress while promoting osteogenesis are central to the management of periodontitis. Here, we present an in situ injectable antioxidant nanoparticle system designed to initiate a sequential chemico-biological cascade, achieving dual therapeutic outcomes of inflammation suppression and bone regeneration. The engineered nanoparticles were fabricated by encapsulating 4-octyl itaconate (4OI) within mesoporous polydopamine nanoparticles [4OI-loaded mesoporous dopamine (MDAI)]. Following cellular uptake, MDAI activates a two-step antioxidant mechanism. First, the mesoporous polydopamine scaffold undergoes ROS-triggered degradation within inflammatory macrophages, directly scavenging excessive ROS. Subsequently, the released 4OI activates the Nrf-2/HO-1 signaling axis, leading to robust antioxidant and cytoprotective effects, as evidenced by the pronounced upregulation of Nrf-2 and modulation of HO-1 activity. This signaling cascade shifts macrophage polarization toward the anti-inflammatory M2 phenotype and suppresses pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin 6. Transcriptome sequencing further confirmed broad downregulation of inflammatory pathways and associated genes. Moreover, the ROS-scavenging activity of MDAI indirectly enhanced osteoblast differentiation and bone formation. When incorporated into a thermosensitive hydrogel for localized administration, MDAI exhibited prolonged retention and sustained bioactivity within periodontal pockets. In a murine periodontitis model, this formulation effectively reduced inflammatory infiltration, decreased cytokine expression, modulated macrophage polarization and enhanced alveolar bone regeneration. Collectively, these findings establish MDAI-mediated chemico-biological cascade therapy as a potent and integrative platform for treating periodontitis and restoring periodontal tissue homeostasis.