Chiral Fe3O4/GelMA hydrogels regulate the osteoimmune microenvironment via Itgb3-mediated macrophage polarization to combat peri-implantitis

Peri-implantitis continues to pose a significant clinical challenge due to its complex osteoimmune microenvironment, which evolves through distinct pathological phases characterized by acute infection-driven oxidative stress and chronic immune-bone dysregulation. This stage-specific progression complicates clinical management, necessitating targeted therapeutic strategies. To address this challenge, we developed injectable chiral hydrogels based on gelatin methacryloyl (GelMA) and L/D-cysteine-modified Fe 3 O 4 nanoparticles. Our results show that L-FG promotes M2 macrophage polarization through YTHDF1-m 6 A- Itgb3 axis, supporting bone formation during chronic bone resorption phase, while D-FG enhances the peroxidase-like activity of Fe 3 O 4 and activates PI3K/Akt signaling to mitigate oxidative stress in acute inflammation. In the rat peri-implantitis model, both hydrogels significantly enhanced bone regeneration, with L-FG elevating M2 macrophage infiltration and YTHDF1/CD61 co-expression. This study presents a stage-adaptive chiral hydrogel system that separately addresses oxidative stress in acute phases and immunomodulation in chronic phases, providing a therapeutic strategy for peri-implantitis. Illustration of the synthesis of L-/D-cys-Fe 3 O 4 /GelMA(L-/D-FG) hydrogels and the mechanisms for suppressing inflammation and promoting bone regeneration in peri-implantitis, wherein L-FG regulates macrophage polarization via the m 6 A methylation-dependent axis to drive osteogenesis, while D-FG enhances nanozyme activity and reduces reactive oxygen species (ROS) levels through activation of the PI3K/Akt pathway. • Injectable chiral hydrogel systems targeting different stages of peri‑implantitis were constructed. • L‑FG activated the YTHDF1–m⁶A–Itgb3 axis to induce M2 macrophage polarization, promoting osteogenesis in the chronic phase. • D‑FG alleviated acute oxidative stress through enhanced nanozyme activity and PI3K/Akt activation.