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

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 Fe₃O₄ nanoparticles. Our results show that L-FG promotes M2 macrophage polarization through YTHDF1-m⁶A-Itgb3 axis, supporting bone formation during chronic bone resorption phase, while D-FG enhances the peroxidase-like activity of Fe₃O₄ 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.