Nanozyme-integrated hydrogels orchestrate Schwann cell-macrophage crosstalk for enhanced peripheral nerve regeneration

Peripheral nerve injuries remain a major clinical burden, as current surgical and biomaterial strategies primarily restore anatomical continuity but fail to adequately modulate the immune microenvironment required for complete functional recovery. Here, we report a nanozyme-integrated hydrogel designed to modulate redox balance and immune responses to promote peripheral nerve repair. The nanozyme–integrated hydrogel (USCu@GelMA) was engineered by encapsulating ultrasmall copper nanozymes (USCu) within Gelatin methacryloyl (GelMA), which serves as a biocompatible carrier enabling localized and sustained nanozyme-driven redox regulation. In vitro , USCu@GelMA enhances Schwann cell (SC) migration, survival under oxidative stress, and secretion of TGF-β1 and BDNF, while reprogramming the SC secretome through FAK–ROCK–YAP–linked mechanotransduction and metabolic priming to establish an anti-inflammatory, pro-regenerative profile. SC–conditioned media derived from USCu@GelMA cultures subsequently drive macrophage polarization toward an M2-dominant state characterized by elevated IL-10 secretion and increased CD206 expression, reflecting a balanced yet M2-biased activation rather than a binary switch. In a rat facial nerve transection model, local USCu@GelMA implantation accelerates M2 macrophage accumulation, reduces oxidative DNA damage, and enhances axonal regeneration in both proximal and distal segments, resulting in higher compound muscle action potential amplitudes, improved facial palsy scores, and sustained recovery without detectable systemic toxicity in major organs. Collectively, these findings identify USCu@GelMA as a multifunctional, clinically translatable hydrogel platform that integrates nanozyme-driven redox control, matrix mechanics, and SC–macrophage immunoregulation to coordinate the complex cellular programs required for peripheral nerve regeneration. • Novel USCu@GelMA hydrogel integrates ultrasmall Cu nanozymes with GelMA for bioactive support. • Hydrogel modulates Schwann cell proliferation, migration, and neurotrophic support. • Schwann cell secretome from hydrogel treatment promotes macrophage M2 polarization. • Hydrogel treatment in nerve injury enhances axonal regeneration, remyelination, and recovery.