In Situ Photo‑Crosslinked Functional Bilayer Hydrogel Modulates Local Microenvironment and Remyelination After Optic Nerve Injury.

Optic nerve injury often causes irreversible vision loss due to limited self-regeneration capacity, persistent neuroinflammation, and failed remyelination. Current therapies partially promote axonal regeneration but rarely achieve meaningful visual recovery, limited mainly by unstable myelin reconstruction and inadequate injury microenvironment modulation. Here, we developed a photo-crosslinkable bilayer hydrogel system (GO/GI@MPDA-Cle). Its outer layer (GM-Odex) provides strong wet tissue adhesion for optic nerve sheath sealing, while the inner layer (GM-imid) enables sustained local release of drug-loaded nanoparticles (MPDA-Cle) for microenvironment modulation. In Vitro, the system exhibited excellent antioxidant and anti-inflammatory properties and polarized microglia toward an anti‑inflammatory phenotype. In a rat partial optic nerve injury model, the hydrogel protected retinal ganglion cells through local immunomodulation and was associated with improved oligodendrocyte-associated maturation and remyelination-associated repair, accompanied by partial improvement in optic nerve conduction-related function. Transcriptomic analysis further revealed that the treatment downregulated pathways related to inflammation, oxidative stress, and neuronal apoptosis, while upregulating genes involved in neuronal regeneration, axonal growth, and myelination. By integrating physical sealing, immunomodulation, and myelin repair, this study proposes a promising multifunctional strategy for optic nerve injury treatment.