A dual-responsive bilayer hydrogel orchestrates immunomodulation and axonal regeneration after spinal cord injury

Spinal cord injury (SCI) presents a therapeutic challenge owing to its highly dynamic pathological microenvironment, which evolves from acute inflammatory damage to chronic regenerative insufficiency. However, most biomaterial-based drug delivery systems are inherently static and fail to meet these temporally distinct therapeutic demands. Here, we present a spatiotemporally programmable bilayer hydrogel that synchronizes therapeutic delivery with the pathological progression of SCI. The outer gelatin methacryloyl (GelMA) layer is engineered to undergo rapid degradation in response to the acute upregulation of matrix metalloproteinase-2 (MMP-2), enabling the release of an antioxidant agent to attenuate oxidative stress and reprogram macrophages toward a pro-regenerative M2 phenotype. As the injury microenvironment shifts to repair phase, the inner layer becomes functionally dominant. Composed of hyaluronic acid methacrylate–polydopamine (HAMA–PDA), this layer serves as a biocompatible, photothermally responsive scaffold that enables near-infrared (NIR) light–triggered, on-demand basic fibroblast growth factor (bFGF) release to promote neuronal differentiation and axonal regeneration. Notably, the integration of enzyme-initiated immunomodulation with externally controlled regenerative stimulation markedly enhances functional recovery in a mouse SCI model. Collectively, this work establishes a pharmaco–physical biomaterial paradigm for spatiotemporal regulation of the injury microenvironment, offering a versatile strategy for neural regeneration.