Interferon regulatory factor 4–releasing 3D-printed scaffolds enhance spinal cord repair by modulating macrophage polarization

Three-dimensional (3D)-printed hydrogel scaffolds are widely used in spinal cord injury repair, with gelatin methacrylate being particularly favored owing to its excellent biocompatibility. However, traditional scaffolds have a small contact area with tissues and lack the ability to regulate the inflammatory microenvironment. Therefore, there is a need to develop smart scaffolds with drug delivery and immune regulation functions. In this study, a 3D-printed gelatin methacrylate scaffold was developed to deliver interferon regulatory factor 4 in a targeted and sustained manner. The scaffold showed good mechanical properties, biocompatibility, and sustained interferon regulatory factor 4 release. The sustained-release interferon regulatory factor 4 competitively bound to myeloid differentiation factor 88 to inhibit the pro-inflammatory effects of interferon regulatory factor 5, and activated the signal transducer and activator of transcription 6 pathway to promote M2 macrophage polarization, thereby facilitating neural regeneration and recovery of spinal cord function. This indicates that the constructed interferon regulatory factor 4-loaded 3D-printed methyl acrylate-modified gelatin scaffold can regulate macrophage polarization through the interferon regulatory factor 4/5 axis, improve the inflammatory microenvironment after spinal cord injury, and thus provide a new target for promoting neural regeneration.