Exosome-functionalized photocrosslinked GelMA/HAMA hydrogel promotes facial nerve recovery via inflammatory microenvironment regulation

Facial nerve crush injuries frequently lead to incomplete functional restoration owing to constrained regenerative approaches and suboptimal treatment methods. While hydrogel-based systems have emerged as viable alternatives among bioengineered scaffolds, their therapeutic potential remains compromised by inadequate biological activity and unfavorable inflammatory conditions. Our research engineered a photoactivated GelMA/HAMA composite hydrogel incorporating bone marrow mesenchymal stem cell-derived exosomes (BExos), with comprehensive characterization of its material attributes. We systematically assessed the biomaterial's regenerative capacity through in vitro experiments involving BMSCs and RAW264.7 macrophages, complemented by comprehensive in vivo evaluations in a rodent facial nerve injury model incorporating functional restoration metrics, neurophysiological testing, tissue analysis, and biomolecular profiling. The BExos-integrated hydrogel established a favorable niche promoting BMSCs transdifferentiation toward Schwann cell-mimetic lineages while demonstrating marked improvement in neuromuscular functional restoration. Compared to untreated cohorts, the composite hydrogel demonstrated enhanced axonal regrowth, improved remyelination processes, and notably reduced oxidative damage. The biomaterial effectively shifted macrophage differentiation from M1 pro-inflammatory states toward M2 anti-inflammatory phenotypes through modulation of PI3K/NF-κB/P38 signaling cascades, with Neuronatin emerging as a key regulatory element in this pathway. Mechanistic investigations demonstrated that the therapeutic benefits stemmed from synergistic structural reinforcement combined with exosome-mediated immune regulation, positioning this dual-action hydrogel as an innovative solution for facial nerve repair. • A photocrosslinked GelMA/HAMA hydrogel loaded with BMSC exosomes was engineered as a biomimetic 3D niche for facial nerve repair. • BExos@GelMA/HAMA hydrogel significantly promoted axonal regrowth, myelination and functional recovery in facial nerve injury model. • Immunomodulatory microenvironment was regulated by shifting macrophages from M1 to M2 phenotype via PI3K/NF-κB/P38 pathways. • Nnat exerts anti-inflammatory effects by inhibiting the PI3K/NF-κB/P38 signaling pathway, thereby promoting macrophage polarization to M2.