Targeted Neuroimmune Modulation via FGF21-Loaded Dual-Layer Electrospun Nanofibrous Scaffold to Suppress Secondary...

Containment of secondary injury following severe traumatic brain injury (sTBI) is crucial for preserving neural tissue and function, especially when a dysregulated neuroimmune response exacerbates inflammation. However, effective therapeutic interventions targeting neuroimmune remodeling remain lacking. In this study, fibroblast growth factor 21 (FGF21) is identified as a promising immunomodulatory candidate, and a dual-layer electrospun scaffold is developed for efficient FGF21 delivery to the brain. FGF21 is stabilized within poly(lactic acid) (PLA), as confirmed by molecular docking, and incorporated into a PLA/triglycerol monostearate (PT) nanofiber inner layer for matrix metalloproteinase-9 (MMP-9)-responsive drug release. A crosslinked zein/gelatin (CZG) outer layer is added to support dura mater recovery. In a murine sTBI model, RNA sequencing revealed that FGF21 modulates neuroinflammation by suppressing type I interferon signaling and downstream chemotaxis, thereby shifting microglia from an aggressive pro-inflammatory to a restorative phenotype, with concurrent reductions in microglial proportion and amoeboid morphology. Magnetic Resonance Imaging (MRI)Magnetic Resonance Imaging imaging and behavioral assessments further confirmed the neuroprotective effects of FGF21@PT/CZG and demonstrated improvements in sensorimotor and neurological functions. These findings suggest that this nanofibrous scaffold offers a promising therapeutic strategy for targeted immunomodulation and functional recovery following sTBI.