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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\u2010layer 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\u20109 (MMP\u20109)\u2010responsive 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\u2010inflammatory 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.<\/jats:p>","DOI":"10.1002\/adhm.202500905","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T05:05:47Z","timestamp":1750827947000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeted Neuroimmune Modulation via FGF21\u2010Loaded Dual\u2010Layer Electrospun Nanofibrous Scaffold to Suppress Secondary Injury After Severe Traumatic Brain Injury"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6862-2672","authenticated-orcid":false,"given":"Xiaoyan","family":"Bao","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences Wenzhou Medical University  Wenzhou 325035 P. R. 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