Juveniles are at increased risk for mild traumatic brain injury (mTBI) due to recreational activities, domestic violence, and vulnerabilities of the developing skull. In industrialized nations, adolescents often consume high-sugar, high-fat diets (HFD), which can impair CNS health and exacerbate mTBI outcomes. Secondary injury following mTBI is characterized by prolonged neuroinflammation, with nuclear factor kappa B (NF-κB) acting as a central regulator of these inflammatory responses. We developed a polypeptide biologic, SynB1-ELP-p50i, consisting of an elastin-like polypeptide delivered NF-κB inhibitor (p50i) and the cell-penetrating peptide SynB1. This study investigates the interaction between diet and NF-κB inhibition in juvenile rats with mTBI by examining SynB1-ELP-p50i biodistribution, pharmacokinetics, therapeutic efficacy, and cell-specific effects. Long Evans rats were assigned to chow or HFD groups at postnatal day 20 (PND20), and mTBI or sham injury was induced at PND30 using the CHIMERA TBI model. Rats received 50 mg/kg SynB1-ELP-p50i or saline post-injury. Behavioral outcomes were assessed with the Morris water maze (MWM), and neuroinflammatory markers were measured using RT-qPCR and single-nucleus RNA sequencing (snRNA-seq). SynB1-ELP-p50i accumulated at injury sites (p < 0.05), and SynB1-ELP-p50i treated chow-fed rats showed improved MWM performance compared to vehicle controls and HFD subjects (p < 0.05). RT-qPCR confirmed increased Aif1 and Gfap expression post-injury (p < 0.05), and snRNA-seq revealed upregulation of markers of microgliosis in activated microglia. These findings indicate that mTBI triggers acute cognitive deficits and neuroinflammation, worsened by HFD. SynB1-ELP-p50i mitigated memory deficits in chow-fed animals, supporting NF-κB inhibition as a promising therapeutic strategy for juvenile mTBI.
