Neonatal Treatment with Astaxanthin-Loaded Stealth Solid Lipid Nanoparticles Activates the Impaired NRF2 Pathway and Reduces Hippocampal Oxidative Stress in a Mouse Model of Trisomy 21

Background: Oxidative stress is an important contributor to brain abnormalities in Down syndrome (DS), but the status of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant pathway during early postnatal development remains poorly understood. The current study aimed to investigate whether an impairment of the NRF2 pathway is already present in the Ts65Dn mouse model of trisomy 21 at neonatal life stages and whether early treatment with astaxanthin-loaded stealth solid lipid nanoparticles (AST-SSLNs) positively impacts NRF2 signaling and reduces oxidative stress. Methods: Hippocampal NRF2 pathway components and oxidative stress markers were analyzed in neonate Ts65Dn and euploid mice. From postnatal day (P)3 to P15, mice received daily subcutaneous injections of AST-SSLNs or unloaded nanoparticles. NRF2 pathway activation, reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and safety parameters were evaluated. Results: Untreated Ts65Dn mice exhibited early impairment of the NRF2 pathway, characterized by increased BACH1, reduced NRF2 activation, and decreased HO-1 expression. Neonatal AST-SSLN treatment enhanced NRF2 activation, improved HO-1 levels, and normalized ROS accumulation, lipid peroxidation, and protein carbonylation in the hippocampus, a brain region critically impaired in DS. Treatment had no adverse effects on survival, body weight, or brain weight. Conclusions: These findings demonstrate that NRF2 pathway dysfunction is an early event in trisomy 21 and identify the neonatal period as a potential therapeutic window to counteract oxidative stress. AST-SSLNs represent a promising nanomedicine-based strategy to activate the impaired NRF2 pathway and reduce early hippocampal oxidative damage in DS.