Parkinson's disease (PD) is characterized by progressive dopaminergic neurodegeneration driven by mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired gut-brain communication. Here, we report a biogenic selenium nanoparticle (Se-NP) platform derived from mussel tissue and demonstrate its nano-enabled neuroprotective efficacy in a rotenone-induced zebrafish model of Parkinsonian neurotoxicity. Selenium was extracted from the tissue of Perna viridis (mussel) and used for the biogenic synthesis of Se-NPs through a green reduction approach under controlled conditions. The mussel-derived Se-NPs exhibited high redox-buffering capacity, enabling efficient attenuation of rotenone-induced oxidative stress, lipid peroxidation, and nitric oxide accumulation. Se-NP treatment preserved dopaminergic neuronal architecture, reduced microglial activation, and maintained gut epithelial integrity, indicating coordinated neuro-intestinal protection. Mechanistically, Se-NPs activated NRF2-driven antioxidant signaling through upregulation of NFE2L2a and HMOX1a and suppression of KEAP1a, thereby restoring endogenous antioxidant defences. At the neurovascular interface, Se-NPs enhanced blood-brain barrier integrity by upregulating tight junction proteins Claudin-5a and ZO-1, linking redox regulation to barrier stabilization. Notably, Se-NPs restored dopaminergic gene expression, modulated inflammatory signaling pathways, and normalized gut-associated microbial markers, thereby supporting nano-mediated regulation of the gut-brain axis. Collectively, this study establishes biogenic Se-NPs as a multifunctional nanotherapeutic that integrates antioxidant signaling, neurovascular protection, and gut-brain axis modulation to counteract rotenone-induced neurodegeneration, highlighting their potential as a nano-enabled strategy for PD intervention.
