Encephalitis, a life-threatening neurological disorder with high mortality and debilitating long-term sequelae, remains a formidable clinical challenge due to limited therapeutic strategies targeting its underlying pathological mechanisms. Current interventions, constrained by blood-brain barrier (BBB) impermeability and a focus on symptomatic relief, fail to mitigate ferroptosis and reactive oxygen species (ROS)-mediated neurotoxicity-central drivers of disease progression. Here, we present CeO₂/3TT@NP-RVG, a multifunctional nanomaterial engineered for integrated diagnosis and treatment of encephalitis. The nanoplatform combines ROS-scavenging cerium oxide (CeO₂) with photothermal NIR-II-emissive (3TT) nanoparticles, enabling real-time fluorescence imaging of encephalitis with deep-tissue resolution. Functionalization with rabies virus glycoprotein-derived RVG peptide ensures BBB penetration and neuron-targeted delivery. In LPS-induced encephalitis models, CeO₂/3TT@NP-RVG demonstrated dual therapeutic efficacy: alleviating oxidative stress by neutralizing ROS, suppressing pro-inflammatory cytokines (TNF-α, IFN-β), and inhibiting ferroptosis via ubiquitination-mediated downregulation of the POR-ACSL4-LPCAT3 pathway, thereby reducing polyunsaturated fatty acid peroxidation. These synergistic actions significantly improved survival rates and mitigated neuroinflammation. Our findings highlight CeO₂/3TT@NP-RVG as a pioneering theranostic platform that bridges molecular mechanism-based therapy with precision imaging, offering a transformative strategy for encephalitis and related neurological disorders.

Keywords: Encephalitis; Ferroptosis; Inflammation-targeted; Oxygen species.