Background <p>Neuromyelitis optica spectrum disorder (NMOSD) is a chronic inflammatory autoimmune disease affecting the central nervous system (CNS), characterized by anti-aquaporin 4 (AQP4) antibody-mediated damage to astrocytes, resulting in subsequent demyelination. Our prior work identified the protective effects of the apolipoprotein E_130−149 (ApoE_130−149) peptide in NMOSD mice by promoting astrocyte-microglia intercellular communication. However, its therapeutic potential is restricted due to the limited penetration of the blood-brain barrier (BBB) with systemic administration. Here, we designed a heavy-chain ferritin (HFn)-based nanocarrier containing the ApoE_130−149 peptide (HFn-ApoE_130−149), specifically engineered for CNS delivery.</p> Methods <p>HFn-ApoE_130−149 was constructed through genetic engineering by fusing the coding sequence of HFn with that of the ApoE_130−149 peptide in a recombinant plasmid. An acute NMOSD mouse model was induced by transcranial co-injection of AQP4-IgG and human complement (hC) into the brain. The distribution of Cy5.5-labeled HFn-ApoE_130−149 post intravenous injection was tracked using in vivo fluorescence imaging to confirm its presence in the brain and peripheral organs. Lesions in the brain were quantified using T2-weighted 7 Tesla magnetic resonance imaging (7T-MRI). Neuropathological features of NMOSD were evaluated by immunostaining of brain sections. Neuroinflammation and immune cell infiltration were analyzed via flow cytometry. The key signaling pathways regulated by HFn-ApoE_130−149 were investigated through Western blot (WB) analysis. The interaction between HFn-ApoE_130−149 and its receptors was validated through co-immunoprecipitation and visualized on microglia using proximity ligation assay (PLA). Finally, the therapeutic effect on spatial learning and memory was evaluated using the Morris water maze (MWM) test.</p> Results <p>The HFn-ApoE_130−149 effectively crossed the BBB, attenuated lesion progression and demyelination, as well as preserved AQP4 expression and astrocytic integrity in NMOSD mice. The treatment induced a spatial and phenotypic restructuring of the astrocytic response, notably reducing excessive astrocyte accumulation around lesions while encouraging a proliferative and reparative phenotype. Furthermore, HFn-ApoE_130−149 influenced microglial polarization towards an anti-inflammatory state, reducing infiltration of peripheral immune cells. Mechanistically, HFn-ApoE_130−149 exerted its anti-inflammatory effects through the low-density lipoprotein receptor-related protein 1 (LRP1) -nuclear factor kappa B (NF-κB) signaling axis in microglia. Functional binding of HFn-ApoE_130−149 to LRP1 suppressed inhibitor of NF-κB (IκBα) phosphorylation, thereby inhibiting NF-κB nuclear translocation and the subsequent release of pro-inflammatory cytokines, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Knocking down LRP1 reversed these effects, highlighting the importance of the LRP1-NF-κB signaling axis in the nanotherapeutic’s efficacy. Treatment with HFn-ApoE_130−149 improved spatial learning and rescued memory deficits in NMOSD mice.</p> Conclusion <p>This study demonstrates that the engineered nanodrug HFn-ApoE_130-149 is a promising targeted therapy for alleviating NMOSD pathology by enhancing BBB penetration and suppressing neuroinflammation through the LRP1-NF-κB signaling axis.</p>