Neuroinflammation in aging is a chronic, low-grade inflammatory state in the brain that worsens with age and is linked to neurodegeneration. It is characterized by elevated pro-inflammatory cytokines, oxidative stress, impaired microglial function, activated glia, and astrocytes. Higher ApoE2 expression in the brain attenuates neuroinflammation. The nano-hybrid-mediated approach was employed for effective intranasal (IN) delivery of a plasmid encoding ApoE2 (pApoE2) to investigate its effect on age-related neuroinflammation. The nanohybrid demonstrated enhanced pDNA loading (89.1%) compared to extracellular vesicles (EVs) (10.4%), was <230 nm in size, and was non-toxic to brain cells. The nanohybrid/pApoE2 complex demonstrated significantly higher (p  ≤  0.05) cellular transfection efficiency in primary astrocytes and neurons than EVs (12.3 ± 3.8 and 10.5 ± 1.5 ng/mg of protein, respectively). In vivo brain transfection via nanohybrid/pApoE2 showed significantly higher (p  ≤  0.05) ApoE expression across all treated groups, at 57.7 ± 13.8 ng/mg of protein. Comparative analysis of pro-inflammatory cytokines in 3-month-old and 24-month-old mice revealed higher neuroinflammation in the older mice. The nanohybrid/pApoE2 complex-treated mice have shown a significant reduction in the TNF- α, IL-6, and IL-1β expression in the brain, plasma, and spleen. Our study elucidates a therapeutic approach of nanohybrid-mediated IN administration of pApoE2 against inflammaging.