Immunomodulation of Neuropsychiatric Disorders via Spleen-Specific Targeted Treatment 2093

Description A novel approach to immunomodulating behavioral impairment in a human MECP2 transgenic mouse model (B6.MECP2Tg1) using spleen-targeting lipid nanoparticles (LNPs) was investigated. LNPs encapsulated with antisense oligonucleotides (ASO) were employed. We found splenic immune cells, including B and T cells, particularly plasma B cells, were significantly reduced after LNP-ASO treatment. Levels of autoantibodies against typical nuclear antigens such as Sm, U1-snRNP B/B, and nucleosome antigens, as well as brain antigens including OLIG2, GAD2, GJA1, and YWHAE, were significantly alleviated. Proinflammatory molecules such as IL-5, TNF-α, CCL20, and TGF-β1 showed significant reduction. Additionally, after the in vivo knockdown of MeCP2, splenic phospho-CREB, phospho-mTOR as well as brain deposition of IgG in B6.Mecp2Tg1 mice were reduce. Interestingly, behavioral functions and defects of the blood-brain barrier (BBB) were attenuated after spleen-targeted LNP-ASO treatment. Collectively, spleen-specific knockdown of a disease-promoting gene, MECP2, via spleen-targeting LNPs effectively modulated the peripheral immune system, resulting in subsequent amelioration of autoantibody production, inflammation, and behavioral deficits, suggesting it may be a promising therapeutic strategy for neuropsychiatric diseases.