Immunomodulation of behavior impairment via spleen-specific targeting lipid nanoparticles in a MeCP2 transgenic mouse model

This study investigates a novel approach using spleen-targeting lipid nanoparticles (LNPs) to immunomodulate behavioral impairment in a Methyl-CpG-binding protein 2 (Mecp2) transgenic mouse model. In a human Mecp2 transgenic mouse model (B6.Mecp2^Tg1), spleen-targeting lipid nanoparticles encapsulated with antisense oligonucleotides (ASO) were employed as a mitigating agent. Splenic immune cells were analyzed using flow cytometry; autoantibody production was assessed using autoantigen protein microarrays, including a central nervous system (CNS) protein microarray. Furthermore, proinflammatory cytokines, MeCP2-mediated signaling pathways, and manifestations of behavior functions and kidney disease were examined. Our findings indicated a reduction in splenic MeCP2 levels following in vivo knockdown via ASO. Notably, 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, levels of MeCP2 protein, phospho-CREB, and phospho-mTOR were reduced compared to the placebo group. A reduced IgG deposition in the brain of the B6.Mecp2^Tg1 mice were observed following treatment. Interestingly, behavioral functions and defects of the blood-brain barrier (BBB) were attenuated after spleen-targeted LNP-ASO treatment. Tissue-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. These preclinical findings suggest that immunomodulation may be a promising therapeutic strategy for neuropsychiatric diseases.