The minimalist epigenetic nano-adjuvant gMSN reprograms dendritic cells to enhance the mucosal immune response of oral vaccines.

Weak response is the bottleneck for subunit prophylactic vaccines to trigger efficient immunization. The emergence of highly effective adjuvants will revolutionize. Considering that genomic epigenetic reprogramming plays an important role in the immune response, we herein present an minimalist epigenetic nano-adjuvant gMSN constructed of β-glucan-modified functional mesoporous silica (MSN), which we term as OVA/gMSN after loaded with the model antigen ovalbumin (OVA). Oral administration of OVA/gMSN ensures that enough antigen reach dendritic cells (DCs) in intestinal mucosal lymphoid follicles via intestinal M cells while relying on gMSN to exhibit good adjuvant properties to trigger an effective systemic co-mucosal immune response. gMSN upregulates genes associated with aerobic glycolysis, promoting metabolic reprogramming in DCs and enhancing the expression of genes related to DC activation, cross-presentation, maturation, and migration. Simultaneously, it increases the accumulation of key epigenetic markers H3K27ac, H3K4me1, and H3K4me3. ATAC-seq results reveal enhanced chromatin accessibility of key immune genes, such as Il2rα1, Il18r1, and Cd83, in gMSN-treated DCs. This integrative molecular mechanism demonstrates that gMSN induces epigenomic remodeling in DCs after oral administration, showcasing the potential of combining epigenetic adjuvants and nanotechnology in oral vaccine design, and providing new directions and a theoretical basis for vaccine adjuvant development.