Fusobacterium nucleatum-induced ulcerative colitis (UC) is characterized by persistent intestinal inflammation and an imbalance in immune homeostasis, in which abnormal activation of antigen-presenting cells (APCs) and a Th17/Treg imbalance play critical roles in disease progression. This study aimed to construct the mannose-modified lipid nanoparticles (LNPs) loaded with siZDHHC9 (Man-LNP@siZDHHC9). By integrating single-cell RNA sequencing (scRNA-seq) and multi-omics technologies, we systematically elucidated the molecular mechanisms by which Man-LNP@siZDHHC9 remodels APC-T cell interactions by inhibiting the HRas palmitoylation-mediated ERK signaling axis, thereby ameliorating Th17/Treg imbalance and alleviating Fusobacterium nucleatum-induced UC.