We highlighted a poly lactic acid-co-glycolic acid (PLGA)-block-polyethylene glycol (PEG) and chitosan-based nanoparticle system to deliver sterol O-acyltransferase 2 (SOAT2) siRNAs into the small intestines of mice to effectively inhibit lipid uptake and tackle obesity. Intestinal SOAT2 can regulate fatty acid uptake and its inhibition can enhance ubiquitination-based CD36 degradation in the enterocytes. This work demonstrates a potential modulatory function of intestinal SOAT2 on lipid uptake, highlighting the therapeutic effect of targeting intestinal SOAT2 against obesity. It exhibits promising translational relevance in the siRNA therapeutics-based treatment for obesity.