<p>Inflammatory bowel disease (IBD) is a relapsing disorder characterized by uncontrolled chronic inflammation of the gastrointestinal tract, posing a significant therapeutic challenge owing to the limited efficacy and undesirable side effects of current therapeutic options. A key pathological hallmark of IBD is the excessive production of reactive oxygen species (ROS). Hence, therapeutic strategies aimed at reducing ROS levels are promising for relieving these inflammatory conditions. Vitamin C—a natural nutrient for the human body—is well known for its potent antioxidant effects. However, the clinical development of vitamin C as a therapeutic drug has been hindered by its poor stability, rapid metabolism, and inadequate tissue accumulation. Herein, we report that the bioavailability of vitamin C can be enhanced by chemically reprogramming it with a small panel of long-chain fatty acids that aid in the aqueous self-assembly of the resulting drug conjugates to create self-deliverable nanoassemblies, enhancing their inflammation disease–oriented delivery and cellular uptake. In mice with dextran sulfate sodium–induced colitis, the optimal vitamin C–lipid nanoassemblies preferentially accumulated in inflamed colonic tissues following systemic administration and substantially ameliorated disease severity. We extended this strategy to incorporate the clinically approved glucocorticoid budesonide into the vitamin C nanosystem, facilitating a synergistic combination. In the chronic colitis model, the combination treatment reduced inflammation without compromising global immunity. Mechanistically, the treatment modulated the intestinal inflammatory microenvironment and altered the immune cell landscape, partly through regulation of the gut microbiome. Given its anticipated negligible side effects, this novel nanoassembly platform leveraging small-molecule lipidation may become a promising therapeutic for treating various inflammatory diseases.</p>