Diabetic colitis is a severe gastrointestinal complication of type 2 diabetes, which presents the key pathophysiological hallmarks of hyperglycemia, intestinal barrier disruption, immune dysregulation, and microbial metabolic imbalance, posing significant therapeutic challenges in clinical practice. Here, we leveraged artificial intelligence to identify the therapeutic potential of 1-deoxynojirimycin (DNJ) for addressing diabetic colitis. To improve its bioavailability and efficacy, we developed a mulberry-derived nanotherapeutic with surface functionalization of zwitterionic polymer (PpC) for DNJ encapsulation. Following oral administration, the resultant nanotherapeutics, PpC@DNJ-LNPs, efficiently traversed the gastrointestinal tract, enabling controlled DNJ release while inhibiting the α-glucosidase activity to regulate glucose homeostasis. Concurrently, they orchestrated colonic mucosa-microbiome interaction, promoting intestinal immune balance and microbiota remodeling. These synergistic effects collectively confer hypoglycemic, anti-inflammatory, antioxidant, and epithelial barrier-restoring effects, ultimately reshaping the glucose level and intestinal microecology. Our study demonstrates the translational potential of PpC@DNJ-LNPs as a safe and effective oral therapeutic platform for diabetic colitis.