Orally Targeted Cellulose Acetate Butyrate Nanocarriers Serve as a Butyrate Prodrug and Quercetin Delivery Platform for Synergistic Microbiota-Modulated Colitis Therapy.

While oral administration offers distinct advantages for the treatment of ulcerative colitis (UC), its efficacy is often limited by poor drug targeting and the disease's multifactorial pathology. Herein, we report an orally bioavailable nanotherapeutic system, CAB@Que, in which cellulose acetate butyrate (CAB) functions not merely as a delivery vehicle for quercetin (Que) but as a colon-specific butyrate prodrug, enabling synergistic and targeted therapy of UC. The CAB nanocarrier itself exhibits intrinsic therapeutic activity: upon reaching the inflamed colon, its butyryl side chains undergo hydrolysis triggered by colonic alkaline pH and microbial esterases to release butyrate, while residual polymer fragments are further fermented by commensal microbiota to generate additional short-chain fatty acids (SCFAs). This dual-source SCFA supplement actively supports epithelial energy metabolism and mucosal healing. Meanwhile, Que is coreleased to exert potent anti-inflammatory and antioxidant effects. In a murine colitis model, CAB@Que demonstrated superior efficacy over free Que, blank CAB, or their physical mixture, significantly ameliorating clinical symptoms, restoring epithelial barrier integrity, alleviating systemic oxidative stress, and re-establishing gut microbial homeostasis. By integrating carrier-mediated butyrate prodrug action with payload-driven immunomodulation, the CAB@Que platform enables precise, holistic intervention across the "microbiota-mucosa-immune" axis, offering a rationally designed oral strategy for synergistic UC therapy.