Ulcerative colitis (UC) is one type of inflammatory bowel diseases, and adiponectin (APN) is a potential therapeutic protein drug for treating UC. However, source and targeted delivery of APN to improve its effectiveness and bioavailability remain challenges. Here, we report a strategy to develop a sericin hydrogel (rhAPN-sh) through genetically engineering silkworm to spin silks mixed with recombinant human adiponectin (rhAPN), which efficiently overcome APN source and delivery. The rhAPN-sh exhibits desirable material performances such as stable internal crystal structure, fast swelling behavior, good biocompatibility, injectability. The rhAPN-sh effectively protected the APN through harsh gastroenteric environment for oral administration, which alleviated UC symptoms in mice with significant therapeutic effect by reconstructing colonic cell structure and colon length, reducing release of inflammatory factors, and maintaining stability of intestinal microbial population. These results indicate that the fabricated rhAPN-sh is a promising system for colitis treatment. STATEMENT OF SIGNIFICANCE: The present study presents an efficient strategy to treat ulcerative colitis (UC) by developing a genetically engineered sericin hydrogel delivering recombinant human adiponectin (rhAPN). Using transgenic silkworms, the system enables efficient rhAPN production, while the sericin hydrogel protects APN from gastrointestinal degradation, ensuring effective oral delivery. The sericin hydrogel alleviates UC symptoms in mice by reducing inflammation, restoring colon structure, and maintaining gut microbiota stability. This approach overcomes key challenges in APN protein drug delivery, offering a scalable, biocompatible, and effective therapeutic platform for UC and potentially other inflammatory diseases.