Ulcerative colitis (UC), a chronic disease characterized by continuous damage to the intestinal mucosa and inflammation in the colon, comprises a series of gastrointestinal reactions and is difficult to cure. Here, we have designed a nanotherapeutic strategy combining pharmacotherapy with physical protection, which is achieved by constructing a green nanocarrier named cyclodextrin-based nanosponges (CDNSs) and encapsulating the insoluble drug parthenolide (PTL). CDNSs were transformed into a hydrogel driven by water, releasing the anti-inflammatory agent PTL and forming a sticky barrier in the position of the ulcer lesion to confront pathogenic bacteria at the same time. Notably, the resulting PTL-loaded CDNS (PTL@CDNS) had improved the solubility and intestinal cellular uptake of PTL. The orally delivered transformable PTL@CDNS via a colon-specific capsule significantly relieved UC in rats by enhancing the regulation of c-kit and STAT6 pathways as well as normalizing inflammatory cytokines, including IL-4, IL-6, IL-10, IL-13, nitric oxide, malondialdehyde, and TNF-alpha, with excellent biocompatibility. To sum up, transformable PTL@CDNSs were demonstrated as a promising strategy for in situ treatment of mucosal ulcers including UC.