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The progression of ulcerative colitis (UC) is associated with immunologic derangement, intestinal hemorrhage, and microbiota imbalance. While traditional medications mainly focus on mitigating inflammation, it remains challenging to address multiple symptoms. Here, a versatile gas-propelled nanomotor was constructed by mild fusion of post-ultrasonic CaO 2 nanospheres with Cu 2 O nanoblocks. The resulting CaO 2 –Cu 2 O possessed a desirable diameter (291.3 nm) and a uniform size distribution. It could be efficiently internalized by colonic epithelial cells and macrophages, scavenge intracellular reactive oxygen/nitrogen species, and alleviate immune reactions by pro-polarizing macrophages to the anti-inflammatory M2 phenotype. This nanomotor was found to penetrate through the mucus barrier and accumulate in the colitis mucosa due to the driving force of the generated oxygen bubbles. Rectal administration of CaO 2 –Cu 2 O could stanch the bleeding, repair the disrupted colonic epithelial layer, and reduce the inflammatory responses through its interaction with the genes relevant to blood coagulation, anti-oxidation, wound healing, and anti-inflammation. Impressively, it restored intestinal microbiota balance by elevating the proportions of beneficial bacteria (e.g. , Odoribacter and Bifidobacterium) and decreasing the abundances of harmful bacteria (e.g. , Prevotellaceae and Helicobacter). Our gas-driven CaO 2 –Cu 2 O offers a promising therapeutic platform for robust treatment of UC via the rectal route. A versatile gas-propelled nanomotor (CaO 2 –Cu 2 O) was facilely produced to overcome rectal drug delivery barriers and achieve effective synergistic treatment outcomes against ulcerative colitis. [Display omitted] [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) with its rapidly increasing incidence has become an emerging challenge for public health. Therapeutic agents are required to be specifically delivered to colon epithelial cells and macrophages with controlled release in the cytoplasm for wound healing, inflammation alleviation, and microbiota rebalance. As a promising biomaterial for accomplishing this, Antheraea pernyi silk fibroin (ApSF) was selected and engineered to form nanoparticles (NPs) loaded with the anti-inflammatory drug, resveratrol (Res). The intrinsic features of these fabricated Res-ApNPs included targeting of colonic epithelial cells and macrophages, lysosomal escape capacity, and responsiveness to pH, reactive oxygen species (ROS), and glutathione, which were pertinent to their functional units such as arginine-glycine-aspartate tripeptides, α -helixes, β -sheets, and disulfide bonds, enabling on-demand release of Res molecules in the cytoplasm of target cells. The Res-ApNP treatment restored damaged colonic epithelial barriers, polarized macrophages to type M2, alleviated inflammatory reactions, and reduced the level of intracellular ROS. Oral treatment with chitosan-alginate hydrogels embedded with Res-ApNPs substantially relieved UC symptoms, as evidenced by decreased colonic inflammation, increased synthesis of tight-junction proteins, and rebalanced intestinal microbiota. Our findings suggest that these high-performance ApSF-based NPs can be developed as effective drug carriers for oral UC treatment. [Display omitted] [ABSTRACT FROM AUTHOR]