Background: Ulcerative colitis (UC) is a major type of inflammatory bowel disease (IBD), which could induce bloody stool, diarrhea, colon atrophy and eventually lead to colorectal cancer. The conventional daily oral administration of drugs only relieve the inflammatory response of colon in the short term, Biological agents such as antibody drugs has proven its efficiency in inhibiting colitis, while the low drug bioavailability means that large doses of antibodies are required, ultimately causing systemic toxicity. Small interfering RNA (siRNA) has significant advantages over antibody drugs in terms of safety and efficacy, and it have been widely applied as potential candidates for a variety of inflammation-related diseases. However, oral delivery of siRNA fails to overcome the degradation of the gastrointestinal environment to produce a significant therapeutic effect in ulcerative colitis. Herein, we design the hybrid delivery system that the siRNA loaded MOF encapsulated in the sodium alginate particles to overcome the barriers in the oral process. Results: The hybrid delivery system (SA@MOF-siRNA^TNFα) was successfully constructed, and it could not only survive the low pH environment in the stomach and small intestine, but also taken up more by inflammatory macrophages, as well as released much more MOF-siRNA^TNFα. Moreover, SA@MOF-siRNA^TNFα tended to enriched and infiltrated into local colon tissues. As a result, SA@MOF-siRNA^TNFα significantly reduced the progression of colitis, of which the treated mice did not experience significant weight loss, bloody stools and diarrhea. Conclusion: We confirmed that the formulation of hydrogel–metal-organic framework hybrids could improve the protection of incorporated payload in the gastric and early small intestine, enhancing the delivery of MOF-siRNA to colon.

Highest proportion of CD45 + cells in the lower chamber was T cells, which was approximately 90%, and the proportion of CD8 + T cells increased from 32 to 40%, in contrast, CD4 + T cells decreased after VNP αTNF-α incubation (Fig. 1q), which indicated that VNP αTNF-α stimulated CD8 + T cell chemotaxis and activation. As a result, significant tumor apoptosis was induced from 15 to 25% by VNP αTNF-α-stimulated splenic T cells (Fig. 1r, s). Further detection of relative expression of markers by RT-PCR showed that VNP αTNF-α induced CD8 + T cell polarization into cytotoxic T cells, according to the upregulated TNF-α, IFN-γ, IL-2, perforin, and