Oral olsalazine/ellagic acid/ZnCl2‐modified in situ-forming hydrogels alleviates anxiety/depression-like symptoms and brain neural activity in colitis mice

Inflammatory bowel disease (IBD) is a kind of chronic non-specific intestinal inflammatory disease, which accompanied by various abnormal psychological states, such as anxiety and depression. Nevertheless, the pathogenesis of IBD with depression is still unclear. Herein, we synthesized an enable a drinkable, liquid in situ-forming hydrogel, which form directly in the stomach through sequential ingestion of a crosslinker solution of CaCl 2 and ε-poly-l-lysine (ε-PL), followed by a drug-containing polymer solution of sodium alginate (SA). Using olsalazine (Olsa) and antioxidant (ellagic acid (EA) and ZnCl 2 ) as small molecule drug (referred as Olsa/EA/Zn), the resulting hydrogel (referred as Olsa/EA/Zn@SA/ε-PL hydrogel) could form rapidly in gastric fluid and exhibit remarkable stability under acidic conditions, unique low swelling properties and a rational release of drug in entering the intestine. We demonstrated that the oral administration of drug-loaded in situ-forming hydrogel with excellent antioxidant, anti-inflammatory activities, cytocompatibility, intestinal retention capacity of the drug, significantly enhanced the IBD therapeutic outcomes, and relieve accompanying depression-like symptoms in colitis mice. Overall, this designed in situ-forming hydrogel oral delivery system will open up new pathway in combined gastrointestinal therapy and psychological comorbidities for IBD patients, especially those with dysphagia.