Inulin-armored hesperetin‑zinc nanodrugs for synergistic redox-immune modulation and barrier repair in ulcerative colitis

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease with a rising global incidence rate, which poses a significant challenge to clinical management due to the limited efficacy and adverse reactions of current treatments. To overcome these limitations, we engineered Hes-Zn@IN, a novel core-shell nanoparticle system combining a hesperetin‑zinc (Hes Zn) metal-polyphenol coordination core encapsulated in an inulin (IN) polysaccharide shell. This nanotherapeutic platform exhibits synergistic therapeutic benefits: superior antioxidant capacity through metal-polyphenol coordination, demonstrating a 38% reduction in ROS and a 47% decrease in NO production in LPS-activated macrophages; robust immunomodulatory effects, significantly lowering pro-inflammatory cytokines (46% reduction in TNF-α, 42% in IL-6) while increasing anti-inflammatory IL-10 by 78%; a pH-dependent release profile enabling 1.85 times greater drug accumulation in inflamed colon tissue. In murine DSS-induced colitis models, oral administration of Hes-Zn@IN produced remarkable therapeutic outcomes, including 19.2% improvement in colon length, restoration of ZO-1 tight junction protein expression, and substantial mitigation of histopathological inflammation. Our findings establish this inulin-armored metal-polyphenol hybrid as a breakthrough nanomedicine that synergistically targets colonic redox-immune remodeling and barrier repair, presenting a comprehensive therapeutic approach for UC management.