In this study, colon-targeted nanoparticles were fabricated using zein and xanthan gum (XG) as carriers (ZX) via anti-solvent precipitation and electrostatic deposition to encapsulate giant salamander protein hydrolysate (SPH) or its Maillard reaction (MR) products (SPHX). Their alleviative effects on ulcerative colitis (UC) were investigated. Zein and XG primarily formed nanoparticles through hydrogen bonding, hydrophobic interactions, and electrostatic interactions. After encapsulating SPH or SPHX, the resulting nanoparticles exhibited smooth, spherical morphologies with particle sizes below 200 nm and good stability. Compared to SPH-loaded nanoparticles (ZSPHX), those loaded with SPHX (ZSPHXX) exhibited superior in vitro sustained-release properties, enhanced in vivo colitis-targeting ability, and improved cellular reactive oxygen species (ROS) scavenging capacity. The encapsulation of ZX enhanced the cellular uptake of SPHX. In a dextran sulfate sodium (DSS)-induced UC mouse model, dietary intervention with ZSPHX/ZSPHXX (especially ZSPHXX) alleviated UC by exerting anti-inflammatory and antioxidant effects, repairing intestinal barrier damage, and modulating the gut microbiota. Finally, bioactive peptides were isolated from the intestinal contents of mice treated with ZSPHX/ZSPHXX and screened to evaluate their UC-alleviating effects. The results showed that the peptide AVFPSIVGR, identified in the ZSPHXX group, exhibited markedly stronger ROS scavenging activity than IGAPDMAFPR, which was identified in the ZSPHX group. This enhanced antioxidant capacity may be a primary factor contributing to the superior UC-alleviating effects of SPHX. This work provides a simple strategy for constructing a bioactive peptide UC colon targeted delivery system and preliminarily reveals the potential mechanism of MR enhanced peptide UC alleviation.
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