Colon-targeted chitosan-gold nanoparticles loaded with Pueraria flavonoids for ulcerative colitis therapy via barrier repair and immune modulation.

Natural plant-derived flavonoids hold considerable promise for the treatment of ulcerative colitis (UC) due to their intrinsic anti-inflammatory and antioxidant activities as well as their favorable biocompatibility. Nevertheless, clinical translation remains hindered by multiple barriers, including poor structural stability in the harsh gastric environment, low bioavailability, limited intestinal retention and non-specific distribution throughout the gastrointestinal tract. To overcome these limitations, we developed a pH-responsive, colon-localized nanodelivery system composed of chitosan-encapsulated, flavonoid-loaded gold nanoparticles derived from Radix Puerariae thomsonii (CRPT-NPs). CRPT-NPs exhibit pH-dependent degradability, conferring gastric protection and site-preferential release in the inflamed colon. In a dextran sulfate sodium-induced murine colitis model, CRPT-NPs markedly alleviated colonic inflammation, reduced pro-inflammatory cytokine levels, and promoted restoration of epithelial integrity. Proteomic profiling further revealed that the therapeutic effects of CRPT-NPs are associated with modulation of inflammation- and mucosal barrier-related proteins. Further mechanistic studies revealed the involvement of a DSG2-mediated ERK/p38 MAPK signaling axis in the protective effects of CRPT-NPs. Importantly, CRPT-NPs demonstrated favorable biosafety profiles in both in vitro and in vivo. Collectively, these findings support CRPT-NPs as a robust nanotherapeutic platform with translational potential for UC treatment, and provide mechanistic insight into the passive, pH-driven delivery of botanical agents to inflamed intestinal tissues.