An oral pH-activated "nano-bomb" carrier combined with berberine by regulating gene silencing and gut microbiota for site-specific treatment of ulcerative colitis
Abstract
Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease that features colonic epithelial barrier dysfunction and gut dysbiosis. Preclinical studies demonstrated that inhibiting the overexpression of CD98 via small interfering RNA (siRNA) could alleviate CD98-mediated epithelial barrier dysfunction, and the natural product berberine (BBR) has the ability to improve microbial dysbiosis. However, we lacked the knowledge of whether the combined treatment with CD98 siRNA (siCD98) and BBR could generate an optimal anti-UC efficacy. We hypothesized that the combined therapy may synergize gene silencing and dysbiosis modulating functions of each treatment. To enhance the bioavailability and improve the endo/lysosomal escape of siCD98, we designed hyaluronic acid (HA)-modified chitosan-guanidine-CO2 nanoparticles (HA-CG-CO2@NPs), which could target colonic epithelial and macrophage cells and liberate CO2 at endo/lysosomal pH (nano-bomb effect) for cytosolic siCD98 release. Using lipopolysaccharide-induced inflammation in vitro, we observed a better anti-inflammatory effect of HA-siCD98@NPs and BBR. Furthermore, orally administered HA-siCD98@NPs and BBR (co-loaded in a chitosan/alginate hydrogel) could target the colon, downregulate pro-inflammatory cytokines, and alleviate microbial dysbiosis in a mouse model of UC, yielding a much better efficacy than when administered alone. Collectively, this study provides a promising nanotechnology-based precision targeting…
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