期刊
BIOMATERIALS SCIENCE
卷 10, 期 4, 页码 1053-1067出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/d1bm01765a
关键词
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资金
- National Natural Science Foundation of China [82000523]
- Shaanxi Province's Science and Technology Innovation Team Program for Immune-related diseases [2021TD-38]
- Scientific Research Fund of National Health Commission-Major Health Science and Technology Program of Zhejiang Province [WKJ-ZJ-2205]
- Zhejiang Provincial Natural Science Foundation of China [LR22H160008]
- Young Talent Support Plan of Xi'an Jiaotong University, China [YX6J001]
Ulcerative colitis (UC) is characterized by colonic epithelial barrier dysfunction and gut dysbiosis. Combination therapy of CD98 siRNA and berberine shows promising synergistic effects in alleviating inflammation and microbial dysbiosis in UC. The study demonstrates a precision nanotechnology-based strategy with enhanced bioavailability of siRNA for UC treatment.
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 strategy for UC treatment.
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