A Proresolving Peptide Nanotherapy for Site-Specific Treatment of Inflammatory Bowel Disease by Regulating Proinflammatory Microenvironment and Gut Microbiota
A Proresolving Peptide Nanotherapy for Site-Specific Treatment of Inflammatory Bowel Disease by Regulating Proinflammatory Microenvironment and Gut Microbiota
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DOI：
10.1002/advs.201900610
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发表时间：
2019-08-01
期刊：
影响因子：
15.1
通讯作者：
Zhang, Jianxiang
中科院分区：
文献类型：
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作者：
Li, Chenwen;Zhao, Yang;Zhang, Jianxiang
炎症性肠病（IBD）的发病率和患病率在世界范围内稳步上升。迫切需要有效和安全的IBD治疗方法。加速炎症的消退是治疗炎症性疾病的新策略。为了有效和安全的治疗IBD，本文开发了一种智能纳米疗法（即氧化反应纳米颗粒，含有促连接蛋白a1 -模拟肽Ac2-26，定义为AON），它可以释放包装的Ac2-26，以响应病变部位高表达的活性氧（ROS）。AON能有效保护Ac2-26在富含酶的胃肠道环境中不被降解。通过将这种纳米疗法应用于炎症性肠病小鼠的发炎结肠，可以实现针对炎症部位高水平ROS的Ac2-26的部位特异性释放和积累。机制上，含ac2 -26、氧化不稳定的纳米疗法AON有效降低促炎介质的表达，减轻炎症细胞的运输和浸润，促进凋亡中性粒细胞的efferocysis，增加巨噬细胞的表型转换。在治疗上，AON可减轻炎症症状，加速肠黏膜伤口愈合，重塑肠道菌群组成，并增加短链脂肪酸的产生。此外，口服这种纳米药物在小鼠模型中显示出极好的安全性，为进一步开发针对IBD和其他炎症性疾病的靶向精确治疗提供了信心。
The incidence and prevalence of inflammatory bowel disease (IBD) increases steadily worldwide. There is an urgent need for effective and safe IBD therapies. Accelerated resolution of inflammation is a new strategy for the management of inflammatory diseases. For effective and safe IBD treatment, herein a smart nanotherapy (i.e. oxidation-responsive nanoparticles containing a proresolving an nexin A1-mimetic peptide Ac2-26, defined as AON) is developed, which can release packaged Ac2-26, in response to highly expressed reactive oxygen species (ROS) at diseased sites. AON effectively protects Ac2-26 from degradation in the enzyme-rich environment of the gastrointestinal tract. By delivering this nanotherapy to the inflamed colons of mice with IBD, site-specific release and accumulation of Ac2-26 in response to high levels of ROS at the inflammatory sites are achieved. Mechanistically, the Ac2-26-containing, oxidation-labile nanotherapy AON effectively decreases the expression of proinflammatory mediators, attenuates trafficking and infiltration of inflammatory cells, promotes efferocytosis of apoptotic neutrophils, and increases phenotypic switching of macrophages. Therapeutically, AON reduces symptoms of inflammation, accelerates intestinal mucosal wound healing, reshapes the gut microbiota composition, and increases short-chain fatty acid production. Additionally, oral delivery of this nanomedicine shows excellent safety profile in a mouse model, conferring the confidence for further development of a targeted precision therapy for IBD and other inflammatory diseases.