温和光热调控炎症微环境提高口服纳米药物治疗溃疡性结肠炎效率的机制研究

溃疡性结肠炎（UC）是一种常见的消化道难治病。结肠炎症微环境对UC的发展极其重要，但至今仍没有研究揭示炎症微环境调控在UC治疗中的关键作用。申请人在前期口服纳米药物系统研究的基础上，创造性地提出：通过温和光热调控结肠炎症微环境是提高口服纳米药物对UC疗效的一条新途径。本课题组已论证了这一策略的可行性，接下来将系统研究金壳纳米药物的制备工艺，开发具有结肠靶向、黏液渗透、破损上皮层穿越和胞内快速释药的多功能纳米药物系统；研究温和光热对纳米药物黏液渗透、黏膜修复和炎症缓解性能的促进作用；基于UC小鼠模型，研究温和光热对结肠炎症微环境中上皮细胞、巨噬细胞、血液微循环、免疫细胞组成和肠道微生物等的影响，进而阐明温和光热提高口服纳米药物系统对UC疗效的机制。通过本项目的开展，不仅能证实温和光热在UC治疗中的重要作用，而且为新一代口服纳米药物系统的设计和构建提供设计思路和理论依据。

Ulcerative colitis (UC) is a common refractory disease of the digestive tract. The inflammatory microenvironment in the colon is crucial for the development of UC. However, no studies have revealed the critical role of regulation of the inflammatory microenvironment in UC treatment. Based on our previous study on oral nanomedicine systems, we creatively proposed that the regulation of the inflammatory microenvironment in the colon by mild hyperthermia is a novel approach to improve the therapeutic effect of oral nanomedicine against UC. Our team has initially demonstrated the feasibility of this strategy. Subsequently, we will focus on the systematic investigation of the fabrication parameters of gold-shell-coated curcumin-loaded nanoparticles with the properties of colon targeting, mucus penetration, damaged epithelial layer crossing, and rapid intracellular drug release. Thereafter, we will investigate the promoting effect of mild hyperthermia on mucus penetration, mucosal repair, and inflammation alleviation. Using a UC mouse model, we will study the impacts of mild hyperthermia on the epithelial cells, macrophages, blood microcirculation, immune cell composition, and microbiota, and further clarify the mechanism of mild hyperthermia to improve the therapeutic effect of oral nanomedicine system on UC. Implementation of this project will not only confirm the vital role of mild hyperthermia in the treatment of UC, but also provide the essential design ideas and theoretical basis for the design and construction of a new generation of oral nanomedicine systems.