光控外泌体microRNA递送系统精准调控糖尿病创面炎症反应的基础研究

Diabetic wound is a typical type of chronic unhealing wound. Under high glucose condition, wound infection is not easy to control and the continuously expanding inflammatory response leads to wound healing disorders. The treatment of diabetic wound has gradually become the focus and difficulty of tissue repair and regeneration. Regulation of chronic inflammation in the injured area can effectively promote wound healing. MicroRNA is a key regulator of inflammatory reaction. The miRNA expression in diabetic patients is out of rhythm. Regulating the physiological rhythm of key miRNA has important clinical significance in promoting the healing of diabetic wounds. This subject is on the basis of our previous research on sweat gland repair of skin by miRNA and hair follicle regeneration promoted by light-controlled gene expression. The exosome delivery system of targeted miRNA was built and loaded on MSCs to act on the skin wounds of diabetes mice. Using optogenetic tools to accurately control the release of miRNA, the circadian rhythm of miRNA expression could regulate the inflammatory response in the process of wound repair. The regulatory mechanism of miRNA rhythmic expression in wound healing would be further analyzed to provide theoretical support and technical innovation for the clinical treatment of chronic wound repair. This topic captures the current key scientific issues of wound repair and tissue regeneration. Using the principle of light control to break through the technical bottleneck of molecular regulation, the research have broad application value and important clinical significance for the precise targeted therapy of various diseases.

糖尿病创面是一类典型的慢性难愈性创面，在高糖状态下，创面感染不易控制，持续扩大的炎症反应导致创面愈合障碍，其治疗成为组织修复再生的重点和难点。调节损伤部位的慢性炎症可以有效促进创面愈合，microRNA（miRNA）是炎症反应的关键调控因子，而糖尿病患者的miRNA呈现失节律表达，调控有效miRNA的生理性节律，对促进糖尿病创面愈合具有重要的临床意义。本课题在我们前期利用miRNA进行皮肤汗腺修复以及光控基因表达促进毛囊再生的研究基础上，构建外泌体靶向递送miRNA系统，通过干细胞介导作用于糖尿病小鼠皮肤创面，利用光遗传学工具精细调控miRNA的释放强度，实现miRNA节律性表达，从而调节创面炎症反应，为慢性创面修复的临床治疗提供理论支持和技术创新。本课题抓住了当前创伤修复与组织再生的关键科学问题，运用光控原理突破分子精细调控的技术瓶颈，对疾病的精准靶向治疗具有广泛的应用价值和重要意义。

慢性持续感染状态是导致糖尿病创面难以愈合的关键因素。调节损伤部位的慢性炎症可以有效促进创面愈合，糖尿病创面的治疗需要更加前沿有效的策略。近年来，细胞外囊泡及外泌体已应用于各种疾病的治疗。microRNA（miRNA）作为外泌体运载的一部分，可以参与调控炎症反应，本课题通过高效装载抗炎功能性miRNA-146a的胎盘间充质干细胞外泌体，并利用光控技术对miRNA的释放进行生理性节律调控，与此同时，融合丝素蛋白亲和肽实现功能性外泌体在生物材料上的高效加载，提高外泌体活性成分作用于创面过程中的稳定性和持续效应，从而更加有效的调节糖尿病小鼠创面的炎症反应，进而促进了真皮成纤维细胞增殖、胶原沉积、血管再生，加速了皮肤上皮化，促进了创面愈合的进程。利用糖尿病小鼠创面组织进行了转录组测序和生物信息学分析，进一步验证了相关炎性因子参与炎症反应调控的信号通路和分子机制。为糖尿病创面修复的临床治疗提供理论支持和技术创新。本课题抓住了当前创伤修复与组织再生的关键科学问题，运用特异性miRNA捕获技术、生物材料亲和肽及光遗传学技术等突破分子精细调控的技术瓶颈，对疾病的精准靶向治疗具有广泛的应用价值和重要意义。