包载姜黄素的炎症响应性纳米粒子抑制种植体周围炎骨吸收的实验研究

The complex inflammatory microenvironment is an important factor of the inefficacious therapeutic outcome for peri-implantitis. Therefore, it is highly desired to understand the molecular mechanism and develop a highly effective and safe treatment strategy, which might be beneficial to the prevention and treatment of peri-implantitis. The therapeutic strategy should include accurate-targeting and the ability that could regulate the inflammatory microenvironment. Previous studies and our preliminary data have demonstrated that macrophages play a key role in the microenvironmental homeostasis of bone tissue around the dental implant. And M1 macrophage polarization could drive the development and progress of peri-implantitis, while curcumin could alleviate the inflammation reaction by inducing polarization of macrophages from M1 into M2 cells. In order to achieve efficient delivery of curcumin in the inflammatory microenvironment around the implant, we intend to use selenium-bonded mesoporous silica nanoparticles (MSNs) to carry curcumin with macrophages-membrane coating to construct our target biomimetic nanoparticles (MM@MSNs@Cur). In our multifunctional drug-delivery system, we use biomimetic modification of cell membranes to enable homologous targeting of M1-type macrophages, and use degradable MSNs to achieve inflammatory-response drug delivery in inflammatory microenvironment with lots of ROS. Based on the characterization and optimization of the nanoparticles, we will focus on the effectiveness and safety of our cure strategy by regulating the inflammatory microenvironment to inhibit bone resorption. Taken together, our project addresses and develops the new strategy for macrophage-targeted peri-implantitis therapy and implements a novel material and medicine for effective and safe periodontitis treatment.

复杂的炎症微环境是种植体周围炎治疗效果不佳的重要因素，研发一种可精准靶向且调控炎症微环境的策略将有利于种植体周围炎的治疗。相关研究和课题组的前期工作均证实，巨噬细胞在种植体周围骨组织微环境稳态及种植体周围炎发生发展中扮演着关键作用，而姜黄素可通过调控巨噬细胞M1/M2极化以减轻炎症反应。为实现姜黄素在种植体周围炎性微环境中的高效递送，本项目拟利用二硒键桥连的介孔二氧化硅纳米粒子（MSNs）担载姜黄素并包覆巨噬细胞膜以构筑仿生纳米粒子（MM@MSNs@Cur）。在该智能化药物递送体系中，细胞膜的仿生修饰可实现对M1型巨噬细胞的同源靶向，可降解的MSNs可实现炎性微环境ROS响应性的药物释放。本项目将在表征和优化该纳米粒子的基础上，重点研究其通过调控种植体周围炎性微环境、抑制骨吸收从而治疗种植体周围炎的有效性和安全性，亦有望为种植体周围炎防治方法的探寻提供新策略和新材料。

种植体周围炎是在种植体达到骨结合后，由于病原微生物的侵袭和宿主自身免疫反应失衡而导致的种植体周围组织的炎症反应性疾病。种植体周围炎骨微环境具有炎性状态迁延、成骨破骨功能失衡的特点，对骨缺损修复进程产生不良影响。巨噬细胞是种植体周围炎骨微环境中的重要细胞，这些亚型复杂、功能多变的细胞对于种植体周骨结合的建立和长期维持具有重要作用。在不同微环境的活化分子作用下，巨噬细胞可极化为不同亚型，即通过“经典途径”极化的M1型和通过“旁路途经”极化的M2型。两者可在不同的刺激作用下相互转换并影响炎症的转归：在抗病原微生物感染时，巨噬细胞从抗炎症的M2型向促炎症的M1型转化；而在骨损伤修复中，其由M1型向M2型转化。负责人的研究工作表明，姜黄素不仅可通过抑制炎症微环境中M1型巨噬细胞TLR2/4/9活化、促进巨噬细胞M2型极化，还可通过抑制破骨细胞活化而缓解骨吸收，但由于其溶解度低、易被氧化，且经口腔局部给药的药效维持时间较短，限制了其临床应用。针对“研发具备M1型巨噬细胞精准靶向和炎症微环境响应性释药的姜黄素递送体系（MM@MSNs@Cur）”这一目标，本项目以靶向调控巨噬细胞M1型极化为新型生物材料研发的切入点，结合项目负责人一直以来聚焦的介孔二氧化硅纳米粒子在调控骨微环境中的作用，进而设计并构筑了M1型巨噬细胞膜包覆、担载姜黄素、二硒键桥连的介孔二氧化硅纳米粒子，通过细胞膜涂层纳米技术对其表面进行仿生修饰，评估了不同孔径的二硒键掺杂的介孔二氧化硅纳米粒子通过影响巨噬细胞极化调控骨微环境的作用，体外验证了该仿生纳米姜黄素控释系统在M1型巨噬细胞同源靶向和炎症微环境ROS响应性药物高效释放，随后通过动物实验模型评估了该新材料调控种植体周围炎性微环境、抑制骨吸收从而治疗种植体周围炎的有效性和安全性，以调控种植体周围炎骨微环境促进骨缺损修复，解决“如何实现靶向炎症微环境的姜黄素递送”和“如何实现炎症微环境响应性的姜黄素释放”的科学问题，为种植体周围炎骨缺损的治疗提供了新思路和新材料。