改善生物被膜乏氧微环境的工程化活微藻协同治疗体系在耐药菌眼内感染中的治疗作用和机制研究

铜绿假单胞菌（PA）感染是眼内炎中最具破坏性的疾病之一。多重耐药铜绿假单胞菌（MDR-PA）眼内感染治疗手段单一、疗效差、致盲率高，是当前亟需解决的临床难题。生物被膜乏氧微环境是PA产生多重耐药性及制约光动力治疗（PDT）效率的关键原因，提示改善生物被膜乏氧微环境可能成为构建新型抗菌策略的切入点，但目前关于其在眼内感染中尚无相关方案。本项目拟针对眼内MDR-PA感染后生物被膜乏氧微环境难以调节这一关键科学问题，设计制备具有免疫逃避功能的同源红细胞膜修饰工程化活微藻（RM@Algae）作为产氧体系，以此构建RM@Algae-抗菌药物-PDT协同治疗方案。研究其对MDR-PA眼内感染的有效性、安全性、代谢清除途径及较常规抗菌药物优势，并验证相关分子抗菌机制。本项目的开展使眼内抗菌研究深入至微环境水平，可望突破药物治疗瓶颈，预期结果将探索出针对多重耐药菌眼内感染这一重要致盲性眼病的新型抗菌策略。

Pseudomonas aeruginosa (PA) infection is one of the most devastating diseases in endophthalmitis. Due to the oneness of treatment measures, poor effectiveness, and a high blindness rate, the medical problems of multi-drug resistant Pseudomonas aeruginosa (MDR-PA) intraocular infections need to be solved urgently. The hypoxic microenvironment of bacterial biofilm is the key reason for the formation of multi-drug resistance of PA and the restriction of photodynamic therapy (PDT) efficiency, suggesting that improving the biofilm hypoxic microenvironment may become a new key point for exploring antibacterial strategy of MDR-PA infection. However, there is no relevant plan in the treatment of intraocular infection. This project intends to aim at the difficulty to adjust of biofilm hypoxic microenvironment after intraocular MDR-PA infection, which is the key scientific problem. The engineered animate microalgae (RM@Algae) with homologous red blood cell membrane surface modification was designed and prepared as an oxygen generation system which can avoid immune recognition to establish the RM@Algae-antibiotic-PDT synergistic therapy plan. Then its effectiveness, safety, metabolic clearance pathways, and advantages over conventional antimicrobial treatments for MDR-PA intraocular infections were studied, and its related molecular mechanisms were verified. The development of this project has deepened the research of intraocular antibacterial agents to the microenvironmental level. This project is expected to break through the bottleneck of regular antibiotics treatment and will explore a set of new antibacterial strategy for this serious cause of blindness eye disease.