我国是食管癌高发国家，晚期食管癌易发生肺转移且治疗困难。本项目拟在我们前期研究和国际前沿基础上，率先将高稳定性荧光素酶（Luc8）与竹红菌甲素（HA）连接，获得的HA-Luc8与腔肠素（Coe）可通过生物发光共振能量转移（BRET）激发HA对转移肿瘤进行光动力治疗（PDT）；同时，合成具有线粒体靶向和克服细胞耐药的顺铂前药TPP-DDP，PDT中的活性氧将协同TPP-DDP杀伤癌细胞。进而，以巨噬细胞膜包覆的pH敏感脂质体装载黄芪多糖及HA-Luc8、TPP-DDP和Coe，构建三种协同应用的新型纳米载药粒子，发挥巨噬细胞膜免疫逃逸和肿瘤靶向性、BRET诱导PDT、药物逆转巨噬细胞表型和靶向进攻线粒体等优越性，以全新的“免疫治疗+PDT+化疗”协同靶向摧毁食管癌肺转移灶。.本项目克服了常规化疗和PDT等存在的局限性，具有安全、靶向、高效等优势，对于推动食管癌肺转移靶向治疗水平发展意义重大。

China is a region with high incidence of esophageal cancer. Esophageal cancer with lung metastases is usually found in advanced cancer patients and, it is difficult for the treatment of the lung metastases. Based on our previous work and international research frontier, in this project, we will conjugate the mutant of the bioluminescent protein, Renilla reniformis luciferase (Luc8) with hypocrellin A (HA), a photosensitizer, to develop a bioluminescence resonance energy transfer (BRET) system. The HA-Luc8 conjugates obtained catalyzed by coelenterazine (Coe) will be used for photodynamic therapy (PDT) of metastatic cancer based on the BRET. At the same time, cis-Dichlorodiamineplatinum(II) (DDP) will be conjugated with triphenylphosphonium (TPP). The TPP-DDP will target to mitochondria in cells, and the cell killing efficiency will be improved by the reactive oxygen species (ROS) generated by the HA during PDT. Furthermore, astragalus polysaccharides (APS), HA-Luc8, TPP-DDP and Coe will be encapsulated by a pH-sensitive liposome (Lip), and further coated with macrophage membrane (MM) to develop three novel drug loaded nanoparticles. These drug-loaded nanoparticles exhibit multifunctions: immunologic escape, targeting to metastatic foci, BRET-activated PDT, inducing M2 subtype to M1 macrophages, etc., which will significantly suppress the lung metastasis of esophageal cancer through novel targeted combination therapy: “immunotherapy + PDT + chemotherapy”. .The limitations of most common chemotherapy and PDT will be overcome by the methods developed by this project. The drug-loaded nanoparticles and therapy methods developed by this project are safe and highly efficient for cancer targeted therapy, which are very important for improving the therapy level of esophageal cancer with lung metastases.