仿生纳米复合疫苗制剂用于肿瘤深层光动力/免疫协同精准治疗的研究

针对传统光动力治疗（PDT）可见光组织穿透深度受限、只限于浅表性肿瘤且效果差的难题，本项目以“仿生纳米医学”、“免疫疗法”和“个性化精准治疗”的设计思路，发展一种深层PDT协同肿瘤疫苗实现彻底治疗肿瘤的仿生纳米制剂。通过精细调控有机/无机杂化材料体系，考察仿生-结构-组成-增效之间的关系，筛选最佳组合和配比方案，将上转换纳米颗粒、光敏剂、小分子功能药物和肿瘤疫苗结合，一方面构建出近红外光激发荧光共振能量转移介导的深层PDT，掺入特异性8-羟基鸟嘌呤核苷酸酶抑制剂，增强对原位肿瘤的杀伤效果；另一方面，表面修饰个性化生物学重编程融合细胞膜，生物靶向高量富集，协同新型免疫调节因子四氢生物蝶呤，激活机体应答，唤醒免疫力，彻底清除藏匿或转移癌细胞，实现长期防御。本项目利用生物纳米技术提高肿瘤治疗的安全性和高效性，并结合免疫调节，为构建多功能和个性化纳米平台提供实验依据，为肿瘤精准治疗提供新思路。

To overcome the drawbacks of traditional photodynamic therapy (PDT), such as shallow depth of tissue-penetration and treatment of superficial solid tumors with low efficacy, we intend to develop a novel biomimetic nanoformulation that combines deep PDT with cancer vaccine to achieve complete tumor killing, basing on the strategy of biomimetic nanomedicine, immunotherapy and personalized precision medicine. By regulating the organic/inorganic system and investigating the relationship of biomimetic-nanostructure-composition-enhancing performance, the composition and microstructure will be rationally optimized. Herein, Ostwald ripening-mediated grafting of photosensitizers-containing metal-organic frameworks will be immobilised on an upconversion nanoparticle core via heterogeneous nucleation. A novel MTH1 inhibitor will be encapsulated in shell nanopores and modified with fused cell cytomembrane to yield a promising nanosystem, which achieving improved cancer treatment through the combination of fluorescence resonance energy transfer mediated PDT and increase intracellular reactive oxygen species levels. Furthermore, the integration of the nanoplatforms with tetrahydrobiopterin treatment will promote the abscopal effect to completely inhibit the growth of untreated distant tumors by generating specific immunity. Collectively, this project will provide a new strategy to realize the efficiency and biosafety of cancer therapy based on nano-biotechnology and immunotherapy, finally serve as the scientific support to construct versatile and personalized nanoplatforms in cancer treatment.