DNA纳米模板引导的抗体蛋白精确自组装结构及其作为肿瘤治疗平台的研究

Malignant lymphoma is a prevalent cancer with a high mortality rate. Although numerous anti-cancer drugs have been applied over the past few decades, effective and safe therapeutic treatment for non-Hodgkin lymphomas (NHL) remains a challenge. This proposal will provide a strategy based on DNA nanotechnology to address significant scientific problems in lymphoma therapy: (i) Integrate therapeutic monoclonal antibodies with different pattern on the DNA nanostructure template for regulation of cellular response in NHL tumor cell, particularly apoptosis induction; (ii) Develop cancer treatments with high targeting efficiency and low system toxicity...DNA origami nanostructures with controlled size, shape and spatial addressability can be constructed through rational design. DNA strands can be extended site-selectively from designed location to localize DNA modified functional groups such as antibodies or other molecular cargos. On the other hand, immunotherapies using monoclonal antibodies (mAbs) targeted to the B-cell lymphomas surface antigen CD20 have become common treatments for most (85%) NHLs of B-cell origin. Based on these features, we propose to use DNA origami nanostructure as a platform to integrate anti-CD20 antibodies. We will produce various nanoscale patterns of antibodies and investigate different cellular responses by incubation the B-cell origin lymphomas cells with the DNA origami-antibodies nanoconjugates. In this way, we will learn how to alter signal transduction and ultimately enhance apoptotic signaling against B-cell origin NHLs by self-assembled DNA-antibodies therapeutic system. Based on in vitro apoptosis induction, we will screen the optimal antibodies patterns with therapeutic effects and process preclinical evaluations in a murine model of human NHL. By pursuing these goals, the project as a whole will lead to the development of novel step-changing methods for efficient and safe NHL therapy.

恶性淋巴瘤是一类严重影响人类健康的疾病，发展高效低毒的治疗方法已经成为迫在眉睫的重大问题。在纳米尺度上精确控制配体的种类、位置、数目、三维取向以及组装形态对于研究细胞信号转导、发展肿瘤治疗新方法至关重要。本项目拟采用DNA折纸结构作为纳米模板，利用其精确的自组装性能构建多种排布类型的抗体蛋白组装体。结合具体实验和抗体组装体的理论模型，在细胞水平重点研究不同排布模式的抗体蛋白组装体对于肿瘤细胞信号转导的影响，优选出诱导肿瘤细胞凋亡性能最佳的抗体蛋白组装结构。在动物水平上逐步探索基于DNA纳米结构的抗体蛋白组装体的抗肿瘤治疗，进行有效性评价和生物安全性评价，为研制高效、低毒、靶向、可控的生物型抗肿瘤药物系统提供新的思路和途径，具有非常重大的实际意义。

自组装DNA纳米材料具有结构精确可控、可定位修饰、生物可降解的特点。如何利用DNA纳米结构特性，对抗肿瘤功能成分进行有效装载，在生物水平实现高效安全的抗肿瘤治疗是目前亟待解决的问题。.本项目实施过程中，基于形状和表面化学深入研究生物组织表面受体与多种功能基团相互作用的基本机制，通过精确调控DNA纳米结构表面的功能基团排布模式，我们利用结构形状可控、位点可寻址的DNA纳米结构构建了一系列功能化组装结构，实现了如抗体、酶、毒性蛋白、功能核酸片段、金属纳米颗粒等多种功能基团的有效装载，发展了一系列高效、低毒、靶向、多功能的肿瘤治疗平台。我们的研究工作为发展基于DNA纳米结构的新型肿瘤治疗策略提供新思路，为开发新一代抗肿瘤药物运输系统提供新途径和新手段，为最终实现攻克肿瘤这一科学目标奠定实验与理论基础。