Shape Control and Transport Properties of DNA-Copolymer Micelles

 产品说明：模拟病毒颗粒的大小和形状的胶束纳米颗粒作为DNA递送载体是有吸引力的，因为它们改善的胶体稳定性和运输性质、逃避免疫清除的能力和高有效载荷包装能力。此外，纳米颗粒的形状已被明确确定为决定其传输特性和递送效率的重要因素。然而，没有可用的纳米颗粒合成方法用于包装质粒DNA有效载荷，同时允许充分控制颗粒尺寸和形状。最近，我们已经表明，不同的形状控制和调整DNA胶束可以实现通过质粒DNA与工程嵌段或接枝共聚物的聚阳离子和聚（乙二醇）在受控的组装条件下的络合。在这项拟议的研究中，我们将开发一个协同研究计划，包括平行和综合的实验和计算策略，以（1）开发和理解新的方法，为DNA胶束组装，允许可扩展的，高均匀性的合成与形状控制和高稳定性;（2）揭示形状依赖的纳米粒子在体外和体内生理介质中的扩散和运输特性;和（3）使用人转移性癌症的小鼠模型证明通过形状控制的DNA胶束的治疗诊断载体的递送效率及其成像和治疗功效。拟议的研究汇集了DNA纳米颗粒组装，基于微流体的单颗粒分析/荧光相关光谱，体内成像，癌症治疗诊断和计算机模拟方面的专业知识的独特组合，以解决DNA纳米治疗的工程和交付方面的关键知识差距。这不仅为合成形状可控的DNA胶束提供了一种新的、可推广的方法，而且为纳米粒子的形状依赖性输运性质提供了一种机理上的理解。此外，我们的实验和计算方法的综合性质建立了一个新的范式，这将大大加快新的DNA纳米粒子系统的发现和开发，以有效的基因药物输送。

 DESCRIPTION: Micellar nanoparticles that mimic the size and shape of viral particles are attractive as a DNA delivery vehicle because of their improved colloidal stability and transport properties, ability to evade immune clearance, and high payload packaging capacity. Moreover, nanoparticle shape has explicitly been identified as an important factor determining their transport properties and delivery efficiency. However, there is no available nanoparticle synthesis method for packaging plasmid DNA payloads while allowing sufficient control over particle size and shape. Recently, we have shown that distinct shape control and tuning for DNA micelles can be achieved through complexation of plasmid DNA with engineered block or graft copolymers of polycation and poly (ethylene glycol) under controlled assembly conditions. In this proposed study, we will develop a synergistic research program comprising parallel and integrated experimental and computational strategies to (1) develop and understand new methods for DNA micelle assembly that permit scalable, high-uniformity synthesis with shape control and high stability; (2) reveal shape-dependent nanoparticle diffusion and transport properties in physiologically media in vitro and in vivo; and (3) demonstrate the delivery efficiency of a theranostic vector by shape-controlled DNA micelles and their imaging and therapeutic efficacy using mouse models of human metastatic cancers. The proposed study brings together a unique combination of expertise in DNA nanoparticle assembly, microfluidics-based single-particle analysis/fluorescence correlation spectroscopy, in vivo imaging, cancer theranostics, and computer simulations to address a crucial knowledge gap in the engineering and delivery of DNA nano-therapeutics. It will not only offer a new, generalizable method for synthesizing shape-controlled DNA micelles, but also provide a mechanistic understanding of shape- dependent transport properties of nanoparticles. Moreover, the integrated nature of our experimental and computational approach establishes a new paradigm that will greatly accelerate the discovery and development of new DNA nanoparticle systems for efficient gene medicine delivery.