De Novo Design of Biodegradable and Environmentally Responsive Saccharide-Peptide Nanogels for siRNA Delivery

该奖项由加州大学欧文分校材料研究部生物材料项目资助，旨在研究一种新的可生物降解和对环境敏感的基于糖肽共聚物的纳米凝胶，作为小干扰RNA （siRNA）传递的智能纳米载体。近年来发现的siRNA的基因沉默作用，为多种疾病的基因治疗提供了新的途径。然而，其临床应用的一个主要障碍是缺乏siRNA进入靶细胞的有效递送。在不同的递送载体中，阳离子合成聚合物因其高的结构柔韧性和功能性而特别有前景。许多聚合物系统已经测试了siRNA的传递，然而，它们相对较低的转染效率和较高的细胞毒性值得进一步发现新的安全和有效的传递系统。根据PI先前的研究？基础糖肽聚合物结构具有固有的安全性和通用性，为合理设计和优化提供了潜力。通过将一系列刺激响应特性编程到纳米凝胶中，目标是将纳米凝胶-siRNA复合物（纳米复合物）在细胞外运输过程中的高稳定性与siRNA到达细胞内目的地后的高效释放结合起来。鉴于该项目的最终目标是发现真正安全有效的siRNA递送合成载体，目前提出的努力将主要集中在探索纳米凝胶载体的化学设计和合成的新概念，siRNA-纳米凝胶复合物的化学物理性质的研究，以及使用这些纳米凝胶载体进行体外siRNA转染试验。siRNA基因沉默能力的发现预示着利用小干扰RNA治疗遗传性疾病的巨大治疗潜力。阻碍siRNA技术实现临床应用的一个主要障碍是缺乏将siRNA递送到细胞中的有效方法。本研究探索了一种新的环境响应纳米凝胶方法，用于高效的siRNA递送。本研究的目的是测试纳米凝胶载体的新设计理念，了解纳米凝胶载体的基本结构-性能关系，并最终开发出安全高效的合成载体，在生物技术和制药行业具有巨大的潜力。此外，拟议的多学科研究活动将为研究生和本科生，特别是目前从事该项目的少数民族和女性学生提供良好的培训。

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5)This award by the Biomaterials program in the Division of Materials Research to University of California Irvine is to study a new family of biodegradable and environmentally responsive saccharide-peptide copolymer-based nanogels as smart nanocarriers for small interference RNA (siRNA) delivery. The recently discovered gene silencing effects of siRNA presents tremendous potential as a new approach in gene therapy for various disease treatments. However, one major barrier for its clinical use is the lack of efficient delivery of siRNA into the target cells. Among different delivery vectors, cationic synthetic polymers are especially promising because of their high structural flexibility and functionalities. A number of polymeric systems have been tested for siRNA delivery, however, their relatively low transfection efficiency and high cytotoxicity warrants further discovery of new safe and efficient delivery systems. Based on previous studies from the PI?s laboratory, the basic saccharide-peptide polymer construct is inherently safe and versatile, offering potential for rational design and optimization. By programming a number of stimuli-responsive features into nanogels, the goal is to combine high stability for nanogel-siRNA complexes (nanoplexes) during extracellular trafficking with efficient release of siRNA once reaching intracellular destinations. Whereas the ultimate goal of this program is to discover truly safe and efficient synthetic vectors for siRNA delivery, the current proposed efforts will be primarily focused on exploring new concept in chemical design and synthesis of nanogel vectors, investigation of chemical-physical properties of siRNA-nanogel complexes, and in vitro siRNA transfection assays using these nanogel vectors. The discovery of gene silencing capability of siRNA forecasts tremendous therapeutic potential for treating genetic disease using small interference RNA. One major road block preventing it from realization of clinical applications for siRNA technology is the lack of efficient methods to deliver siRNA into cells. This study explores a novel environmentally responsive nanogel approach for efficienct siRNA delivery. The goal of the study is to test a new design concept of nanogel vectors, understand basic structure-property relationship of the nanogel vectors, and ultimately develop safe and efficient synthetic vectors that can potentially have tremendous impact on biotechnological and pharmaceutical industries. In addition, the proposed multi-disciplinary research activity will provide excellent training for graduate and undergraduate students, especially for minority and women students currently working on this project.