CAREER: Assembly of Nanopieces for Controlled Penetration and Binding of Difficult-to-Reach Cartilage Matrix for siRNA Therapy against Osteoarthritis

PI：Chen，Yupeng提案编号：1653702骨关节炎（OA）影响约13.9%的25岁及以上的美国人。这相当于美国估计有3000万人，使其成为残疾的主要原因之一。OA是一种退行性关节疾病，涉及关节软骨的退化。这会导致疼痛、僵硬、运动问题和活动受限。目前，还没有临床上成功的治疗方法来对抗OA。作为诺贝尔奖的发现，siRNA能够有效特异地抑制疾病基因的表达，为OA的治疗提供了巨大的潜力。然而，递送带负电荷的siRNA以渗透无血管的、致密的、带负电荷的组织基质（如软骨）是极其具有挑战性的。这项研究将开发一种新的递送载体，它可以与治疗性siRNA自组装，并以有效和安全的方式将它们递送到富含基质的组织中。 拟议的研究将侧重于了解玫瑰花状纳米管（RNT）和siRNA之间的非共价结构的微妙自组装过程。通过介导组装过程，RNT/siRNA架构将被构建成各种大小和形状的siRNA递送载体。然后，将分析和优化它们穿透组织基质和递送siRNA的能力。该提案还将鉴定和操纵这些非共价递送载体与组织基质分子的结合能力，以实现对基质金属蛋白酶-13（MMP-13）的有效和持久的抑制，基质金属蛋白酶-13（MMP-13）是OA进展期间的关键疾病基因。此外，将在动物模型中评估这种siRNA方法对OA的治疗潜力。此外，该提案还提供了一项计划，以合并科学与医学教育之间的差距，并培养具有跨学科知识的下一代科学家和临床医生，并鼓励他们将科学、工程和技术创新转化为满足临床需求。最后，与罗得岛的巴林顿高中（BHS）合作，该提案将制定一项推广计划，向高中生介绍纳米技术，并向他们展示纳米技术如何帮助克服诊所中的“现实问题”。除了实现本提案的具体目标外，该职业发展计划还可以显着提高对非共价结构自组装的科学理解，并为开发第一种抑制OA进展的siRNA疗法奠定基础。

PI: Chen, YupengProposal #: 1653702Osteoarthritis (OA) affects approximately 13.9% of Americans aged 25 years and older. This equates to an estimated 30 million people in the United States, making it one of the leading causes of disability. OA is a degenerative joint disease involving in the degeneration of joint cartilage. This leads to pain, stiffness, movement problems, and activity limitations. Currently, there is no clinically successful therapeutic to against OA. As a Nobel-prize winning discovery, siRNA can effectively and specifically inhibit disease gene expression, which provides a great therapeutic potential to treat OA. However, it is extremely challenging to deliver negatively-charged siRNAs to infiltrate avascular, dense, negatively-charged tissue matrix, such as cartilage. This research will develop a novel delivery vehicle, which can self-assemble with therapeutic siRNAs and deliver them into matrix-rich tissues in an effective and safe manner. The proposed study will focus on understanding the delicate self-assembly process between rosette nanotubes (RNTs) and siRNA into non-covalent architectures. By mediating the assembly process, the RNT/siRNA architectures will be constructed into siRNA delivery vehicles of various sizes and shapes. Then, their ability to penetrate tissue matrix and deliver siRNA will be analyzed and optimized. This proposal will also identify and manipulate the binding ability of these non-covalent delivery vehicles with tissue matrix molecules to achieve effective and long-lasting inhibition of matrix metalloproteinase-13 (MMP-13), a key disease gene during OA progression. Furthermore, the therapeutic potential of this siRNA approach against OA will be evaluated in an animal model. In addition, this proposal provides a plan to merge the gap between science and medical education and train the next generation of scientists and clinicians with interdisciplinary knowledge and encourage them to translate science, engineering and technology innovations to satisfy clinical needs. Lastly, collaborating with the Barrington High School (BHS) in Rhode Island, this proposal will develop an outreach plan to introduce nanotechnology to high school students and demonstrate to them how it can help overcome "real-life problems" in clinics. Beyond achieving the specific goals of this proposal, this career development plan can significantly improve scientific understanding of the self-assembly of non-covalent structures as well as lay the foundation for the development of the first siRNA therapy to inhibit OA progression.