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

职业：组装纳米片，用于控制穿透和结合难以到达的软骨基质，用于骨关节炎的 siRNA 治疗

• 批准号: 1905785
• 负责人: Yupeng Chen
• 金额: $ 48.06万
• 依托单位: University of Connecticut
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1905785&HistoricalAwards=false
• 关键词: CAREER; Assembly; Nanopieces; Controlled; Penetration

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.

骨关节炎（OA）影响了大约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。骨性关节炎是一种涉及关节软骨变性的退行性关节疾病。这会导致疼痛、僵硬、运动问题和活动限制。目前，尚无临床成功的治疗OA的方法。siRNA作为一项获得诺贝尔奖的发现，能够有效特异性抑制疾病基因表达，为OA的治疗提供了巨大的治疗潜力。然而，将带负电荷的sirna递送到无血管、致密、带负电荷的组织基质（如软骨）中是极具挑战性的。本研究将开发一种新型的递送载体，它可以与治疗性sirna自组装，并以有效和安全的方式将其递送到富含基质的组织中。该研究将集中于了解玫瑰纳米管（RNTs）和siRNA之间非共价结构的精细自组装过程。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，分析和优化它们穿透组织基质和传递siRNA的能力。该项目还将识别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）的有效和持久抑制，MMP-13是OA进展过程中的一个关键疾病基因。此外，将在动物模型中评估这种siRNA方法治疗OA的潜力。此外，该提案还提出了一项计划，以融合科学与医学教育之间的差距，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，该提案将与罗德岛的巴林顿高中（BHS）合作，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”。除了实现该提案的具体目标外，该职业发展计划还可以显著提高对非共价结构自组装的科学认识，并为开发首个抑制OA进展的siRNA疗法奠定基础。

项目成果

A biomimetic layer-by-layer drug-released Nano-Matrix for mesenchymal stem cells chondrogenic differentiation promotion and chondrocytes hypertrophy prevention

仿生层层释药纳米基质促进间充质干细胞软骨分化和预防软骨细胞肥大

• 发表时间: 2021
• 期刊: Trans Orthop Res Soc.
• 作者: Zhou, L.

RNA Delivery via DNA-Inspired Janus Base Nanotubes for Extracellular Matrix Penetration

• DOI: 10.1557/adv.2020.47
• 发表时间: 2020-01-01
• 期刊: MRS ADVANCES
• 影响因子: 0.8
• 作者: Sands, Ian;Lee, Jinhyung;Chen Yupeng
• 通讯作者: Chen Yupeng

mRNA Detection with Fluorescence-base Imaging Techniques for Arthritis Diagnosis. Journal of Rheumatology Research

使用基于荧光的成像技术进行 mRNA 检测，用于关节炎诊断。

• 发表时间: 2019
• 期刊: Journal of rheumatology research
• 作者: A. Yau, H. Yu

A structural and functional comparison between two recombinant human lubricin proteins: Recombinant human proteoglycan-4 (rhPRG4) vs ECF843

两种重组人润滑素蛋白之间的结构和功能比较：重组人蛋白聚糖 4 (rhPRG4) 与 ECF843

• DOI: 10.1016/j.exer.2023.109643
• 发表时间: 2023
• 期刊: Experimental Eye Research
• 影响因子: 3.4
• 作者: Menon, Nikhil G.;Tanguay, Adam P.;Zhou, Libo;Zhang, Ling X.;Bobst, Cedric E.;Han, Mingyu;Ghosh, Mallika;Greene, George W.;Deymier, Alix;Sullivan, Benjamin D.
• 通讯作者: Sullivan, Benjamin D.

Anti-Cancer Drug Delivery via DNA-Inspired Janus Base Nanotubes

通过 DNA 启发的 Janus 基础纳米管进行抗癌药物输送

• 发表时间: 2020
• 期刊: Trans Orthop Res Soc
• 作者: Zhang, W;Shen, Z;Chen, Y.
• 通讯作者: Chen, Y.