Developing Functional Ferritin Nanocages for Blood Brain Barrier Traversing and Cellular Delivery

开发用于血脑屏障穿越和细胞递送的功能性铁蛋白纳米笼

• 批准号: 2001606
• 负责人: Xiaoyang Xu
• 金额: $ 34万
• 依托单位: New Jersey Institute of Technology
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2001606&HistoricalAwards=false
• 关键词: Developing; Functional; Ferritin; Nanocages; Blood

The blood-brain barrier stands between the central nervous system and peripheral blood circulation, preventing entry of potential toxins into the brain but also inhibiting the successful delivery of drugs. This prevents the effective imaging, diagnosis and treatment of deadly brain-related diseases such as Alzheimer’s, Parkinson’s disease and brain cancer. As such, there is a tremendous demand for delivery systems which can solve these problems and effectively treat brain disease. Natural materials such as ferritin proteins have been shown to self-assemble into nanocages and cross the blood-brain barrier. However, a complete understanding of how these nanocages move across the barrier into the brain as well as their structure-function relationships has remained elusive. This research project will combine bioengineering and chemical approaches to understand how these nanostructures interact with the blood-brain barrier and to rationally design nanocages which have the capability to cross blood-brain barriers and to achieve cellular delivery. The project will provide a robust nanoparticle tool to study nanomaterial-biological barrier interactions and will advance the science for the development of next generation brain drug delivery and imaging platforms and techniques. This project brings together several key technology areas, including nanomaterials, chemical engineering, cell biology and biomedical engineering, providing interdisciplinary training for a diverse group of graduate and undergraduate students as well as exposing students from local high schools to cutting-edge research. The central goal of the research project is to achieve a comprehensive understanding of protein based nanocage/blood-brain barrier interactions using ferritin as a model protein and subsequently to use this knowledge to develop a novel family of protein nanocages as brain targeted, modular delivery platforms with additional functionalities available on demand. The central hypothesis is that with rational design, the engineered ferritin protein can maintain its ability to assemble into nanocages, cross the biological interface of the blood-brain barrier, and also be conferred with new abilities for targeted delivery, loading of therapeutics and/or imaging agents. The research project seeks to: 1) design and genetically introduce targeting domains to ferritin proteins, assemble the ferritin proteins into ferritin nanocages, 2) investigate the nanocages’ blood-brain barrier traversing and cellular targeting capabilities using cellular models; and 3) study the nanocage structure-biological function relationship. The scope of the project includes probing protein nanocage interactions with biological systems to elucidate the genetically-directed nanoscale modular design and providing theragnostic data on the potential treatment of many brain diseases. The ultimate goal of the project is to develop a genetically designed and chemically engineered nanoscale delivery system which can deliver therapeutic and diagnostic agents across the impenetrable blood-brain barrier. Overall, the experiments will probe nanoscale transport mechanisms and explore the interactions between engineered nanocages and biological systems, therefore laying the foundation for design and production of a new paradigm of protein-based theranostic systems. The educational components of this proposal will involve youth from underrepresented groups with a goal to attract, inspire and train the next generation of STEM professionals.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

血脑屏障位于中枢神经系统和外周血液循环之间，阻止潜在毒素进入大脑，但也抑制药物的成功递送。这阻碍了对致命的脑相关疾病（如阿尔茨海默病、帕金森病和脑癌）的有效成像、诊断和治疗。因此，对能够解决这些问题并有效治疗脑部疾病的递送系统存在巨大需求。铁蛋白等天然材料已被证明可以自组装成纳米笼并穿过血脑屏障。然而，对这些纳米笼如何穿过屏障进入大脑以及它们的结构-功能关系的完整理解仍然难以捉摸。该研究项目将结合联合收割机生物工程和化学方法，以了解这些纳米结构如何与血脑屏障相互作用，并合理设计具有穿过血脑屏障并实现细胞递送能力的纳米笼。该项目将提供一个强大的纳米粒子工具来研究纳米材料-生物屏障相互作用，并将推动下一代脑药物输送和成像平台和技术的发展。该项目汇集了几个关键技术领域，包括纳米材料，化学工程，细胞生物学和生物医学工程，为不同的研究生和本科生群体提供跨学科培训，并使当地高中的学生接触尖端研究。该研究项目的中心目标是使用铁蛋白作为模型蛋白质，实现对基于蛋白质的纳米笼/血脑屏障相互作用的全面理解，并随后利用这些知识开发一种新型蛋白质纳米笼家族，作为大脑靶向的模块化递送平台，并根据需要提供额外的功能。核心假设是，通过合理的设计，工程化的铁蛋白蛋白可以保持其组装成纳米笼的能力，穿过血脑屏障的生物界面，并且还被赋予靶向递送、装载治疗剂和/或成像剂的新能力。该研究项目旨在：1）设计并遗传性地将靶向结构域引入铁蛋白蛋白，将铁蛋白蛋白组装成铁蛋白纳米笼，2）使用细胞模型研究纳米笼的血脑屏障穿透和细胞靶向能力;以及3）研究纳米笼的结构-生物学功能关系。该项目的范围包括探测蛋白质纳米笼与生物系统的相互作用，以阐明遗传导向的纳米级模块化设计，并提供许多脑部疾病潜在治疗的治疗数据。该项目的最终目标是开发一种基因设计和化学工程的纳米级递送系统，该系统可以穿过不可穿透的血脑屏障递送治疗和诊断剂。 总的来说，这些实验将探索纳米级的传输机制，并探索工程纳米笼和生物系统之间的相互作用，从而为设计和生产基于蛋白质的治疗诊断系统的新范式奠定基础。该计划的教育部分将涉及来自代表性不足群体的青年，其目标是吸引、激励和培训下一代STEM专业人员。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Rational design of engineered H-ferritin nanoparticles with improved siRNA delivery efficacy across an in vitro model of the mouse BBB

合理设计工程化 H-铁蛋白纳米粒子，在小鼠 BBB 体外模型中提高 siRNA 递送效率

• DOI: 10.1039/d1nr07880a
• 发表时间: 2022
• 期刊: Nanoscale
• 影响因子: 6.7
• 作者: Yuan, Ziwei;Wang, Bin;Teng, Yilong;Ho, William;Hu, Bin;Boakye-Yiadom, Kofi Oti;Xu, Xiaoyang;Zhang, Xue-Qing
• 通讯作者: Zhang, Xue-Qing

Enzyme-Catalyzed One-Step Synthesis of Ionizable Cationic Lipids for Lipid Nanoparticle-Based mRNA COVID-19 Vaccines

• DOI: 10.1021/acsnano.2c07822
• 发表时间: 2022-10-21
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Li, Zhongyu;Zhang, Xue-Qing;Xu, Xiaoyang
• 通讯作者: Xu, Xiaoyang