CAREER: Engineering Membrane-Wrapped Nanoparticles for Targeted RNA Delivery

该职业奖的目标是开发模拟癌细胞结构的纳米颗粒，使核糖核酸（RNA）分子的肿瘤特异性传递成为可能。RNA向肿瘤的传递是一个长期存在的问题，其解决方案具有特殊的前景，因为RNA可以抑制促进肿瘤生长的靶基因的表达。该项目将把RNA包裹在聚合纳米颗粒中，然后用来自癌细胞的膜“包裹”纳米颗粒，以便将纳米颗粒隐藏在免疫系统之外，从而能够对体内的肿瘤细胞进行特异性识别。该项目将生成纳米颗粒，表征其材料特性，并评估其细胞特异性和肿瘤特异性RNA递送能力。为了在未来成功地实施这样的新兴技术，必须培训新一代科学家如何开发和分析创新的生物纳米材料。因此，该项目的教育目标是创建一个涵盖K-12，大学和研究生水平的综合计划，以增加学生对该领域的接触，并增加学生，特别是女性和少数民族，在生物纳米技术领域追求职业的管道。这些努力包括开发关于膜包裹纳米粒子的新大学课程模块，创建用于K-12扩展的生物纳米材料演示，以及通过研究实习对高中生和本科生进行生物纳米材料的深入培训。通过将拟议的研究与这些项目结合起来，并针对大量不同的受众，该项目将使该领域的下一代工作者能够在纳米技术、生物学、材料科学和医学的界面上创造创新的解决方案，以应对重大挑战。该项目将开发癌细胞膜包裹纳米颗粒（CCNPs），用于靶向RNA递送到肿瘤。利用膜斗篷来伪装免疫系统中的纳米颗粒并使其能够靶向肿瘤是现代细胞工程、纳米技术和材料科学的前沿，然而这些系统在RNA干扰中的应用所必需的特性仍然未知。虽然先前的研究表明，用膜涂层覆盖合成纳米颗粒可以改善疏水药物的全身递送，但该项目所要实现的提供亲水RNA货物的靶向递送的能力尚未实现。本项目将通过三个目标来开发用于RNA递送的CCNPs，这是：(1)合成携带RNA货物的CCNPs，并表征其材料特性和有效载荷释放；(2)确定CCNPs的大小和膜组成如何影响它们参与细胞受体介导摄取和RNA有效载荷传递的能力；(3)在体外和体内验证携带RNA货物的CCNPs的同型靶向性。总之，这些目标将推进CCNP技术的基础知识，并产生一个可能改善癌症研究和治疗的新平台。该项目还将把这项研究整合到教育活动中，以激励和培养学生从事STEM和生物纳米技术的职业。教育目的：(1)为工程课程中的工程生物医学纳米结构（EBN）课程创建“用于货物运输的膜包裹纳米颗粒”的新模块；(2)与EBN课程的学生合作，开发生物纳米材料演示，用于特拉华大学借阅图书馆推动的K-12推广活动；(3)通过实习，让STEM中代表性不足群体的高中生和本科生参与生物纳米材料的研究。这些教育工作将每年进行评估，以确认它们在增加攻读生物纳米技术和其他STEM学科的高等教育和职业的学生方面取得的成功。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

NON-TECHNICAL The goal of this CAREER award is to develop nanoparticles that mimic the structure of cancer cells to enable tumor-specific delivery of ribonucleic acid (RNA) molecules. RNA delivery to tumors is a long-standing problem whose solution has exceptional promise, as RNA can suppress the expression of target genes that facilitate tumor growth. This project will package RNA inside polymeric nanoparticles, which are then "cloaked" with membranes derived from cancer cells, in order to hide the nanoparticles from the immune system and enable specific recognition of tumor cells inside the body. This project will generate the nanoparticles, characterize their material properties, and evaluate their cell-specific and tumor-specific RNA delivery capabilities. For emerging technologies like this to be successfully implemented in the future, a new generation of scientists must be trained how to develop and analyze innovative bio-nanomaterials. Accordingly, this project's educational goal is to create a comprehensive program spanning the K-12, college, and graduate levels that will increase students' exposure to the field and increase the pipeline of students, particularly women and minorities, pursuing careers in bio-nanotechnology. These efforts include the development of a new college course module about membrane-wrapped nanoparticles, the creation of demonstrations about bio-nanomaterials for use in K-12 outreach, and the in-depth training of high school and undergraduate students in bio-nanomaterials via research internships. By integrating the proposed research with these programs and targeting a large and diverse audience, this project will enable the next generation of workers in the field to create innovative solutions to grand challenges at the interface of nanotechnology, biology, materials science, and medicine.TECHNICAL This project will develop cancer cell membrane-wrapped nanoparticles (CCNPs) for targeted RNA delivery to tumors. The use of membrane cloaks to disguise nanoparticles from the immune system and enable tumor-specific delivery is at the forefront of modern cellular engineering, nanotechnology, and materials science, yet the features of these systems that are essential for their application in RNA interference remain unknown. While prior work has shown that covering synthetic nanoparticles with membrane coatings improves systemic delivery of hydrophobic drugs, the ability to provide targeted delivery of hydrophilic RNA cargos, as this project aims to do, has not yet been realized. This project will develop CCNPs for RNA delivery through three aims, which are to: (1) Synthesize CCNPs carrying RNA cargo and characterize their material properties and payload release; (2) Determine how the size and membrane composition of CCNPs influence their ability to engage cell receptors to mediate uptake and RNA payload delivery, and; (3) Demonstrate the homotypic targeting of CCNPs carrying RNA cargo both in vitro and in vivo. Together, these aims will advance fundamental knowledge of CCNP technology and produce a new platform that may improve the study and treatment of cancer. This project will also integrate this research into educational activities in order to inspire and prepare students for careers in STEM and bio-nanotechnology. The educational aims are to: (1) Create a new module about "membrane-wrapped nanoparticles for cargo delivery" for the Engineering Biomedical Nanostructures (EBN) course in the engineering curriculum; (2) Work with students in the EBN course to develop bio-nanomaterials demos for use in K-12 outreach facilitated by the University of Delaware Lending Library, and; (3) Engage high school and undergraduate students from groups underrepresented in STEM in bio-nanomaterials research via internships. These educational efforts will be evaluated annually to confirm their success in increasing the pipeline of students pursuing higher education and careers in bio-nanotechnology and other STEM disciplines.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.