CAREER: Multifunctional Peptide Nanocarriers for Delivery of Nucleic Acid Therapeutics

第一部分： 非技术总结本职业计划旨在开发一类新的基于肽的生物材料。基于肽的技术将使生物材料的模块化设计能够形成具有多种功能的有序纳米颗粒聚集体，以克服递送生物活性分子的重大障碍。PI将表征所设计纳米材料的结构、电荷和刺激响应性，并确定这些特征对增强细胞特异性摄取和递送货物生物活性的影响。该技术将提供一种新的生物材料平台，用于运输用于调节基因表达的各种核酸。该提案将一项全面的教育计划与一个核心目标结合起来，即增加代表性不足的少数群体对生物工程的参与。该教育计划将使高中生能够通过实践学习模块尽早参与，并使本科生能够通过尽早接触生物工程概念和实验室研究参与。该计划包括与少数民族服务机构建立伙伴关系，建立生物工程研究生学位的管道。第二部分： PI的长期研究目标是通过研究模块化自组装肽来开发新型生物响应纳米载体。为了实现这一目标，该提案的研究目标是开发和表征一类新的多功能肽基生物材料。这些纳米载体将由模块化设计组成，包括各种类型的肽，例如细胞穿透肽、融合肽和靶向肽，每种肽都具有克服显著的递送障碍的能力，包括细胞内化不足和缺乏内体逃逸。将表征基于肽的纳米颗粒以确定1）肽二级结构在诱导内体逃逸中的生物响应性和2）纳米复合物的大小、电荷和血清稳定性。将组合模块化肽组分以产生多功能纳米材料，将对其进行评价以评估细胞-生物材料相互作用，特别是生物相容性、细胞摄取和内体活性。基于肽的技术应用于核酸疗法的递送，例如小干扰RNA（siRNA）或核糖核蛋白（RNP）。PI的长期教育目标是增加生物工程中代表性不足的少数群体的参与。拟议的教育目标是：1）让高中，本科和研究生参与生物工程研究，2）为代表性不足的少数民族一年级学生提供早期接触生物工程主题的机会，以及3）与南卡罗来纳州少数民族服务机构合作。创建一个生物工程研究生学位的管道计划。成果将包括领导一个本科生团队开发实践生物工程和纳米交付实验室模块，这些模块将在当地服务水平低下的高中实施。此外，委员会认为，通过与该州少数民族服务机构的合作，将招募本科生参加暑期研究项目，以建立合作努力，提高生物工程研究生课程中代表性不足的学生的参与度。该项目由材料研究部的生物材料项目和刺激竞争性研究的既定项目（EPSCoR）共同资助该奖项反映了NSF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。

PART 1: NON-TECHNICAL SUMMARYThis CAREER proposal aims to develop a new class of peptide-based biomaterials. The peptide-based technology will enable modular design of biomaterials able to form ordered nanoparticle aggregates with multiple functionalities in order to overcome significant barriers to delivery of bioactive molecules. The PI will characterize the structure, charge, and stimuli-responsiveness of the designed nanomaterials and determine the effect of these characteristics on enhancing cell-specific uptake and bioactivity of delivered cargo. The technology will provide a novel biomaterial platform with applications in transporting a variety of nucleic acids used to regulate gene expression. The proposal integrates a comprehensive education plan with a core objective of increasing the participation of underrepresented minorities in bioengineering. The education plan will enable early engagement of high school students through hands-on learning modules and engagement of undergraduates through early exposure to bioengineering concepts and laboratory research. The plan includes partnerships with minority-serving institutions to establish a pipeline toward graduate degrees in bioengineering. PART 2: TECHNICAL SUMMARYThe PI’s long-term research goal is to develop novel bioresponsive nanocarriers through the investigation of modular self-assembled peptides. In pursuit of this goal, the research objective of the proposal is to develop and characterize a novel class of multifunctional peptide-based biomaterials. These nanocarriers will consist of a modular design including various classes of peptides, such as cell penetrating, fusogenic and targeting peptides, each with the ability to overcome a significant barrier to delivery, including insufficient cellular internalization and lack of endosomal escape. The peptide-based nanoparticles will be characterized to determine 1) the bioresponsiveness of the peptide secondary structure in inducing endosomal escape and 2) the size, charge, and serum stability of the nanocomplexes. The modular peptide components will be combined to create a multifunctional nanomaterial that will be evaluated to assess cell-biomaterial interactions, in particular, biocompatibility, cellular uptake, and endosomal activity. The peptide-based technology has applications in delivery of nucleic acid therapies, such as small interfering RNAs (siRNAs) or ribonucleoproteins (RNPs). The PI’s long-term educational goal is to increase participation of underrepresented minorities in bioengineering. The proposed educational objectives are to: 1) engage high school, undergraduate, and graduate students in bioengineering research, 2) provide underrepresented minority first-year students early exposure to bioengineering topics, and 3) partner with minority-serving institutions in S.C. to create a pipeline program towards graduate degrees in bioengineering. Outcomes will include leading a team of undergraduates in development of hands-on bioengineering and nanodelivery lab modules that will be implemented in local underserved high schools. Furthermore, undergraduates will be recruited to participate in summer research projects through partnerships with minority-serving institutions in the state to establish a collaborative effort toward enhancing participation of underrepresented students in graduate programs in bioengineering.This project is jointly funded by the Biomaterials program in the Division of Materials Research and the Established Program to Stimulate Competitive Research (EPSCoR).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.