CAREER: Multifunctional Peptide Nanocarriers for Delivery of Nucleic Acid Therapeutics

本职业计划书旨在开发一类新的肽类生物材料。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的生物活性的影响。该技术将提供一种新的生物材料平台，应用于运输各种用于调节基因表达的核酸。该提案整合了一个全面的教育计划，其核心目标是增加未被充分代表的少数民族在生物工程领域的参与。该教育计划将通过动手学习模块使高中生早期参与，并通过早期接触生物工程概念和实验室研究使本科生参与。该计划包括与少数族裔服务机构合作，建立生物工程研究生学位的渠道。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反应性纳米载体。为了实现这一目标，本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，如细胞穿透肽、融合肽和靶向肽，每一种都有能力克服递送的重大障碍，包括细胞内化不足和缺乏内体逃逸。以肽为基础的纳米颗粒将被表征，以确定1)肽二级结构在诱导内体逃逸中的生物反应性；2)纳米复合物的大小、电荷和血清稳定性。模块化肽组分将被组合成多功能纳米材料，用于评估细胞-生物材料的相互作用，特别是生物相容性、细胞摄取和内体活性。这种基于肽的技术应用于核酸疗法的递送，如小干扰rna （sirna）或核糖核蛋白（RNPs）。PI的长期教育目标是增加未被充分代表的少数民族在生物工程领域的参与。拟议的教育目标是：1)让高中生、本科生和研究生参与生物工程研究；2)为未被充分代表的少数族裔一年级学生提供早期接触生物工程主题的机会；3)与南卡罗来纳州的少数族裔服务机构合作，创建一个通向生物工程研究生学位的管道项目。结果将包括领导一个本科生团队开发动手生物工程和纳米传递实验室模块，这些模块将在当地服务不足的高中实施。此外，将通过与该州少数民族服务机构的合作伙伴关系，招募本科生参加夏季研究项目，以建立合作努力，以提高代表性不足的学生参与生物工程研究生课程。该项目由材料研究部的生物材料计划和促进竞争研究的既定计划（EPSCoR）共同资助。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。

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.