CAREER: Multifunctional Peptide Nanocarriers for Delivery of Nucleic Acid Therapeutics

职业：用于传递核酸治疗的多功能肽纳米载体

• 批准号: 2046694
• 负责人: Angela Alexander
• 金额: $ 58.77万
• 依托单位: Clemson University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2046694&HistoricalAwards=false
• 关键词: CAREER; Multifunctional; Peptide; Nanocarriers; Delivery

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.

第1部分：非技术总结这项职业计划旨在开发一种新型的基于多肽的生物材料。这种基于多肽的技术将使生物材料的模块化设计成为可能，这些生物材料能够形成具有多种功能的有序纳米颗粒聚集体，以克服传递生物活性分子的重大障碍。PI将表征设计的纳米材料的结构、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运送货物的生物活性的影响。这项技术将提供一个新的生物材料平台，应用于运输用于调控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相结合，即增加未被充分代表的少数群体参与生物工程。该教育计划将使高中生通过动手学习模块及早参与，并使本科生通过及早接触生物工程概念和实验室研究而参与进来。该计划包括与为少数族裔服务的机构建立合作伙伴关系，以建立通往生物工程研究生学位的渠道。第二部分：技术总结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的生物响应性纳米载体。为了追求这一目标，该提案的研究目标是开发和表征一类新型的多功能多肽生物材料。这些纳米载体将由模块化设计组成，包括各种类型的多肽，如细胞穿透性多肽、融合性多肽和靶向性多肽，每种多肽都有能力克服传递的重大障碍，包括细胞内化不足和缺乏内体逃逸。基于多肽的纳米颗粒将被表征为：1)多肽二级结构在诱导内体逃逸方面的生物响应性；2)纳米复合体的大小、电荷和血清稳定性。这些模块化的多肽成分将被组合在一起，以创建一种多功能纳米材料，该材料将被评估以评估细胞-生物材料的相互作用，特别是生物兼容性、细胞摄取和内体活性。基于多肽的技术在核酸治疗方面有应用，例如小干扰RNA(SiRNAs)或核糖核蛋白(RNPs)。该协会的长期教育目标是增加少数族裔在生物工程领域的参与度。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)让代表不足的少数族裔一年级学生及早接触生物工程主题，以及3)与南卡罗来纳州为少数族裔服务的机构合作，创建一个通往生物工程研究生学位的管道计划。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交付实验室模块，这些模块将在当地服务不足的高中实施。此外，本科生将通过与该州少数族裔服务机构的合作关系被招募参加暑期研究项目，以建立一个合作努力，以提高未被充分代表的学生对生物工程研究生课程的参与。该项目由材料研究部的生物材料计划和既定的刺激竞争研究计划(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智力优势和更广泛的影响审查标准进行评估，被认为值得支持。