CAREER: Developing albumin-binding responsive polypeptides for nucleic acid delivery

职业:开发用于核酸递送的白蛋白结合响应性多肽

基本信息

  • 批准号:
    2238812
  • 负责人:
  • 金额:
    $ 65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Continuing Grant
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-01-01 至 2027-12-31
  • 项目状态:
    未结题

项目摘要

PART 1: NON-TECHNICAL SUMMARYNucleic acid-based drugs have been identified as an effective treatment for various diseases including cancer, viral infections, and genetic disorders. This was highlighted by the use of messenger RNA (mRNA) vaccines during the Covid-19 pandemic. Due to the intrinsic physicochemical properties of nucleic acids, including negative charges, high hydrophilicity, and susceptibility to enzymatic degradation positively charged delivery carriers are typically required to successfully exert their functions. However, most of the current carriers suffer from unsatisfactory toxicities and low delivery efficiencies. This limits the widespread use of nucleic acid therapeutics in a clinical setting. This CAREER project proposes innovative approaches to developing biologically friendly, safe, and effective nucleic acid delivery carriers. These polypeptide-based carriers are less toxic and can effectively deliver nucleic acids to diseased sites. The structure of the polypeptide will be systematically investigated for optimized efficacy. Protein-binding molecules will also be used to further reduce the carrier’s toxicity along with an increase in delivery efficiency. This project provides critical insights into the development of biomaterials for nucleic acid delivery and many other biomedical applications in disease treatment. Integrated with the research effort, the principal investigator proposes a series of educational projects to help K-12 students understand chemistry and science. This program aims to train graduate and undergraduate students, particularly women and underrepresented minorities, in the field of biomaterials, and ultimately contribute to the development of the next-generation STEM workforce.PART 2: TECHNICAL SUMMARYThis CAREER project aims to develop safe and effective polymeric delivery carriers for nucleic acid therapeutics, including small interfering RNA (siRNA) and messenger RNA (mRNA). siRNA and mRNA are a class of “information drugs” with far-reaching therapeutic potential and have been investigated for the treatment of various diseases, including cancers, viral infections, and genetic and metabolic disorders. However, broad clinical adoption of nucleic acid therapeutics has been challenged by the fact that nucleic acids are unstable and cannot efficiently cross cell membranes besides being immunogenic. To tackle the challenges of nucleic acid therapeutics for clinical adoption, this project is dedicated to the development of albumin-binding responsive polypeptides that have minimal toxicity. Therefore, these polypeptides can carry, protect, deliver, and release nucleic acid into target tissues and cells, with an emphasis on the delivery process. This will be accomplished through two innovative approaches to reduce toxicity and improve the effectiveness of nucleic acid therapeutics: 1) development of redox-responsive polypeptides, wherein pendant cationic amines are connected via disulfide bonds to polypeptide backbones; 2) conjugation of the albumin-binding molecule Evans Blue to polypeptides (EBylation) to hitchhike endogenous albumin for shielding and camouflaging the positive charge for minimal cytotoxicity and immunotoxicity. This project seeks to systematically investigate the structure-property relationship between responsive amine moieties and nucleic acid delivery efficiency. Additionally, the effect of EBylation on nucleic acid binding, cellular uptake, and transfection will be studied. The concept of reversible protein binding will also be introduced to camouflage the self-assembled materials for enhancement of biocompatibility and reduction of undesirable interactions. This proposal will help prepare a diverse group of undergraduate and graduate students to tackle social challenges and complex scientific problems. It will be complemented with outreach activities and efforts for students in K-12, ultimately contributing to the development of the next-generation STEM workforce.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.
第一部分:非技术综述核酸类药物已被确定为治疗各种疾病的有效药物,包括癌症、病毒感染和遗传性疾病。在2019冠状病毒病大流行期间使用信使RNA(mRNA)疫苗突显了这一点。由于核酸的固有物理化学性质,包括负电荷、高亲水性和对酶降解的敏感性,通常需要带正电荷的递送载体来成功地发挥其功能。然而,大多数目前的载体遭受不令人满意的毒性和低递送效率。这限制了核酸治疗剂在临床环境中的广泛使用。这个CAREER项目提出了开发生物友好,安全和有效的核酸递送载体的创新方法。这些基于多肽的载体毒性较低,并且可以有效地将核酸递送到患病部位。将系统地研究多肽的结构以优化功效。蛋白质结合分子也将用于进一步降低载体的毒性,沿着递送效率的增加。该项目为核酸输送生物材料的开发和疾病治疗中的许多其他生物医学应用提供了重要见解。结合研究工作,首席研究员提出了一系列教育项目,以帮助K-12学生了解化学和科学。该项目旨在培养生物材料领域的研究生和本科生,特别是女性和少数民族,并最终为下一代STEM劳动力的发展做出贡献。第2部分:技术总结该职业项目旨在开发用于核酸治疗的安全有效的聚合物递送载体,包括小干扰RNA(siRNA)和信使RNA(mRNA)。 siRNA和mRNA是一类具有深远治疗潜力的“信息药物”,并且已经被研究用于治疗各种疾病,包括癌症、病毒感染以及遗传和代谢紊乱。然而,核酸治疗剂的广泛临床应用受到以下事实的挑战:核酸是不稳定的,并且除了具有免疫原性之外不能有效地穿过细胞膜。为了解决核酸治疗临床应用的挑战,该项目致力于开发具有最小毒性的白蛋白结合应答多肽。因此,这些多肽可以携带、保护、递送和释放核酸到靶组织和细胞中,重点在于递送过程。这将通过两种创新的方法来实现,以降低毒性并提高核酸治疗剂的有效性:1)开发氧化还原响应性多肽,其中侧挂的阳离子胺通过二硫键连接到多肽主链上; 2)白蛋白结合分子伊文思蓝与多肽的缀合(EBylation)以搭便车内源性白蛋白,用于屏蔽和包裹正电荷,以实现最小的细胞毒性和免疫毒性。本项目旨在系统地研究响应性胺部分与核酸递送效率之间的结构-性质关系。此外,将研究EB化对核酸结合、细胞摄取和转染的影响。可逆的蛋白质结合的概念也将被引入到伪装的自组装材料,以增强生物相容性和减少不良的相互作用。这项建议将有助于培养一批多样化的本科生和研究生,以应对社会挑战和复杂的科学问题。该奖项将辅之以针对K-12学生的外展活动和努力,最终为下一代STEM劳动力的发展做出贡献。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进行评估而被认为值得支持。和更广泛的影响审查标准。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Synthesis of cyclic carbonate monomer using a simple and efficient method
一种简单高效的环状碳酸酯单体合成方法
  • DOI:
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Eva Bukhryakova, Xiao Zhang
  • 通讯作者:
    Eva Bukhryakova, Xiao Zhang
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Fuwu Zhang其他文献

Correction to "Improving Paclitaxel Delivery: In Vitro and In Vivo Characterization of PEGylated Polyphosphoester-Based Nanocarriers".
对“改善紫杉醇递送:基于聚乙二醇化聚磷酸酯的纳米载体的体外和体内表征”的更正。
  • DOI:
    10.1021/jacs.5b04944
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    15
  • 作者:
    Fuwu Zhang;Shiyi Zhang;Stephanie F Pollack;Richen Li;Amelia M. Gonzalez;Jingwei Fan;J. Zou;Sarah E. Leininger;Adriana Pavía;Rachel Johnson;Laura D. Nelson;Jeffery E. Raymond;Mahmoud Elsabahy;D. Hughes;M. Lenox;Tiffany P. Gustafson;K. Wooley
  • 通讯作者:
    K. Wooley
Polypeptide-protein conjugation: A new paradigm for therapeutic protein delivery
多肽-蛋白质偶联:治疗性蛋白质递送的新范例
  • DOI:
    10.1016/j.jconrel.2025.113953
  • 发表时间:
    2025-08-10
  • 期刊:
  • 影响因子:
    11.500
  • 作者:
    Xiao Zhang;Shiwei Fu;Bowen Zhao;Yilin Liu;Ronald S. Seruya;Fuwu Zhang
  • 通讯作者:
    Fuwu Zhang

Fuwu Zhang的其他文献

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