Expanding the Biomaterials Space of DNA through Polymerization

通过聚合扩展 DNA 的生物材料空间

• 批准号: 2004947
• 负责人: Ke Zhang
• 金额: $ 47.5万
• 依托单位: Northeastern University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2004947&HistoricalAwards=false
• 关键词: Expanding; Biomaterials; Space; DNA; through

NON-TECHNICAL SUMMARYDNA, a basic building block of life, is a form of natural biopolymer. Yet, DNA research and polymer science are separate scientific disciplines with very limited crossover. The lack of deeper integration of the two fields stems in part from the incompatibility of DNA with the conditions and reagents by which synthetic polymers are made. If this barrier is overcome, DNA can be freely used to craft many DNA-polymer composite materials, which can potentially lead to better disease diagnostics, therapeutics, and biotechnology tools than currently possible today. In the proposed project, the PI’s team will develop a form of protected DNA compatible with polymer chemistry, which can be restored to its natural form once the polymer has been made. Using the protected DNA, several DNA-based polymers previously deemed difficult or impossible will be synthesized to validate the methodology. Finally, a DNA-peptide copolymer, to be enabled by the protected DNA for the first time, will be prepared and tested as a vaccine in human cells. The biomaterials developed here represents only the tip of an iceberg; the successful marriage between DNA and the vast knowledge base of polymer science should result in limitless possibilities. These research activities will intertwine with educational programs to provide a diverse range of laboratory training to graduate/undergraduate students (including undergraduates from institutions lacking research capabilities) and to promote learning, awareness, and interest in science-related careers among high school students and STEM teachers.TECHNICAL SUMMARYDNA-based biomaterials are primarily achieved through solid-phase reactions or aqueous couplings using pre-synthesized oligonucleotides. Both methods pose limitations for certain types of constructs, such as highly branched architectures and amphiphilic structures. The goal of this proposal is to greatly expand the types of biomaterials accessible using oligonucleotide building blocks by removing the barriers between nucleic acid chemistry and polymerization. Towards this goal, the PI will design chemically masked DNA structures that can participate in polymerization reactions (e.g. free radical, coordination, etc) in the organic phase. The masked DNA can be restored to native phosphodiester DNA under mild conditions following polymerization. Thus, many difficult and/or unprecedented DNA-containing polymers with controlled architecture, composition, sequence, and end-group functionality are possible with this approach. Among the various DNA-based materials to be prepared, a peptide-DNA brush copolymer will be investigated in a biological setting as a self-delivering/adjuvanting peptide vaccine. By facilitating the marriage of nucleic acids with the vast range of polymerization reactions, a diversity of new structures with technologically useful properties will become possible. From the educational perspective, the cross-disciplinary nature of the project (design, synthesis, and materials/biological characterizations) is a great teaching tool for the students at all levels to be involved in the project. The PI will continue to create research opportunities for undergraduate students and high school students/teachers through active recruiting, internship programs, course development, and online presence.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.

DNA是生命的基本组成部分，是一种天然生物聚合物。然而，DNA研究和聚合物科学是独立的科学学科，交叉非常有限。这两个领域缺乏更深层次的整合，部分原因是DNA与合成聚合物的条件和试剂不相容。如果这一障碍被克服，DNA可以自由地用于制造许多DNA-聚合物复合材料，这可能导致比目前更好的疾病诊断，治疗和生物技术工具。在拟议的项目中，PI的团队将开发一种与聚合物化学相容的受保护DNA形式，一旦聚合物制成，它可以恢复到其自然形式。使用受保护的DNA，将合成几种以前被认为很难或不可能的基于DNA的聚合物，以验证该方法。最后，首次被保护的DNA激活的DNA-肽共聚物将被制备并在人类细胞中作为疫苗进行测试。这里开发的生物材料只是冰山一角; DNA与聚合物科学庞大知识库之间的成功结合应该会带来无限的可能性。这些研究活动将与教育计划相结合，为研究生/本科生提供各种实验室培训（包括来自缺乏研究能力的机构的本科生），并促进学习、认识、技术概述基于DNA的生物材料主要通过固相反应或使用预聚物的水相偶联来实现。合成的寡核苷酸。这两种方法都对某些类型的构建体造成了限制，例如高度支化的结构和两亲性结构。该提案的目标是通过消除核酸化学和聚合之间的障碍，极大地扩展使用寡核苷酸构建块可获得的生物材料的类型。为了实现这一目标，PI将设计化学掩蔽的DNA结构，这些结构可以参与有机相中的聚合反应（例如自由基，配位等）。掩蔽的DNA可以在聚合后在温和条件下恢复为天然磷酸二酯DNA。因此，许多困难的和/或前所未有的含DNA的聚合物与受控的架构，组成，序列，和端基功能是可能的，与这种方法。在待制备的各种基于DNA的材料中，肽-DNA刷共聚物将在生物环境中作为自递送/佐剂肽疫苗进行研究。通过促进核酸与广泛的聚合反应的结合，具有技术上有用的特性的各种新结构将成为可能。从教育的角度来看，该项目的跨学科性质（设计，合成和材料/生物表征）是各级学生参与该项目的重要教学工具。PI将继续通过积极招聘、实习计划、课程开发和在线展示为本科生和高中生/教师创造研究机会。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

项目成果

Exploring the Structural Diversity of DNA Bottlebrush Polymers Using an Oligonucleotide Macromonomer Approach.

• DOI: 10.1021/acs.macromol.1c02624
• 发表时间: 2022-03-22
• 期刊: MACROMOLECULES
• 影响因子: 5.5
• 作者: Lu, Hao;Cai, Jiansong;Fang, Yang;Ren, Mengqi;Tan, Xuyu;Jia, Fei;Wang, Dali;Zhang, Ke
• 通讯作者: Zhang, Ke

A Long-Circulating Vector for Aptamers Based upon Polyphosphodiester-Backboned Molecular Brushes.

基于聚磷酸二酯的分子刷，用于适体的长循环载体。

• DOI: 10.1002/anie.202204576
• 发表时间: 2022-10-10
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Wang, Yuyan;Wang, Dali;Lin, Jiachen;Lyu, Zidi;Chen, Peiru;Sun, Tingyu;Xue, Chenyang;Mojtabavi, Mehrnaz;Vedadghavami, Armin;Zhang, Zheyu;Wang, Ruimeng;Zhang, Lei;Park, Christopher;Heo, Gyu Seong;Liu, Yongjian;Dong, Sijia;Zhang, Ke
• 通讯作者: Zhang, Ke

Targeting oncogenic KRAS with molecular brush-conjugated antisense oligonucleotides.

• DOI: 10.1073/pnas.2113180119
• 发表时间: 2022-07-19
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

A mechanistic study on the cellular uptake, intracellular trafficking, and antisense gene regulation of bottlebrush polymer-conjugated oligonucleotides.

• DOI: 10.1039/d2cb00149g
• 发表时间: 2023-02-08
• 期刊: RSC CHEMICAL BIOLOGY
• 影响因子: 4.1
• 作者: Zhang, Lei;Wang, Yuyan;Chen, Peiru;Wang, Dali;Zhang, Zheyu;Wang, Ruimeng;Kang, Xi;Fang, Yang;Lu, Hao;Cai, Jiansong;Ren, Mengqi;Dong, Sijia;Zhang, Ke;Sun, Tingyu
• 通讯作者: Sun, Tingyu

Self-Assembled DNA-PEG Bottlebrushes Enhance Antisense Activity and Pharmacokinetics of Oligonucleotides.

• DOI: 10.1021/acsami.0c13995
• 发表时间: 2020-10-14
• 期刊: ACS applied materials & interfaces
• 影响因子: 9.5
• 作者: Wang Y;Wang D;Jia F;Miller A;Tan X;Chen P;Zhang L;Lu H;Fang Y;Kang X;Cai J;Ren M;Zhang K
• 通讯作者: Zhang K