Engineered Protein-Lipid Systems for siRNA and Small Molecule Delivery

非技术：该奖项由材料研究部生物材料项目授予纽约大学，旨在开发能够双重基因和药物递送系统的生物材料，用于治疗多药耐药癌细胞。该奖项由化学，生物工程，环境和运输系统（工程局）部门的颗粒和多相过程计划以及BioMaPS计划共同资助。拟议的实验将导致生物医学新试剂的产生，并改变传统的治疗观点。这些系统还将影响生物技术，因为从这些研究中吸取的教训可用于其他基因和制剂的输送，其应用范围扩展到非医疗行业，包括个人护理，化妆品和农业。这项多学科研究将培养下一代学生，科学家和工程师在生物材料，化学，工程和细胞生物学方面采用尖端技术。除了教学和指导研究生和博士后研究人员外，PI还将监督实验室研究中代表性不足的本科生和高中生。PI还计划将技术和社交媒体整合到本科和研究生课程中，并使这些学生接触前沿研究。为了推广，PI将继续参与科学与工程应用研究创新计划，让纽约当地10年级和11年级的学生参与生物材料研究。作为暑期生物工程项目的负责人，PI将积极招募未被充分代表的高中生参加生物启发材料课程。技术：核酸和小分子疗法拥有控制生物过程的关键指令，在基础细胞和有机体研究，生物技术和医学中具有切实的意义。然而，主要由于质膜屏障，核酸和小分子的细胞内递送一直是一个挑战。本项目的目标是开发一种多功能的工程化蛋白质-脂质系统（脂蛋白复合物），能够：1）有效地与siRNA复合; 2）封装小分子药物（姜黄素，阿霉素等）。而不需要共价修饰;和3）一旦在细胞内触发双重有效载荷的释放，导致程序化的细胞结果。为了生产能够递送基因和治疗性小分子的载体，PI提出了一种创新的方法来重新设计软骨寡聚基质蛋白的卷曲螺旋结构域，使得它能够与核酸和小分子结合脂质复合，这是基于PI通过蛋白质工程在表面上引入正电荷的初步成功。这些工程化脂蛋白复合物的创新包括：1）易于整合突变，从而实现快速优化; 2）双重药物和基因封装;以及3）控制递送和自组装。所提出的工程化蛋白质-脂质系统的多功能性将不仅证明可用于递送小分子和siRNA以治疗多药耐药癌症，而且还可用于单独或组合递送各种化学试剂和基因以深入了解细胞功能。

Non-Technical: This award by the Biomaterials program in the Divison of Materials Research to New York University is to develop biomaterials capable of dual gene and drug delivery system, for potential treatment of multi-drug resistant cancer cells. This award is cofunded by Particulate and Multiphase Processes program in the Division of Chemical, Bioengineering, Environmental, and Transport Systems (Directorate for Engineering) and the BioMaPS program. The proposed experiments would lead to the generation of novel agents for biomedicine, and transform the traditional view of therapeutics. These systems will also impact biotechnology as the lessons learned from these studies that can be employed for delivery of other genes and agents with applications extending to non-medical industries including personal care, cosmetics and agriculture. This multidisciplinary research will train the next generation students, scientists and engineers to employ cutting edge technologies in biomaterials, chemistry, engineering and cell biology. In addition to teaching and mentoring graduate students and postdoctoral researchers, the PI will supervise underrepresented undergraduates and high-school students in laboratory research. The PI is also planning to integrate technology and social media into both undergraduate and graduate courses, and exposing these students to cutting-edge research. For outreach, the PI will continue to participate in the Applied Research Innovations in Science and Engineering program in engaging local NYC 10th and 11th grade students to biomaterials research. As director of the Summer Bioengineering Program, the PI will be actively recruiting underrepresented high school students to participate in a biologically inspired materials course.Technical: Nucleic acids and small molecule therapeutics possess critical instructions for controlling biological processes with tangible implications in fundamental cell and organismal studies, biotechnology and medicine. However, the intracellular delivery of nucleic acids and small molecules has been a challenge predominantly due to the plasma membrane barrier. The goal of this project is to develop a multifunctional engineered protein-lipid system (lipoproteoplexes) capable of: 1) effectively complexing with siRNA; 2) encapsulating a small molecule drug (curcumin, doxorubicin, etc.) without the need for covalent modification; and 3) triggering release of the dual payload once inside the cell leading to a programmed cellular outcome. In order to produce a vehicle capable of delivering both gene and therapeutic small molecule, the PI proposes an innovative approach to re-engineer the coiled-coil domain of cartilage oligomeric matrix protein so that it is able to complex with nucleic acids and small molecules in conjunction with lipids based on PI's initial success in introducing positive charge on the surface through protein engineering. Innovations in these engineered lipoproteoplexes include: 1) the ease of integrating mutations enabling rapid optimization; 2) dual drug and gene encapsulation; and 3) control over the delivery and self-assembly. The versatility of the proposed engineered protein-lipid systems will not only prove useful for delivering small molecules and siRNA to treat multi-drug resistant cancers, but also for delivering a variety of chemical agents and genes alone or in combination to gain insight into cell functions.